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H EALTH S YS TEMS EDITION
NO
VEM
B E R 20
09
T H E J O U R N A L F O R P H A R M A C I S T S ’ E D U C AT I O N
Treating Alcoholism
for Optimal Results
Opioid Dependence
& Withdrawal
Controlling
Schizophrenia
Symptoms
Prophylactic Medications
in Traumatic Brain Injury
2 CE Credits
Emergency Contraception:
Clinical and Regulatory Update
New Products in This Issue:
Afinitor / Novartis Pharmaceuticals Corporation • Authorized
Generics / Greenstone LLC • Distinctive Labeling / Baxter
Healthcare • Embeda / King Pharmaceuticals • Injectables /
Pfizer Injectables • Kapidex / Takeda Pharmaceuticals • Onglyza /
AstraZeneca • Product Labeling / Teva Pharmaceuticals • Uloric /
Takeda Pharmaceuticals • Welchol / Daiichi-Sankyo
F OR FR EE C E, GO TO:
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A J O B S O N P U B L I C AT I O N
Indication
ULORIC is a xanthine oxidase (XO) inhibitor indicated for
the chronic management of hyperuricemia in patients
with gout. ULORIC is not recommended for the treatment
of asymptomatic hyperuricemia.
Important Safety Information
• ULORIC is contraindicated in patients being treated
with azathioprine, mercaptopurine, or theophylline.
• An increase in gout flares is frequently observed
during initiation of anti-hyperuricemic agents,
including ULORIC. If a gout flare occurs during
treatment, ULORIC need not be discontinued.
Prophylactic therapy (i.e. - NSAIDs or colchicine)
upon initiation of treatment may be beneficial for
up to six months.
• Cardiovascular Events: In randomized controlled studies,
there was a higher rate of cardiovascular thromboembolic
events (cardiovascular deaths, non-fatal myocardial
infarctions, and non-fatal strokes) in patients treated
with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than
allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)]. A causal
relationship with ULORIC has not been established.
Monitor for signs and symptoms of MI and stroke.
• Liver Enzyme Elevations: In randomized controlled studies,
transaminase elevations greater than 3 times the upper
limit of normal (ULN) were observed (AST: 2%, 2%, and
ULORIC® is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc.
©2009 Takeda Pharmaceuticals North America, Inc. TXF-00319 08/09
ULORIC powerfully lowers
serum uric acid levels for long-term
control of gout.
Powerfully lowers serum uric acid1
• In the largest phase 3 study (6 months):
- 45% of patients who received ULORIC 40 mg achieved serum uric acid
levels of <6 mg/dL (N=757) compared to 42% of patients who received
allopurinol 300 mg (N=755; p=0.233)
- 67% of patients who received ULORIC 80 mg achieved serum uric acid
levels of <6 mg/dL (N=756) compared to 42% of patients who received
allopurinol 300 mg (N=755; p<0.001)
Extensively studied safety profile1
• The safety profile of ULORIC has been evaluated2
- In more than 4000 patients
- In some for more than 5 years
Simple, once-daily dosing1
• Available in 40- and 80-mg tablets for once-daily dosing with a starting
dose of 40 mg
• No dose adjustments required in patients with mild to moderate renal
or hepatic impairment*
*There are insufficient data in patients with severe renal dysfunction, and no
studies have been conducted in patients with severe hepatic impairment.
Caution should be exercised in these patients.
ALT: 3%, 2% in ULORIC and allopurinol-treated patients,
respectively). No dose-effect relationship for these
transaminase elevations was noted. Laboratory
assessment of liver function is recommended at, for
example, 2 and 4 months following initiation of ULORIC
and periodically thereafter.
• Adverse reactions occurring in at least 1% of ULORIC-treated
patients, and, at least 0.5% greater than placebo, are liver
function abnormalities, nausea, arthralgia, and rash.
Individual results may vary based on factors such as baseline
serum uric acid levels.
Please see brief summary of complete Prescribing Information
on adjacent pages.
References:
1. ULORIC® (febuxostat) full prescribing information, February 2009.
2. Data on file, Takeda Pharmaceuticals North America, Inc.
For more information,
please visit www.ULORIC.com.
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for
ULORIC® (febuxostat) tablets
INDICATIONS AND USAGE
ULORIC® is a xanthine oxidase (XO) inhibitor indicated for the chronic management
of hyperuricemia in patients with gout.
ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.
CONTRAINDICATIONS
ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Drug Interactions].
WARNINGS AND PRECAUTIONS
Gout Flare
After initiation of ULORIC, an increase in gout flares is frequently observed. This
increase is due to reduction in serum uric acid levels resulting in mobilization of
urate from tissue deposits.
In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic
treatment with an NSAID or colchicine is recommended.
Cardiovascular Events
In the randomized controlled studies, there was a higher rate of cardiovascular
thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions,
and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y
(95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see
Adverse Reactions]. A causal relationship with ULORIC has not been established.
Monitor for signs and symptoms of myocardial infarction (MI) and stroke.
Liver Enzyme Elevations
During randomized controlled studies, transaminase elevations greater than 3 times
the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2%
in ULORIC and allopurinol-treated patients, respectively). No dose-effect
relationship for these transaminase elevations was noted. Laboratory
assessment of liver function is recommended at, for example, 2 and 4 months
following initiation of ULORIC and periodically thereafter.
ADVERSE REACTIONS
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared
to rates in the clinical trials of another drug and may not reflect the rates observed
in practice.
A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC
40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients
were treated for r 6 months. For ULORIC 80 mg, 1377 subjects were treated for
r 6 months, 674 patients were treated for r 1 year and 515 patients were treated
for r 2 years.
Most Common Adverse Reactions
In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were
6 to 12 months in duration, the following adverse reactions were reported by
the treating physician as related to study drug. Table 1 summarizes adverse
reactions reported at a rate of at least 1% in ULORIC treatment groups and at
least 0.5% greater than placebo.
Table 1: Adverse Reactions Occurring in r 1% of ULORIC-Treated
Patients and at Least 0.5% Greater than Seen in Patients
Receiving Placebo in Controlled Studies
Placebo
Adverse Reactions
Liver Function
Abnormalities
Nausea
Arthralgia
Rash
ULORIC
allopurinol*
(N=134)
40 mg
daily
(N=757)
80 mg
daily
(N=1279)
(N=1277)
0.7%
6.6%
4.6%
4.2%
0.7%
1.1%
1.3%
0.8%
0%
1.1%
0.7%
0.7%
0.7%
0.5%
1.6%
1.6%
*Of the subjects who received allopurinol, 10 received 100 mg, 145 received
200 mg, and 1122 received 300 mg, based on level of renal impairment.
The most common adverse reaction leading to discontinuation from therapy
was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC
80 mg, and in 0.9% of allopurinol-treated subjects.
In addition to the adverse reactions presented in Table 1, dizziness was reported
in more than 1% of ULORIC-treated subjects although not at a rate more than
0.5% greater than placebo.
Less Common Adverse Reactions
In phase 2 and 3 clinical studies the following adverse reactions occurred in less
than 1% of subjects and in more than one subject treated with doses ranging from
40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than
1% of subjects) associated with organ systems from Warnings and Precautions.
Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic
purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly,
thrombocytopenia; Cardiac Disorders: angina pectoris, atrial fibrillation/flutter,
cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia;
Ear and Labyrinth Disorders: deafness, tinnitus, vertigo; Eye Disorders: vision
blurred; Gastrointestinal Disorders: abdominal distention, abdominal pain,
constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis,
gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain,
haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis,
peptic ulcer, vomiting; General Disorders and Administration Site Conditions:
asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait
disturbance, influenza-like symptoms, mass, pain, thirst; Hepatobiliary
Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly;
Immune System Disorder: hypersensitivity; Infections and Infestations: herpes
zoster; Procedural Complications: contusion; Metabolism and Nutrition Disorders:
anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia,
weight decreased/increased; Musculoskeletal and Connective Tissue Disorders:
arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness,
musculoskeletal pain/stiffness, myalgia; Nervous System Disorders: altered
taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache,
hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental
impairment, migraine, paresthesia, somnolence, transient ischemic attack,
tremor; Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability,
libido decreased, nervousness, panic attack, personality change; Renal and
Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal
failure, renal insufficiency, urgency, incontinence; Reproductive System and
Breast Changes: breast pain, erectile dysfunction, gynecomastia; Respiratory,
Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis,
nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory
tract congestion, sneezing, throat irritation, upper respiratory tract infection;
Skin and Subcutaneous Tissue Disorders: alopecia, angio edema, dermatitis,
dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal,
hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin
discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria;
Vascular Disorders: flushing, hot flush, hypertension, hypotension; Laboratory
Parameters: activated partial thromboplastin time prolonged, creatine increased,
bicarbonate decreased, sodium increased, EEG abnormal, glucose increased,
cholesterol increased, triglycerides increased, amylase increased, potassium
increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin
decreased, MCV increased, RBC decreased, creatinine increased, blood urea
increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased,
alkaline phosphatase increased, LDH increased, PSA increased, urine output
increased/decreased, lymphocyte count decreased, neutrophil count decreased,
WBC increased/decreased, coagulation test abnormal, low density lipoprotein
(LDL) increased, prothrombin time prolonged, urinary casts, urine positive for
white blood cells and protein.
Cardiovascular Safety
Cardiovascular events and deaths were adjudicated to one of the pre-defined
endpoints from the Anti-Platelet Trialists’ Collaborations (APTC) (cardiovascular
death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized
controlled and long-term extension studies. In the Phase 3 randomized controlled
studies, the incidences of adjudicated APTC events per 100 patient-years of exposure
were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (95% CI 0.00-1.08),
ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI
0.16-1.53).
In the long-term extension studies, the incidences of adjudicated APTC events were:
ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24).
Overall, a higher rate of APTC events was observed in ULORIC than in allopurinoltreated patients. A causal relationship with ULORIC has not been established.
Monitor for signs and symptoms of MI and stroke.
DRUG INTERACTIONS
Xanthine Oxidase Substrate Drugs
ULORIC is an XO inhibitor. Drug interaction studies of ULORIC with drugs that
are metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) have
not been conducted. Inhibition of XO by ULORIC may cause increased plasma
concentrations of these drugs leading to toxicity [see Clinical Pharmacology].
ULORIC is contraindicated in patients being treated with azathioprine,
mercaptopurine, or theophylline [see Contraindications].
Cytotoxic Chemotherapy Drugs
Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been
conducted. No data are available regarding the safety of ULORIC during
cytotoxic chemotherapy.
In Vivo Drug Interaction Studies
Based on drug interaction studies in healthy subjects, ULORIC does not have
clinically significant interactions with colchicine, naproxen, indomethacin,
hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used
concomitantly with these medications.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C: There are no adequate and well-controlled studies in
pregnant women. ULORIC should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg
(40 and 51 times the human plasma exposure at 80 mg per day for equal body
surface area, respectively) during organogenesis. However, increased neonatal
mortality and a reduction in the neonatal body weight gain were observed when
pregnant rats were treated with oral doses up to 48 mg per kg (40 times the
human plasma exposure at 80 mg per day) during organogenesis and through
lactation period.
Nursing Mothers
Febuxostat is excreted in the milk of rats. It is not known whether this drug is
excreted in human milk. Because many drugs are excreted in human milk, caution
should be exercised when ULORIC is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients under 18 years of age have not
been established.
Geriatric Use
No dose adjustment is necessary in elderly patients. Of the total number of subjects
in clinical studies of ULORIC, 16 percent were 65 and over, while 4 percent were
75 and over. Comparing subjects in different age groups, no clinically significant
differences in safety or effectiveness were observed but greater sensitivity of
some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat
following multiple oral doses of ULORIC in geriatric subjects (r 65 years) were
similar to those in younger subjects (18-40 years).
Renal Impairment
No dose adjustment is necessary in patients with mild or moderate renal
impairment (Clcr 30-89 mL per min). The recommended starting dose of ULORIC
is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per
dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended.
There are insufficient data in patients with severe renal impairment (Clcr less
than 30 mL per min); therefore, caution should be exercised in these patients.
Hepatic Impairment
No dose adjustment is necessary in patients with mild or moderate hepatic
impairment (Child-Pugh Class A or B). No studies have been conducted in
patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution
should be exercised in these patients.
Secondary Hyperuricemia
No studies have been conducted in patients with secondary hyperuricemia (including
organ transplant recipients); ULORIC is not recommended for use in patients whom
the rate of urate formation is greatly increased (e.g., malignant disease and its
treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine
could, in rare cases, rise sufficiently to allow deposition in the urinary tract.
OVERDOSAGE
ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven
days without evidence of dose-limiting toxicities. No overdose of ULORIC was
reported in clinical studies. Patients should be managed by symptomatic and
supportive care should there be an overdose.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC
resulted in a dose dependent decrease in 24-hour mean serum uric acid
concentrations, and an increase in 24-hour mean serum xanthine concentrations.
In addition, there was a decrease in the total daily urinary uric acid excretion.
Also, there was an increase in total daily urinary xanthine excretion. Percent
reduction in 24-hour mean serum uric acid concentrations was between 40% to
55% at the exposure levels of 40 mg and 80 mg daily doses.
Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization
as assessed by the QTc interval was evaluated in normal healthy subjects and in
patients with gout. ULORIC in doses up to 300 mg daily, at steady state, did not
demonstrate an effect on the QTc interval.
Special Populations
Renal Impairment: Following multiple 80 mg doses of ULORIC in healthy subjects
with mild (Clcr 50-80 mL per min), moderate (Clcr 30-49 mL per min) or severe
renal impairment (Clcr 10-29 mL per min), the Cmax of febuxostat did not change
relative to subjects with normal renal function (Clcr greater than 80 mL per min).
AUC and half-life of febuxostat increased in subjects with renal impairment in
comparison to subjects with normal renal function, but values were similar
among three renal impairment groups. Mean febuxostat AUC values were up to
1.8 times higher in subjects with renal impairment compared to those with
normal renal function. Mean Cmax and AUC values for 3 active metabolites
increased up to 2- and 4-fold, respectively. However, the percent decrease in
serum uric acid concentration for subjects with renal impairment was
comparable to those with normal renal function (58% in normal renal function
group and 55% in the severe renal function group).
No dose adjustment is necessary in patients with mild to moderate renal
impairment [see Dosage and Administration and Use in Specific Populations].
The recommended starting dose of ULORIC is 40 mg once daily. For patients
who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg,
ULORIC 80 mg is recommended. There is insufficient data in patients with
severe renal impairment; caution should be exercised in those patients [see Use
in Specific Populations.
ULORIC has not been studied in end stage renal impairment patients who are
on dialysis.
Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients
with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic
impairment, an average of 20-30% increase was observed for both Cmax and
AUC24 (total and unbound) in hepatic impairment groups compared to subjects
with normal hepatic function. In addition, the percent decrease in serum uric
acid concentration was comparable between different hepatic groups (62% in
healthy group, 49% in mild hepatic impairment group, and 48% in moderate
hepatic impairment group). No dose adjustment is necessary in patients with
mild or moderate hepatic impairment. No studies have been conducted in
subjects with severe hepatic impairment (Child-Pugh Class C); caution should
be exercised in those patients [see Use in Specific Populations.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats
and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary
bladder was observed at 24 mg per kg (25 times the human plasma exposure
at maximum recommended human dose of 80 mg per day) and 18.75 mg per
kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and
female mice, respectively. The urinary bladder neoplasms were secondary to
calculus formation in the kidney and urinary bladder.
Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal
aberration assay in a Chinese hamster lung fibroblast cell line with and without
metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay
and chromosomal aberration test in human peripheral lymphocytes, and L5178Y
mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat
unscheduled DNA synthesis and rat bone marrow cells.
Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day
(approximately 35 times the human plasma exposure at 80 mg per day) had no
effect on fertility and reproductive performance of male and female rats.
Animal Toxicology
A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals
and calculi in kidneys at 15 mg per kg (approximately 4 times the human plasma
exposure at 80 mg per day). A similar effect of calculus formation was noted in
rats in a six-month study due to deposition of xanthine crystals at 48 mg per kg
(approximately 35 times the human plasma exposure at 80 mg per day).
PATIENT COUNSELING INFORMATION
[see FDA-Approved Patient Labeling in the full prescribing information]
General Information
Patients should be advised of the potential benefits and risks of ULORIC. Patients
should be informed about the potential for gout flares, elevated liver enzymes and
adverse cardiovascular events after initiation of ULORIC therapy.
Concomitant prophylaxis with an NSAID or colchicine for gout flares should
be considered.
Patients should be instructed to inform their healthcare professional if they
develop a rash, chest pain, shortness of breath or neurologic symptoms
suggesting a stroke. Patients should be instructed to inform their healthcare
professional of any other medications they are currently taking with ULORIC,
including over-the-counter medications.
Distributed by
Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015
U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520.
ULORIC® is a registered trademark of Teijin Pharma Limited and used under
license by Takeda Pharmaceuticals America, Inc.
All other trademark names are the property of their respective owners
©2009 Takeda Pharmaceuticals America, Inc.
February 2009
For more detailed information, see the full prescribing information for
ULORIC (febuxostat) tablets (PI1114 R1; February 2009) or contact
Takeda Pharmaceuticals America, Inc. at 1.877.825.3327.
PI1114 R1-Brf; February 2009
L-TXF-0209-3
Straight Talk
Pharmacy Technicians:
Truth and Consequences
ith the flu season quickly
approaching, imagine an
absolutely unbearable workday in your pharmacy. Anticipating the
worst, you call in extra pharmacists and
pharmacy technicians to help fill what
are expected to be some of the busiest
prescription days of the year. Sure
enough, on a typical day during the flu
outbreak, a line starts early at the prescription drop-off counter and continues to build throughout the day. Cars
are stacked up at the drive-through prescription window as though McDonald’s
were giving out free Big Macs. As physicians’ offices open, the pharmacy’s
phones ring incessantly with new prescription orders and permissions to refill
older prescriptions. Everyone is working
to their fullest capacity, which necessitates extra effort from all pharmacy personnel. Pharmacists’ and technicians’
fingers are furiously tapping the computer keyboards trying to input data as
quickly as possible while making sure important information is accurately recorded into patients’ medical
records. Medication stock bottles are being pulled
from every shelf in the pharmacy, with their tablets
and capsules ready to be poured out into the smaller
prescription containers and bottles lined up on the
prescription counter, each awaiting a label with
instructions to be affixed to it. Once filled, the prescriptions will be checked by a pharmacist before
being dispensed to the patient. The pharmacy counter
is a mess and resembles the trading floor of the New
York Stock Exchange after a busy day, with notes on
scrap paper strewn everywhere. Pharmacy technicians
and pharmacists line up to fill the waiting prescription
bottles and vials like a General Motors assembly line.
And then it happens . . . a pharmacy technician prepares a prescription that contains a fatal dose of the
medication. Because of the craziness in the pharmacy,
the error gets passed over by a pharmacist who is sup-
W
posed to check each and every prescription before it is dispensed.
A doomsday scenario, you say, that
would never happen in your pharmacy?
Maybe, but the truth is, it does happen, and it is more than likely that the
pharmacist, not the technician, will pay
the consequences of any error. Depending on its severity, the error could result
in a hefty fine and prison time for the
pharmacist. While the above scenario
may be fictitious, a case reported by
U.S. Pharmacist’s legal contributor, Jesse
C. Vivian, BS Pharm, JD, in this
month’s Legal Considerations column
(page 66), is unfortunately all too real.
In that case of a fatal error, the technician was charged with negligent
homicide but was given a “get out of
jail free” card by the court, wasn’t even
fined, and actually went back to work
in a retail pharmacy. The pharmacist,
however, was found guilty of involuntary manslaughter and faced up to 5
years in prison and a $10,000 fine. His license was
revoked, and he will probably never work again as a
pharmacist. All this because he did not check the
accuracy of a prescription filled by the technician.
The column should be a wake-up call for every
pharmacist who works closely with one or more pharmacy technicians. While it is true that each case of
negligence involving a technician will be judged on
the merits of the case, the message is clear. The truth
is that if a pharmacist is not diligent about checking a
technician’s work, the consequences could be dire.
Harold E. Cohen, RPh
Editor-in-Chief
[email protected]
4
U.S. Pharmacist • November 2009 • www.uspharmacist.com
U.S. Pharmacist
What’s News
Editorial Board of Advisors
Joseph Bova, RPh
Community Pharmacy Owner,
Cary’s Pharmacy,
Dobbs Ferry, New York;
Member, NYS Board of Pharmacy
Carmen Catizone, RPh
Executive Director, National Association
of Boards of Pharmacy
John M. Coster, PhD, RPh
Senior VP of Government Affairs
National Community Pharmacists Assoc.
Hewitt (Ted) W. Matthews, PhD
Dean, Southern School of Pharmacy,
Mercer University, Atlanta
David G. Miller, RPh
Pharmacy Affairs, Merck & Co., Inc.,
West Point, Pennsylvania
Mario F. Sylvestri, PharmD, PhD
Senior Director, Medical Science Liaisons, Amylin Pharmaceuticals
Ray A. Wolf, PharmD
Medical Education, Sanofi Aventis
Mary Ann E. Zagaria,
PharmD, MS, CGP
Senior Care Consultant and
President, MZ Associates, Inc.,
Norwich, New York
Contributing Editors
Loyd V. Allen, Jr., PhD
Connie Barnes, PharmD
Bruce Berger, PhD
R. Keith Campbell, RPh, CDE
Patrick N. Catania, PhD, RPh
R. Rebecca Couris, PhD, RPh
Ed DeSimone, PhD, RPh
Ronald W. Maddox, PharmD
Somnath Pal, BS (Pharm), MBA, PhD
W. Steven Pray, PhD, DPh
M. Saljoughian, PharmD, PhD
Jesse C. Vivian, BS Pharm, JD
Send your comments via
E D I T O R @ U S P H A R M A C I S T. C O M
Mail: 160 Chubb Avenue, Suite 306
Lyndhurst, NJ 07071
Telephone: (201) 623-0999
Editorial Dept. Fax: (201) 623-0991
Internet: www.uspharmacist.com
FDA Approves Gardasil for Genital Warts in Men and Boys
Silver Spring, MD — The FDA approved the vaccine Gardasil for the
prevention of genital warts resulting from the human papillomavirus (HPV)
types 6 and 11 in boys and men age 9 through 26 years. A randomized trial of
4,055 males age 16 through 26 showed that Gardasil was 90% effective in
preventing genital warts, and studies measuring the immune response of males
age 9 through 15 were equally positive. Each year, about two out of every
1,000 men in the United States are diagnosed with genital warts. Gardasil
currently is approved for use in girls and women age 9 through 26 for the
prevention of cervical, vulvar, and vaginal cancer caused by HPV types 16 and
18; precancerous lesions caused by types 6, 11, 16, and 18; and genital warts
caused by types 6 and 11. Most genital warts are caused by HPV infection,
which is the most common sexually transmitted infection in the U.S.
IMS Predicts 4% to 6% Global Pharma Market Growth Next Year
Norwalk, CT — IMS Health reported that the value of the global
pharmaceutical market in 2010 is expected to grow 4% to 6% on a
constant-dollar basis, exceeding $825 billion. The forecast predicts global
pharmaceutical market sales to grow at a 4% to 7% compound annual rate
through 2013, and considers the impact of the global macroeconomy, the
changing mix of innovative and mature products, and the rising influence of
health care access and funding on market demand. The value of the global
pharmaceutical market is expected to expand to $975+ billion by 2013.
“Overall, market growth is expected to remain at historically low levels, but
stronger-than-expected demand in the U.S. is lifting both our short- and
long-term forecasts,” said Murray Aitken, senior vice president, Healthcare
Insight, IMS Health.
FDA Warns About Illegal H1N1 Vaccines on the Web
Silver Spring, MD — The FDA warned consumers about purchasing any
products over the Internet that claim to diagnose, prevent, treat, or cure the
H1N1 influenza virus. The warning comes after the FDA recently purchased
and analyzed several products represented online as Tamiflu (oseltamivir) that
may pose risks to patients. One of the orders, which arrived in an unmarked
envelope with a postmark from India, consisted of unlabeled white tablets
taped between two pieces of paper. When analyzed by the FDA, the tablets
were found to contain talc and acetaminophen, but none of the active
ingredient oseltamivir. The Web site disappeared shortly after the FDA placed
the order.
Smoking Bans Reduce Heart Attack Risk
Washington, DC — A report from the Institute of Medicine says that
smoking bans are effective at reducing the risk of heart attacks and heart
disease associated with secondhand smoke. The report also provides evidence
that breathing secondhand smoke boosts the risk for heart problems in
nonsmokers, adding that there is evidence that relatively brief exposures could
lead to a heart attack. About 43% of nonsmoking children and 37% of
nonsmoking adults are exposed to secondhand smoke in the U.S., according
to public health data.
5
U.S. Pharmacist • November 2009 • www.uspharmacist.com
NO
VEM
BE R 20
Vol. 34 No. 11
PERFORATION
Bipolar
Disorder
TEAR ALONG
HEALTH SYSTEMS EDITION
PATIENT TEACHING AID
09
The Journal for Pharmacists’ Education
Dramatic High
and
Low Mood Swi
ngs
Bipolar disorder,
sometimes called
manic depression,
is a mental illness
that is described
in mood extremes
as
. Patients with bipolar a fluctuation
experience high
disorder may
(mania) and low
and the lives of
(depressi
swings
those around them.
low moods and
The classic picture that are dramatic, seriously affecting on) mood
back again, with
of bipolar disorder
their lives
each
normal mood in
includes swings
between the extremes swing lasting from weeks to months
from high to
their days with
.
During
and
often
mania, patients
increased activity,
are often agitated, with periods of
little sleep, erratic
focused. During
speeding through
depressio
behavior, and problems
with suicidal thoughts n, feelings of exhaustion,
concentrating
hopelessness, and
.
futility are common or staying
The cause of bipolar
, sometimes
disorder is most
imbalance may
likely an imbalan
be hereditary, since
ce in brain chemical
within families.
s that affect mood.
Diagnosis depends there is an increased risk of bipolar
about 1% of the
on a thorough history
disorder and schizoph This
population has
of mood and
renia
been
probably much
higher due to misdiagndiagnosed with bipolar disorder, behavior in the past. Although
the actual number
Without treatmen
osis.
of people is
The goal of treatmen t, bipolar disorder is a debilitat
ing
There are a variety t is to stabilize the patient’s mood condition that will not improve
of
on its own.
to avoid drastic
the cause of bipolar medications that act to even
and
damaging mood
out the
swings.
ily therapy to help symptoms. Therapy for bipolar disorder imbalance of brain chemical
s thought to be
patients and their
often includes individu
ment of this condition
friends and family
al, group,
understand the
.
triggers, early signs, and famand treat-
U.S. Pharmacist is a Peer-Reviewed Journal
Copyright Jobson
Medical Informati
on LLC, 2009
cont inue d
FEATURES
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COVER IMAGE:
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Progressive Supranuclear Palsy...20
Difficulty looking up without extending the
neck or trouble using the stairs may be an initial
symptom of this condition.
PTA0911 Bipolar
10_14scbo.indd
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PM
PATIENT TEACHING AID
Bipolar Disorder. See page 17
Pharmacologic Management
of Alcohol Dependence ............. 60
Several medications are available that may help
patients achieve abstinence and avoid relapse.
Krina H. Patel, PharmD
Mary Ann E. Zagaria, PharmD, MS, CGP
Pharmacy Law
So Many Options, So Little
Difference in Efficacy: What Is the
Appropriate Antidepressant? ...... 26
TeriMcDermott.com
These agents are equal in effectiveness, but it
is hard to predict which one will work best for
a given patient.
As part of the reward pathway in alcohol
use, endorphins are released. Naltrexone
blocks the binding of endorphins to opioid
receptors, preventing dopamine release.
Marjorie Rochette DeLucia, PharmD, MS,
and Michael J. Schuh, PharmD, MBA
CE CREDITS
Emergency Contraception:
An Update of Clinical and
Regulatory Changes. See page 70
THIS MONTH
Editorial Focus: Psychotropics
NEXT MONTH
Editorial Focus:
Gastroenterologic Diseases
Criminalization of
Medication Errors ............ 66
A recent case equating a pharmacist’s mistake
with manslaughter raises the question of pharmacy
technician responsibility.
Jesse C. Vivian, BS Pharm, JD
2 CE Credits
●
Medications Used in Opioid
Maintenance Treatment ............ 40
Emergency Contraception:
An Update of Clinical and
Regulatory Changes ................ 70
It is important to keep abreast of current
therapeutic options as increasingly more
patients are treated for dependence.
Current information about levonorgestrel-based
emergency birth control and strategies for educating
consumers are discussed.
Christie Choo, PharmD, BCPS
Kathleen H. Besinque, PharmD, MSEd
HEALT H S YS TE M S E DI TI ON
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CE PROGRAMS ON THE
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[email protected].
Schizophrenia: A Review of Pharmacologic and
Nonpharmacologic Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HS-2
Pharmacists should play an active role in the management of this complicated form of mental illness.
Stacy Eon, PharmD, and Jennifer Durham, PharmD
Prophylactic Therapies in Traumatic Brain Injury Management . . . . . HS-10
Clear guidelines for the proper administration of drugs used to treat this condition are lacking.
Jennifer Confer, PharmD, and Jon Wietholter, PharmD
Newly Approved mTOR Inhibitors for the Treatment of
Metastatic Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . HS-20
Temsirolimus and everolimus are now indicated as therapy for this type of cancer.
Diana Hey Cauley, PharmD, BCOP
In-Service Primers
Nutrition and Clinical Depression . . . . . . . . . . . . . . . . . . . . . . . . . . HS-28
Manouchehr Saljoughian, PharmD, PhD
U.S. PHARMACIST® (ISSN 01484818; USPS No. 333-490) is published monthly by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Periodicals postage
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6
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Q. Which Global Generic Company’s Transdermal
Patches Were Most Dispensed in the U.S.
Last Year?
A.
Mylan Pharmaceuticals.*
With one of the most advanced transdermal development and manufacturing facilities in the
United States—brand or generic—Mylan is well-recognized as an innovator in transdermal
drug delivery technology. In fact, last year 65% of all generic patches dispensed in the U.S.
carried the Mylan name.*
We have developed more generic transdermal patches than any company in the U.S. and all
of our patches are designed with patient safety in mind. None have a bulky, liquid, gel-filled
reservoir, which eliminates any concern about the dangers associated with leakage, and
none have aluminum or other metals in their backing, which may cause potential burns in
MRI patients. So when you need generic transdermal patches…think Mylan.
*IMS National Prescription Audit. 12 months ending December 2008.
©2009 Mylan Pharmaceuticals Inc.
MYNMKT308
Vol. 34 No. 11
U.S. Pharmacist
A Jobson Publication
Senior Vice President–Editor-in-Chief
Harold E. Cohen, RPh
Executive Editor
Robert Davidson
Senior Editor
NO
VEM
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09
The Journal for Pharmacists’ Education
Bonnie Ostrowski
U.S. Pharmacist is a Peer-Reviewed Journal
Senior Associate Editor
Marjorie Borden
Projects Editor
Nancy Robertson, MS
Consulting Clinical Editor
Mary Gurnee, PharmD, RPh
Senior Vice President–Publisher
Harold E. Cohen, RPh (201) 623-0982
Associate Publisher
Jack McAleer (201) 623-0987
East Coast Regional Sales Manager
Mark Hildebrand (201) 623-0984
DEPARTMENTS
Straight Talk
Consult Your Pharmacist
Marketing Manager
Pharmacy Technicians:
Truth and Consequences . . . . . . 4
Deborah Mortara (201) 623-0990
Harold E. Cohen, RPh
Fatigue and Drowsiness:
Everyday Exhaustion
and Beyond . . . . . . . . . . . . . . 12
Midwest/West Regional Sales Manager
Megan Conley (773) 450-7339
Classified Advertising Sales
Heather Brennan (800) 983-7737 x106
What’s News. . . . . . . . . . . . . . 5
Design Director
TrendWatch
Sharyl Sand Carow
Production Manager
Dina Romano (201) 623-0942
Corporate Production Director
John Anthony Caggiano
W. Steven Pray, PhD, DPh
Acute Negative Feelings
Among Adults . . . . . . . . . . . . 10
Nonpositive beliefs and emotions generally
occur to a similar degree across age groups.
Director, Continuing Education Processing
Vice President, Circulation Director
Worthlessness 2.9
3.1
3.0
2.6
18-44 years
Vice President,
Creative Services and Production
Monica Tettamanzi
In lozenge form, this analgesic and
anesthetic agent can be prepared to suit
the patient’s individual flavor preference.
45-64 years
Helplessness
3.5
4.2
3.7
65-74 years
2.7
75+ years
Restlessness
5.2
Sadness
6.7
“Everything is
an effort”
3.9
4.9
7.9
Loyd V. Allen, Jr, PhD
3.1
7.3
Classified Advertising . . . . . . 80
7.5
7.9
7.4
Career and business opportunities, products,
and services for the pharmacist.
7.4
7.9
Chief Executive Officer
Jeff MacDonald
Chief Financial Officer
Derek Winston
Nervousness
9.6
10.1
0
5
10
15
Generic Trends . . . . . . . . . . . 54
Ketamine Hydrochloride
10-mg Troches . . . . . . . . . . . 58
Prevalence of Selected Acute Negative Feelings
Emelda Barea
FDA Fast Facts . . . . . . . . . . . 24
Contemporary
Compounding
Somnath Pal, BS (Pharm), MS, MBA, PhD
Regina Combs (800) 825-4696
Prolonged tiredness and sleepiness are a
concern for many people.
20
25
Product News . . . . . . . . . . . . 82
8.4
8.4
30
35
40
Percentage of adults surveyed
© JUPITERIMAGES
CEO, Information Services Division
Marc Ferrara
Senior Vice President, Operations
Jeff Levitz
Vice President, Human Resources
Lorraine Orlando
U.S. Pharmacist
160 Chubb Avenue, Suite 306
Lyndhurst, NJ 07071
Tel: (201) 623-0999
Fax: (201) 623-0991
E-mail: [email protected]
Web: www.uspharmacist.com
Printed on paper containing an
average of 96 percent post-consumer
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New Products in This Issue
Afinitor / Novartis Pharmaceuticals Corporation • Authorized Generics / Greenstone LLC •
Embeda / King Pharmaceuticals • Kapidex / Takeda Pharmaceuticals • Onglyza / AstraZeneca •
Uloric / Takeda Pharmaceuticals • Welchol / Daiichi-Sankyo
Health Systems Edition: Distinctive Labeling / Baxter Healthcare • Injectables / Pfizer Injectables •
Product Labeling / Teva Pharmaceuticals
8
U.S. Pharmacist • November 2009 • www.uspharmacist.com
If key products
are missing from your
multi-source topical inventory
perhaps you should
rely on the specialist.
E. FOUGERA & CO.
A division of Nycomed US Inc., Melville, NY 11747 • Toll free: 800-645-9833 • www.fougera.com
© 2009 Fougera. All rights reserved.
Iss. 9/09
TrendWatch
Acute Negative Feelings
Among Adults
The 2007 National
Health Interview
Survey for noninstitutionalized
adults provides an
understanding of
the prevalence of
acute feelings of
sadness, hopelessness, worthlessness,
or nervousness or
that everything is
an effort.
Prevalence of Selected Acute Negative Feelings
Worthlessness 2.9
3.1 3.0
2.6
18-44 years
45-64 years
Helplessness
3.7
3.5
4.2
65-74 years
2.7
75+ years
Restlessness
Sadness
5.2
6.7
3.9
4.9
7.3
3.1
7.9
7.5
Sadness, Hopeless- “Everything is
7.9
7.4
7.4
7.9
an effort”
ness, Worthlessness, or Everything Feeling Like
Nervousness
8.4
9.6
8.4
10.1
an Effort: Ten
percent of respon0
5
10
15
20
25
30
35
dents experienced
Percentage of adults surveyed
sadness; 6% felt
© JUPITERIMAGES
hopeless; 5% felt
worthless; and 13% felt
these feelings had at
sadness, compared with
that everything was an
least a bachelor’s degree.
11% of those with only
effort. Twelve percent of Adults in poor families
Medicare coverage and
women felt sad, comwere twice as likely as
8% of those with private
pared with 8% of men.
adults in families that
health insurance.
More non-Hispanic
were better off to feel
Divorced respondents
black respondents than
sad, hopeless, worthless,
were more likely than
non-Hispanic white
or that everything is an
other respondents to feel
respondents felt that
effort.
sad or that everything is
everything is an effort.
Among respondents
an effort.
The highest percentage
under age 65 years, 25%
of respondents with
of those with Medicaid
Feelings of Nervousness
these feelings had less
coverage experienced
or Restlessness: Thirteen
than a high-school
feelings of sadness, com- percent of respondents
diploma, and responpared with 15% of those experienced nervousness,
dents least likely to have who were uninsured and and 15% reported rest6% of those who had
lessness. Sixteen percent
private health insurance. of women felt nervous,
Somnath Pal,
BS (Pharm), MBA, PhD
Among individuals aged
versus 11% of men.
Professor of Pharmacy
65 years and over, 19%
Non-Hispanic white
Administration, College of
of
those
with
Medicaid
respondents had more
Pharmacy & Allied Health
and
Medicare
coverage
feelings of nervousness
Professions, St. John’s University,
experienced feelings of
than non-Hispanic black
Jamaica, New York
10
U.S. Pharmacist • November 2009 • www.uspharmacist.com
respondents. The
highest percentage
of adults with
these feelings had
less than a highschool diploma;
those least likely
to have these feelings possessed a
bachelor’s degree
or higher. Adults
in poor families
were more likely
to feel nervous
than adults in
families that were
better off.
Among individuals under age 65
years, 26% of
40
those with Medicaid coverage experienced feelings of
nervousness, compared
with 15% of those who
were uninsured and 12%
of those who had private
health insurance. Among
adults aged 65 years and
over, 25% of those with
Medicaid and Medicare
coverage experienced
feelings of nervousness,
versus 11% of those who
had only Medicare coverage and 11% of those
with private health
insurance. Adults who
were married were least
likely to have feelings of
nervousness or restlessness, compared with
adults who were
divorced or separated,
never married, or living
with a partner.
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8402 A
Consult Your Pharmacist
Fatigue and Drowsiness:
Everyday Exhaustion and Beyond
atigue and drowsiness are a part of
everyday life for millions
of people, and prolonged
fatigue is a concern for
10% to 25% of those
who visit general practitioners.1 The high incidence of fatigue is due to
such issues as today’s
hectic lifestyle, lack of
leisure time, poor sleep
habits, and certain medical conditions. Pharmacists are in an ideal position to provide assistance
to patients complaining
about continual fatigue
and daytime drowsiness.
Fatigue
Fatigue is commonly
experienced and is the
feeling of tiredness or
exhaustion that follows a
hard day of work or
mentally and physically
challenging exercise.2,3
Patients may also complain that they are weary,
that their energy is gone,
or that they feel lack of
motivation to accomplish
other tasks.
Counseling Patients
With Fatigue: When
counseling patients with
fatigue, the pharmacist
W. Steven Pray, PhD, DPh
Bernhardt Professor, Nonprescription
Products and Devices
College of Pharmacy, Southwestern
Oklahoma State University
Weatherford, Oklahoma
© JUPITERIMAGES
F
Caffeine's stimulant effect is well known and is the primary reason
for its ubiquitous use. The dose approved as safe and effective is
100 to 200 mg, not more often than every 3 to 4 hours.
should first attempt to
ascertain whether the
fatigue is a normal
response to overwork or
a continual problem that
seems unrelated to the
amount or extent of
effort performed that
day, week, or month. If
it is the former, the
problem is probably a
short-term, minor difficulty that will resolve on
its own once the stressors
have subsided. However,
if the patient is able to
sleep normally but still
experiences continual
fatigue that seems unrelated to ongoing mental
or physical stress, the
fatigue may be secondary
to medications or a medical condition.3 For
example, patients with
hypothyroidism com-
plain that they awaken
refreshed, but that activity results in rapid onset
of fatigue.3
Causes of Fatigue:
Fatigue can be caused by
a wide variety of medical
conditions.1,3,4 As many
as 40% of those reporting symptoms of chronic
fatigue were eventually
discovered to have a psychiatric or medical condition that had not yet
been diagnosed but was
ultimately treated successfully.4 Etiologies
include premenstrual
syndrome, premenstrual
dysphoric disorder, allergic rhinitis, asthma, anemias, hypo- or hyperthyroidism, Addison’s
disease, fibromyalgia,
arthritis, lupus, cancer,
12
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Parkinson’s disease, congestive heart failure, diabetes, conditions causing
persistent pain, infections (e.g., AIDS, mononucleosis), renal disease,
and hepatic disease.4-8
Depression and grief
induce fatigue. Sleep disorders cause fatigue,
including insomnia, narcolepsy, and obstructive
sleep apnea. Alcohol and
other drugs of abuse
(e.g., cocaine, narcotics)
cause fatigue, and the
patient may find that
making healthier lifestyle
choices will resolve the
problem. Malnutrition
leads to fatigue, as do
anorexia and other eating
disorders. The wide spectrum of potential etiologies makes it critical for
pharmacists to refer
patients with unexplained fatigue to a physician for a full medical
evaluation.
Chronic Fatigue
Syndrome: Chronic
fatigue syndrome (CFS)
is a cause of chronic
tiredness that affects 1 to
4 million Americans.4 Its
ramifications are profound, in that one-fourth
of sufferers are not
employed and many are
receiving disability benefits. It differs from normal fatigue in its sever-
✁
PATIENT INFORMATION
Combating Fatigue and Drowsiness
Steps You
Can Take
Before you take any
medications for fatigue
and drowsiness, you
may wish to try some
relatively easy solutions.
You should not go to
bed and arise at odd
times or at different
times each day. The
best advice is to set a
time for going to bed
and also for arising and
try to stick to them as
much as possible.
Everyone has experienced the “fun” of staying up till 4 AM or later
and then sleeping in
until noon the next day.
Even 8 hours of sleep
cannot fool your body
into normalcy, and you
will feel the effects of
your altered schedule
the next day. In addition, strive to get at
least 7 to 8 hours of
sleep a night. Trying to
get through the next
day without adequate
sleep leads to daytime
drowsiness that is a
major cause of fatal
automobile accidents.
Avoid stimulants such
as caffeine or oral nasal
decongestants (e.g.,
Sudafed) too close to
bedtime, as the stimulant effect may not
allow you to drop off to
sleep at the right time,
leaving you fatigued the
following day.
You should always
eat a healthy, balanced
diet and drink sufficient
water to keep fully
hydrated. Avoid all
alcohol, nicotine, and
drugs of abuse. If you
habitually drink caffeine-containing soft
drinks, coffee, or tea,
try to reduce the
amount or eliminate
them completely to
determine whether they
are responsible for a
tired feeling. You
should also be aware of
any medications you are
taking that may cause
drowsiness, such as
antihistamines, antihypertensives, corticosteroids, diuretics, and
sleep aids.
One method to
reduce fatigue is to
reduce life stresses. It
may be necessary to
change from a job that
causes severe stress to
one that allows a more
relaxing day of work.
When you have spare
time, do not spend it
playing high-stress video
games that require splitsecond timing and fast
reflexes. Instead, go for a
walk, read a book, or
have a pleasant conversation with family and
friends. If you are caught
in a relationship that is
fraught with problems,
deal with them directly
or end the relationship.
Nonprescription
Medications
The only pharmacy
product proven safe and
effective in helping
fight fatigue and drowsiness is caffeine, found
PHARMACY STAMP
© JUPITERIMAGES
Everyone has felt tired or sleepy during the day.
Undue tiredness may be caused by a number of
serious medical conditions, so if simple advice or
OTC products containing caffeine do not help, it is
wise to see a physician.
in such OTC products
as Vivarin and NoDoz.
Each caplet or tablet
contains 200 mg of caffeine. Take one dose
not more often than
every 3 to 4 hours.
These products are only
safe for those aged 12
years and above. They
are not a substitute for
healthy sleep and
should never be used to
keep you awake all
night. They should not
be used if you are pregnant or breastfeeding
without speaking to
your physician first.
Energy Drinks
Avoid the use of the
popular energy drinks.
Virtually all contain
ingredients of unknown
safety and effectiveness,
such as herbs and
dietary supplements.
One contains such
unproven ingredients as
ginkgo, guarana, inositol, L-carnitine, ginseng, and milk thistle.
Using products such as
these is a risky gamble
with your health, since
they can have adverse
effects and are not
proven to provide a safe
boost of energy.
Remember, if you have questions, Consult Your Pharmacist.
13
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Consult Your Pharmacist
ity, in the incapacitating
feeling that patients
experience, and in the
fact that bed rest does
not relieve it.1,9 The
degree of fatigue limits
or halts social engagements, educational
efforts, work, and personal activity. Studies
from the CDC reveal
that the disabling effects
of CFS rival those of
such overwhelming conditions as chronic
obstructive pulmonary
disease (COPD), rheumatoid arthritis, lupus,
multiple sclerosis, heart
disease, and end-stage
renal disease.
The degree of disability varies widely among
patients and in the same
patient from episode to
episode. Some patients
experience periods where
they are relatively free of
symptoms, followed by a
period of extreme disability.1 This cyclical pattern
is often seen with CFS.
To meet the formal
diagnosis of CFS,
patients should have
experienced symptoms
for 6 months or more.1
Further, the fatigue is
not caused by any underlying medical conditions
and is accompanied by
such nonspecific ancillary symptoms as sore
throat, joints that are
painful but lack erythema or inflammation,
unrelenting muscle pain,
headaches that differ
from the norm in severity or symptoms, and
What’s in Red Bull?
The popular product known as Red Bull claims to be an
“energy drink.” The company Web site does not directly
state that the taurine (an amino acid) in the product provides energy, but it does mention other beneficial
effects.13 It says that “one can of Red Bull Energy Drink
contains approximately the same amount of caffeine as a
cup of coffee,” a vague statement that should be clarified
to disclose the exact amount. The drink also contains
glucuronolactone, B vitamins, sucrose, and glucose.
Patients should not assume that its formula is safer or
more effective than caffeine alone.
lymph node tenderness
(axillary or cervical).1
Patients do not feel
refreshed after sleep, and
they also notice that
physical or mental exercise produces a malaise
that persists for more
than 24 hours. Their
ability to concentrate on
tasks is reduced, and
their memory is
impaired. These are
referred to as the eight
symptoms that define
CFS.
Treatment options for
CFS are diverse and of
variable use. The CDC
urges practitioners to
adapt treatment plans to
the individual patient’s
present symptoms.10
Sleep disturbances may
be initially treated with
simple sleep hygiene
measures, followed by
nonprescription antihistamine sleep aids such as
Sominex and Unisom. If
these medications are
needed beyond 14 days,
however, the patient
should be urged to seek
care from a physician.
Muscle and joint pain
and headache may be
amenable to nonprescription acetaminophen, ibuprofen, or naproxen.
The CDC alerts
patients to the fallacies
of using nutritional and
herbal supplements for
CFS.10 Although some
patients report relief
from these products,
they are not regulated by
the FDA, and thus
objective data to prove
their efficacy and safety
are often lacking. The
CDC warns patients
against such herbs as
comfrey, ephedra, kava,
germander, chaparral,
bitter orange, licorice
root, and yohimbine due
to reports of toxicity
coupled with lack of efficacy data.10
The CDC also mentions the use of alternative therapies such as
acupuncture, aquatic
therapy, gentle massage,
meditation, deep breathing, biofeedback, yoga,
and tai chi.10 The agency
urges patients to discuss
these options with a
health care provider to
14
U.S. Pharmacist • November 2009 • www.uspharmacist.com
make sure that they have
been proven safe and
effective.
Medications That Cause
Fatigue: Medications
that are reported to cause
fatigue include antihistamines, antihypertensives,
corticosteroids, diuretics,
and sleep aids for insomnia.2 Some agents induce
toxic myopathy that can
lead to fatigue.11 If prescription medications are
suspected to be the cause
of fatigue or of CFS,
patients should be asked
to visit their prescriber
for a full evaluation and
consideration of alternative medications.
Drowsiness
Drowsiness differs from
fatigue in that it is a subjective feeling that sleep
is needed. A patient may
not be tired at all, but
falls prey to an overwhelming need for sleep
at an inappropriate time
or in an inappropriate
situation.12
Counseling Patients
With Drowsiness: It is
normal to experience
drowsiness after inadequate sleep because the
patient has a “sleep debt.”
However, some patients
complain of abnormal
sleepiness in spite of having obtained sufficient
sleep the night before.
The pharmacist can question these patients about
their sleep patterns, how
much they normally
Consult Your Pharmacist
sleep, whether they snore,
and whether their bed
partner complains that
they have episodes of
breathing cessation during the night (sleep
apnea). If the answers to
these are unrevealing, the
patient should be urged
to visit a physician, who
may conduct sleep studies
to determine the root
cause of this abnormal
drowsiness. If the
patient’s habits seem to
demonstrate poor sleep,
interrupted sleep, or
inadequate sleep, he or
she should be advised to
adopt the principles of
sleep hygiene. Patients
may be asked whether
they are depressed, anxious, stressed, or suffering
general life boredom. A
trial of antidepressants
may help some of these
patients.
Causes of Drowsiness:
Drowsiness may be
caused by such widely
varying etiologies as
rotating shift work,
sedating medications
(e.g., antihistamines,
antidepressants, pain
medications), hypothyroidism, hypercalcemia,
REFERENCES
1. Chronic fatigue syndrome.
Symptoms. CDC. www.cdc.gov/cfs/
cfssymptomsHCP.htm. Accessed
September 30, 2009.
2. Pray WS. Nonprescription Product
Therapeutics. 2nd ed. Baltimore,
MD: Lippincott Williams &
Wilkins; 2006.
3. Fatigue. National Library of Medicine. www.nlm.nih.gov/medlineplus/ency/article/003088.htm.
Accessed September 30, 2009.
4. Chronic fatigue syndrome. Back-
hyponatremia or hypernatremia, sleep apnea,
and narcolepsy.12
Nonprescription
Products
In addition to helping
patients uncover the
sources of fatigue or
drowsiness and referring
them when appropriate,
pharmacists can also recommend nonprescription
treatment. The only
medication found to be
safe and effective for selfuse when used as labeled
is caffeine.2 Caffeine’s
stimulant effect is wellknown and is the primary reason for its ubiquitous recreational use.
The stimulant dose
approved as safe and
effective is 100 to 200
mg, not more often than
every 3 to 4 hours.2
Products include Vivarin
and NoDoz, both containing 200 mg of caffeine per tablet/caplet.
These products are not
to be recommended for
anyone under the age of
12 years.
Labels will warn
patients that these products contain approximately as much caffeine
ground. CDC. www.cdc.gov/cfs/.
Accessed September 30, 2009.
5. Zanni GR. Diagnosing and treating fibromyalgia. Consult Pharm.
2009;24:572-589.
6. Cuatrecasas G. Fibromyalgic syndromes: could growth hormone therapy be beneficial? Pediatr Endocrinol
Rev. 2009;6(suppl 4):529-533.
7. Rapkin AJ, Winer SA. Premenstrual syndrome and premenstrual
dysphoric disorder: quality of life
and burden of illness. Expert Rev
Pharmacoecon Outcomes Res.
as a cup of coffee and
that they should limit or
stop caffeine use while
taking them. Failure to
do so could lead to nervousness, sleeplessness,
irritability, and tachycardia. Of course, a cup of
coffee can contain widely
divergent amounts of
caffeine, so the FDA
warning is only an estimate for consumer use.
Labels warn patients that
these products are for
occasional use only and
that they will not substitute for sleep. Furthermore, if drowsiness or
fatigue persists or recurs,
patients should consult
their physician. These
products are not to be
used if the patient is
pregnant or breastfeeding. Their optimal use is
for patients who are performing boring, repetitive tasks that lead to
inattention (e.g., assembly-line work). They may
also be useful to maintain maximal attentiveness during driving.
Some patients are
already consuming the
recommended amount of
caffeine in the form of
coffee, tea, and soft
2009;9:157-170.
8. Lou JS. Physical and mental
fatigue in Parkinson’s disease:
epidemiology, pathophysiology and
treatment. Drugs Aging.
2009;26:195-208.
9. Chronic fatigue syndrome.
National Library of Medicine.
www.nlm.nih.gov/medlineplus/
chronicfatiguesyndrome.html.
Accessed September 30, 2009.
10. Chronic fatigue syndrome.
Treatment options. CDC. www.cdc.
gov/cfs/cfstreatmentHCP.htm.
15
U.S. Pharmacist • November 2009 • www.uspharmacist.com
drinks. Eight ounces of
brewed coffee contains
135 mg of caffeine, and
the same amount of
brewed tea contains 50
mg.2 A 12-oz can of
Coca-Cola or Pepsi-Cola
contains 34 to 38 mg of
caffeine, where the
amount in other soft
drinks may be as high as
55 mg/12 oz. A patient
who drinks several cans
of caffeinated soft drinks
daily, along with a 20-oz
cup of coffee from a
popular coffee chain like
Starbucks (480 mg of
caffeine) is already consuming a considerable
amount of stimulant.2
The 200 mg in a single
NoDoz or Vivarin may
not be enough to provide
any benefit beyond the
already high daily intake
and could lead to
unwanted effects.
Conclusion
Fatigue and drowsiness
are common medical
conditions that can be
caused by a host of serious disorders. Unless the
cause is trivial and shortterm, the patient should
be referred to a physician
for a full evaluation.
Accessed September 30, 2009.
11. Dalakas MC. Toxic and druginduced myopathies. J Neurol Neurosurg Psychiatry. 2009;80:832-838.
12. Drowsiness. National Library of
Medicine. www.nlm.nih.gov/medlineplus/ency/article/003208.htm.
Accessed September 30, 2009.
13. Red Bull Energy Drink.
Ingredients. www.redbull.com/cs/
Satellite/en_INT/Products/Red-BullEnergy-Drink-021242751115866?p=
1242745950125. Accessed
September 30, 2009.
Use as directed.
FOR YOUR
PATIENTS WITH
HYPERTENSION
RECOMMEND COLD MEDICINE
WITH A HEART.
Tell your patients about the only
cold brand that won’t raise their
blood pressure: Coricidin® HBP.
Like many of your patients, S. Epatha Merkerson has hypertension. Since decongestants are contraindicated for
hypertensive patients, they need to be careful when they get a cold. So assure your patients that Coricidin HBP is the smart
choice because it’s decongestant-free and specially made to relieve cold symptoms without raising blood pressure.
Recommend the full line of products from Coricidin HBP. Powerful cold medicine with a heart.
®
Schering-Plough, maker of Coricidin HBP,
sponsors the AHA High Blood Pressure website.
©2009 Schering-Plough HealthCare Products, Inc.
PATIENT TEACHING AID
TEAR ALONG PERFORATION
Bipolar
Disorder
Bipolar disorder, sometimes called manic depression,
is a mental illness that is described as a fluctuation
in mood extremes. Patients with bipolar disorder may
experience high (mania) and low (depression) mood
swings that are dramatic, seriously affecting their lives
and the lives of those around them. The classic picture of bipolar disorder includes swings from high to
low moods and back again, with each swing lasting from weeks to months and often with periods of
normal mood in between the extremes. During mania, patients are often agitated, speeding through
their days with increased activity, little sleep, erratic behavior, and problems concentrating or staying
focused. During depression, feelings of exhaustion, hopelessness, and futility are common, sometimes
with suicidal thoughts.
The cause of bipolar disorder is most likely an imbalance in brain chemicals that affect mood. This
imbalance may be hereditary, since there is an increased risk of bipolar disorder and schizophrenia
within families. Diagnosis depends on a thorough history of mood and behavior in the past. Although
about 1% of the population has been diagnosed with bipolar disorder, the actual number of people is
probably much higher due to misdiagnosis.
Without treatment, bipolar disorder is a debilitating condition that will not improve on its own.
The goal of treatment is to stabilize the patient’s mood to avoid drastic and damaging mood swings.
There are a variety of medications that act to even out the imbalance of brain chemicals thought to be
the cause of bipolar symptoms. Therapy for bipolar disorder often includes individual, group, and family therapy to help patients and their friends and family understand the triggers, early signs, and treatment of this condition.
Dramatic High and
Low Mood Swings
Copyright Jobson Medical Information LLC, 2009
continued
PATIENT TEACHING AID
Medications Can Level the Extremes
and Restore a More Normal Mood
Bipolar disorder can occur in several symptom patterns. These
include cyclothymia (mild mood swings), bipolar I (one period
of mania sometimes following a period of depression), and the
most common form, bipolar II (at least one period of mild or
hypomania and one period of depression). When mania and
depression occur together, it is called mixed-state bipolar disorder.
The manic phase is characterized
Identifying Symptoms: Bipolar symptoms typically begin in by euphoria, racing thoughts, and
the late teens to early 30s and are first seen after a significant impulsiveness.
stressful or traumatic event. The tendency to develop this disease may be hereditary in some cases,
since many families have more than one member with this condition.
Symptoms of mania include excitation, exhilaration, feelings of self-importance, confusion,
racing thoughts, problems concentrating, little interest in food or rest, and impulsiveness. These
symptoms take a toll on the physical and mental health of the patient. Since thoughts are
jumbled and the mood is euphoric, patients often make poor decisions that make little sense.
Psychosis can also be a symptom. During a psychotic episode, patients see or hear things that
do not exist (hallucinations), or believe things that are not in touch with reality (delusions).
Symptoms of depression include feelings of hopelessness and despondency, with little interest
in activities that were once pleasurable. During the depressive phase of bipolar disorder, many
patients have problems eating and sleeping, feel nervous and irritable, and consider suicide.
Seeking Help: Most patients with bipolar disorder recognize that they have a problem, but not
all seek help. This is for a variety of reasons. Bipolar disorder is considered a mental illness, which
may evoke feelings of shame and inadequacy. Many patients also do not want to treat their mood
swings with medications. However, the only reliable and effective treatment for bipolar disorder is
medication to level the extremes and restore a more normal mood. Without therapy, bipolar disorder will only worsen with time. Untreated, it can lead to serious depression and suicide, problems
with functioning in life, and drug or alcohol addiction. That is why it is important for patients to
find support in family, friends, and therapists who can help them lead a productive, normal life.
Therapy for bipolar disorder can include individual therapy to help patients understand the
condition and care for themselves, group therapy to help patients understand how others are suffering from this condition, and family therapy to educate patients’ loved ones about the disorder
and what to do when they observe the beginnings of mood swings that patients may or may not
notice themselves.
Drug therapy for bipolar disorder includes medications that rebalance the chemicals in the brain
that affect mood, thereby equalizing mood. The medication cannot be discontinued during periods
of normal mood, since bipolar disorder is a chronic condition that requires treatment of symptoms
as well as prevention of symptoms. Although younger patients may not accept the idea of a lifetime
of medication, eventually they begin to understand its importance after suffering serious relapses
when they discontinue therapy.
Drug therapy for bipolar disorder might start out with lithium, quetiapine, or an antiseizure
medicine such as valproic acid. These drugs help stabilize mood and avoid swings. Some patients
may require additional medicine for psychosis (antipsychotics such as risperidone or olanzapine)
or sleep aids. Many doctors find that a combination of medicines that work in different ways is
the most effective treatment. All drugs take a period of weeks to months to work best, and sometimes doses need to be increased or decreased to work better while avoiding side effects. Once the
right drug therapy is established, patients need to be aware of the importance of continuing their
medicines to avoid future episodes of mania or depression.
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H E A LT H S Y S T E M S E D I T I O N
Schizophrenia
A Review of
Pharmacologic and
Nonpharmacologic
Treatments
© JUPITERIMAGES
P
atients with mental illness constitute a population
that can be challenging for any health care provider,
but they offer great opportunities for a pharmacist to make a meaningful contribution. The pharmacist’s role might involve assisting in the selection of medication regimens, managing adverse drug reactions, or
facilitating adherence. These interventions can be particularly important for patients with schizophrenia.
(see TABLE 1), involve the diminution or absence of
normal functions; they often are refractory to treatment.3,4 Cognitive symptoms are highly prevalent and
may include difficulties with verbal fluency, attention, and working memory.3 Antipsychotic medications have little effect on cognitive symptoms; as a
result, these symptoms affect a patient’s ability to obtain
employment, establish personal relationships, and function in many social settings.3
According to Diagnostic and Statistical Manual of
Mental Disorders-IV-TR criteria, a patient can be
diagnosed with schizophrenia if he or she presents with
at least two of the following symptoms in addition to
social dysfunction for a significant amount of time during a 1-month period, with some symptoms persisting for at least 6 months: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic
behavior, or negative symptoms.4 The diagnosis can
also be made solely on the basis of bizarre delusions
or hallucinations involving voices.4
DIAGNOSIS AND CLINICAL PRESENTATION
Schizophrenia is a chronic, debilitating mental illness
that affects approximately 1% of the population.1 Owing
to the 10% lifetime prevalence of suicide in patients
with the disorder, early recognition and appropriate
treatment are imperative.2 Schizophrenia typically presents in late adolescence and persists throughout the
patient’s life, and males typically experience symptoms
5 to 7 years earlier than females.1,3
Symptoms of schizophrenia may be classified as positive, negative, or cognitive. Positive symptoms include
disorganized speech or behavior and psychotic characteristics such as delusions or hallucinations. Delu- PATHOPHYSIOLOGY
sions, or fixed false beliefs, occur when a patient mis- Although the neurochemistry behind schizophrenia is
not fully understood, the disorder is
interprets an experience, leading to
Stacy Eon, PharmD
thought to be caused by increased
erroneous beliefs involving paranoia
PGY2 Pharmacy Resident in Psychiatry
dopaminergic transmission. 1 This
or persecution. Hallucinations involve
University of North Carolina Hospitals
increase in dopamine effect causes the
more vivid sensory disruptions, with
Chapel Hill, North Carolina
brain to be hypersensitive to stimauditory hallucinations being the
Jennifer Durham, PharmD
uli, making it difficult for the patient
most common.1,3 Negative symptoms,
Clinical Pharmacist
including affective flattening, alogia,
to distinguish between reality and his
Moses Cone Memorial Hospital
avolition, and reduced social drive
or her delusions or hallucinations.1
Greensboro, North Carolina
HS-2
U.S. Pharmacist • November 2009 • www.uspharmacist.com
IN THE TREATMENT OF MRSA BACTEREMIA AND MRSA COMPLICATED SKIN INFECTIONS
INSIDE.OUTSIDE.ON HIS SIDE.
n Landmark clinical trial of CUBICIN 6 mg/kg once daily demonstr ated
efficacy in S. aureus bacteremia caused by MRSA and MSSA
n Proven clinical success of CUBICIN 4 mg/kg once daily in S. aureus
complicated skin infections — both MRSA and MSSA
INDICATIONS AND IMPORTANT SAFETY INFORMATION
CUBICIN is indicated for the following infections:
Complicated skin and skin structure infections caused by susceptible
isolates of the following Gram-positive microorganisms: S. aureus (including
methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus
agalactiae, Streptococcus dysgalactiae subspecies equisimilis, and
Enterococcus faecalis (vancomycin-susceptible isolates only). Combination
therapy may be clinically indicated if the documented or presumed
pathogens include Gram-negative or anaerobic organisms.
S. aureus bloodstream infections (bacteremia), including those with
right-sided infective endocarditis, caused by methicillin-susceptible and
methicillin-resistant isolates. Combination therapy may be clinically indicated
if the documented or presumed pathogens include Gram-negative or
anaerobic organisms.
The efficacy of CUBICIN in patients with left-sided infective endocarditis due
to S. aureus has not been demonstrated. The clinical trial of CUBICIN in
patients with S. aureus bloodstream infections included limited data from
patients with left-sided infective endocarditis; outcomes in these patients
were poor. CUBICIN has not been studied in patients with prosthetic valve
endocarditis or meningitis.
Patients with persisting or relapsing S. aureus infection or poor clinical
response should have repeat blood cultures. If a culture is positive for
www.cubicin.com
©2007 Cubist Pharmaceuticals, Inc.
3974071907 September 2007
CUBICIN is a registered trademark of Cubist Pharmaceuticals,Inc.
S. aureus, MIC susceptibility testing of the isolate should be performed
using a standardized procedure, as well as diagnostic evaluation to rule
out sequestered foci of infection. Appropriate surgical intervention (eg,
debridement, removal of prosthetic devices, valve replacement surgery)
and/or consideration of a change in antibiotic regimen may be required.
CUBICIN is not indicated for the treatment of pneumonia.
Clostridium difficile-associated diarrhea (CDAD) has been r eported with the
use of nearly all antibacterial agents, including CUBICIN, and may range in
severity from mild diarrhea to fatal colitis. CDAD has been reported to occur
over 2 months post-antibiotic treatment. If CDAD is suspected, antibiotic
treatment may need to be suspended.
Patients receiving CUBICIN should be monitored for the development of
muscle pain or weakness, particularly of the distal extremities. In patients
who receive CUBICIN, creatine phosphokinase (CPK) levels should be
monitored weekly, and more frequently in patients who received recent prior
or concomitant therapy with an HMG-CoA reductase inhibitor. In patients
with renal insufficiency, both renal function and CPK should be monitored
more frequently. Patients who demonstrate unexplained elevations in CPK
while receiving CUBICIN should be monitored more frequently.
CUBICIN should be discontinued in patients with unexplained signs and
symptoms of myopathy in conjunction with CPK elevation >1000 U/L
(~5X ULN), or in patients without reported symptoms who have marked
elevations in CPK >2000 U/L (≥10X ULN).
Most adverse events reported in CUBICIN clinical trials were mild to moderate
in intensity. The most common CUBICIN adverse events were anemia,
constipation, diarrhea, nausea,
vomiting, injection-site reactions,
and headache.
Please see Brief Summary
of Prescribing Information
on adjacent page.
Brief summary of prescribing information.
INDICATIONS AND USAGE CUBICIN (daptomycin for injection) is indicated
for the following infections (see also DOSAGE AND ADMINISTRATION and
CLINICAL STUDIES in full prescribing information): Complicated skin
and skin structure infections (cSSSI) caused by susceptible isolates
of the following Gram-positive microorganisms: Staphylococcus aureus
(including methicillin-resistant isolates), Streptococcus pyogenes, S. agalactiae, S. dysgalactiae subsp equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only). Combination therapy may be clinically
indicated if the documented or presumed pathogens include Gram-negative
or anaerobic organisms. Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis,
caused by methicillin-susceptible and methicillin-resistant isolates. Combination therapy may be clinically indicated if the documented or presumed
pathogens include Gram-negative or anaerobic organisms. The efficacy of
CUBICIN in patients with left-sided infective endocarditis due to S. aureus
has not been demonstrated. The clinical trial of CUBICIN in patients with
S. aureus bloodstream infections included limited data from patients with
left-sided infective endocarditis; outcomes in these patients were poor (see
CLINICAL STUDIES in full prescribing information). CUBICIN has not been
studied in patients with prosthetic valve endocarditis or meningitis. Patients
with persisting or relapsing S. aureus infection or poor clinical response
should have repeat blood cultures. If a culture is positive for S. aureus, MIC
susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci
of infection (see PRECAUTIONS). CUBICIN is not indicated for the treatment of pneumonia. Appropriate specimens for microbiological examination
should be obtained in order to isolate and identify the causative pathogens
and to determine their susceptibility to daptomycin. Empiric therapy may
be initiated while awaiting test results. Antimicrobial therapy should be
adjusted as needed based upon test results. To reduce the development
of drug-resistant bacteria and maintain the effectiveness of CUBICIN and
other antibacterial drugs, CUBICIN should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they
should be considered in selecting or modifying antibacterial therapy. In the
absence of such data, local epidemiology and susceptibility patterns may
contribute to the empiric selection of therapy.
CONTRAINDICATIONS CUBICIN is contraindicated in patients with
known hypersensitivity to daptomycin.
WARNINGS Clostridium difficile–associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including CUBICIN,
and may range in severity from mild diarrhea to fatal colitis. Treatment
with antibacterial agents alters the normal flora of the colon, leading to
overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C.
difficile cause increased morbidity and mortality, since these infections
can be refractory to antimicrobial therapy and may require colectomy.
CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD
has been reported to occur over 2 months after the administration of
antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.
Appropriate fluid and electrolyte management, protein supplementation,
antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
PRECAUTIONS General The use of antibiotics may promote the selection
of non-susceptible organisms. Should superinfection occur during therapy,
appropriate measures should be taken. Prescribing CUBICIN in the absence
of a proven or strongly suspected bacterial infection is unlikely to provide
benefit to the patient and increases the risk of the development of drugresistant bacteria. Persisting or Relapsing S. aureus Infection Patients
with persisting or relapsing S. aureus infection or poor clinical response
should have repeat blood cultures. If a culture is positive for S. aureus, MIC
susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci
of infection. Appropriate surgical intervention (eg, debridement, removal of
prosthetic devices, valve replacement surgery) and/or consideration of a
change in antibiotic regimen may be required. Failure of treatment due to
persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (15.8%) CUBICIN-treated patients (12 with
MRSA and 7 with MSSA) and 11/115 (9.6%) comparator-treated patients
(9 with MRSA treated with vancomycin and 2 with MSSA treated with antistaphylococcal semi-synthetic penicillin). Among all failures, 6 CUBICINtreated patients and 1 vancomycin-treated patient developed increasing
MICs (reduced susceptibility) by central laboratory testing on or following
therapy. Most patients who failed due to persisting or relapsing S. aureus
infection had deep-seated infection and did not receive necessary surgical
intervention (see CLINICAL STUDIES in full prescribing information).
Skeletal Muscle In a Phase 1 study examining doses up to 12 mg/kg
q24h of CUBICIN for 14 days, no skeletal muscle effects or CPK elevations
were observed. In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg,
elevations in CPK were reported as clinical adverse events in 15/534
(2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients. In the S. aureus bacteremia/endocarditis trial, at a
dose of 6 mg / kg, elevations in CPK were reported as clinical adverse
events in 8/120 (6.7%) CUBICIN-treated patients compared with 1/116
(<1%) comparator-treated patients. There were a total of 11 patients who
experienced CPK elevations to above 500 U/L. Of these 11 patients, 4 had
prior or concomitant treatment with an HMG-CoA reductase inhibitor. Skeletal muscle effects associated with CUBICIN were observed in animals (see
ANIMAL PHARMACOLOGY in full prescribing information). Patients receiving CUBICIN should be monitored for the development of muscle pain
or weakness, particularly of the distal extremities. In patients who receive
CUBICIN, CPK levels should be monitored weekly, and more frequently in
patients who received recent prior or concomitant therapy with an HMGCoA reductase inhibitor. In patients with renal insufficiency, both renal function and CPK should be monitored more frequently. Patients who develop
unexplained elevations in CPK while receiving CUBICIN should be monitored more frequently. In the cSSSI studies, among patients with abnormal
CPK (>500 U/L) at baseline, 2/19 (10.5%) treated with CUBICIN and 4/24
(16.7%) treated with comparator developed further increases in CPK while
on therapy. In this same population, no patients developed myopathy.
CUBICIN-treated patients with baseline CPK >500 U/L (N=19) did not experience an increased incidence of CPK elevations or myopathy relative to
those treated with comparator (N=24). In the S. aureus bacteremia/endocarditis study, 3 (2.6%) CUBICIN-treated patients, including 1 with trauma
associated with a heroin overdose and 1 with spinal cord compression, had
an elevation in CPK >500 U/L with associated musculoskeletal symptoms.
None of the patients in the comparator group had an elevation in CPK
>500 U/L with associated musculoskeletal symptoms. CUBICIN should be
discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation >1,000 U/L (~5x ULN), or in patients
without reported symptoms who have marked elevations in CPK >2,000
U/L (r10x ULN). In addition, consideration should be given to temporarily
suspending agents associated with rhabdomyolysis, such as HMG-CoA
reductase inhibitors, in patients receiving CUBICIN. In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no evidence
of nerve conduction deficits or symptoms of peripheral neuropathy was
observed. In a small number of patients in Phase 1 and Phase 2 studies at
doses up to 6 mg/kg, administration of CUBICIN was associated with
decreases in nerve conduction velocity and with adverse events (eg, paresthesias, Bell’s palsy) possibly reflective of peripheral or cranial neuropathy.
Nerve conduction deficits were also detected in a similar number of comparator subjects in these studies. In Phase 3 cSSSI and communityacquired pneumonia (CAP) studies, 7/989 (0.7%) CUBICIN-treated patients
and 7/1,018 (0.7%) comparator-treated patients experienced paresthesias. New or worsening peripheral neuropathy was not diagnosed in any of
these patients. In the S. aureus bacteremia/endocarditis trial, a total of
11/120 (9.2%) CUBICIN-treated patients had treatment-emergent adverse
events related to the peripheral nervous system. All of the events were
classified as mild to moderate in severity; most were of short duration and
resolved during continued treatment with CUBICIN or were likely due to an
alternative etiology. In animals, effects of CUBICIN on peripheral nerve were
observed (see ANIMAL PHARMACOLOGY in full prescribing information).
Therefore, physicians should be alert to the possibility of signs and symptoms of neuropathy in patients receiving CUBICIN. Drug Interactions
Warfarin Concomitant administration of CUBICIN (6 mg/kg q24h for 5
days) and warfarin (25 mg single oral dose) had no significant effect on the
pharmacokinetics of either drug, and the INR was not significantly altered.
As experience with the concomitant administration of CUBICIN and warfarin
is limited, anticoagulant activity in patients receiving CUBICIN and warfarin
should be monitored for the first several days after initiating therapy with
CUBICIN (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions in
full prescribing information). HMG-CoA Reductase Inhibitors Inhibitors
of HMG-CoA reductase may cause myopathy, which is manifested as
muscle pain or weakness associated with elevated levels of CPK. There
were no reports of skeletal myopathy in a placebo-controlled Phase 1 trial
in which 10 healthy subjects on stable simvastatin therapy were treated
concurrently with CUBICIN (4 mg/kg q24h) for 14 days. In the Phase 3 S.
aureus bacteremia/endocarditis trial, 5/22 CUBICIN-treated patients who
received prior or concomitant therapy with an HMG-CoA reductase inhibitor
developed CPK elevations >500 U/L. Experience with co-administration of
HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore,
consideration should be given to temporarily suspending use of HMG-CoA
reductase inhibitors in patients receiving CUBICIN (see ADVERSE
REACTIONS, Post-Marketing Experience). Drug-Laboratory Test
Interactions There are no reported drug-laboratory test interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term
carcinogenicity studies in animals have not been conducted to evaluate the
carcinogenic potential of daptomycin. However, neither mutagenic nor
clastogenic potential was found in a battery of genotoxicity tests, including
the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus
assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters. Daptomycin did not affect the fertility or
reproductive performance of male and female rats when administered
intravenously at doses up to 150 mg/kg/day, which is approximately 9
times the estimated human exposure level based upon AUCs. Pregnancy
Teratogenic Effects: Pregnancy Category B Reproductive and teratology studies performed in rats and rabbits at doses of up to 75 mg/kg, 2 and
4 times the 6 mg/kg human dose, respectively, on a body surface area
basis, have revealed no evidence of harm to the fetus due to daptomycin.
There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of
human response, this drug should be used during pregnancy only if clearly
needed. Nursing Mothers It is not known if daptomycin is excreted in
human milk. Caution should be exercised when CUBICIN is administered to
nursing women. Pediatric Use Safety and efficacy of CUBICIN in patients
under the age of 18 have not been established. Geriatric Use Of the 534
patients treated with CUBICIN in Phase 3 controlled clinical trials of cSSSI,
27.0% were 65 years of age or older and 12.4% were 75 years of age or
older. Of the 120 patients treated with CUBICIN in the Phase 3 controlled
clinical trial of S. aureus bacteremia/endocarditis, 25.0% were 65 years of
age or older and 15.8% were 75 years of age or older. In Phase 3 clinical
studies of cSSSI and S. aureus bacteremia/endocarditis, lower clinical success rates were seen in patients r65 years of age compared with those
<65 years of age. In addition, treatment-emergent adverse events were
more common in patients r65 years old than in patients <65 years of age.
ADVERSE REACTIONS Because clinical trials are conducted under
widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared with rates in the clinical trials
of another drug and may not reflect the rates observed in practice. The
adverse reaction information from clinical trials does, however, provide a
basis for identifying the adverse events that appear to be related to drug
use and for approximating rates. Clinical studies sponsored by Cubist enrolled 1,667 patients treated with CUBICIN and 1,319 treated with comparator. Most adverse events reported in Cubist-sponsored Phase 1, 2, and
3 clinical studies were described as mild or moderate in intensity. In Phase
3 cSSSI trials, CUBICIN was discontinued in 15/534 (2.8%) patients due to
an adverse event, while comparator was discontinued in 17/558 (3.0%)
patients. In the S. aureus bacteremia/endocarditis trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse event, while
comparator was discontinued in 21/116 (18.1%) patients. GramNegative Infections In the S. aureus bacteremia/endocarditis trial, serious Gram-negative infections and nonserious Gram-negative bloodstream
infections were reported in 10/120 (8.3%) CUBICIN-treated and 0/115
comparator-treated patients. Comparator patients received dual therapy
that included initial gentamicin for 4 days. Events were reported during
treatment and during early and late follow-up. Gram-negative infections
included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn’s disease, recurrent line sepsis, and
recurrent urosepsis caused by a number of different Gram-negative organisms. One patient with sternal osteomyelitis following mitral valve repair
developed S. aureus endocarditis with a 2 cm mitral vegetation and had a
course complicated with bowel infarction, polymicrobial bacteremia, and
death. Other Adverse Reactions The incidence (%) of adverse events
that occurred in r2% of patients in either CUBICIN 4 mg/kg (N=534) or
comparator* (N=558) treatment groups in Phase 3 cSSSI studies were as
follows: Gastrointestinal disorders: constipation 6.2% and 6.8%; nausea
5.8% and 9.5%; diarrhea 5.2% and 4.3%; vomiting 3.2% and 3.8%; dys-
pepsia 0.9% and 2.5%; General disorders: injection site reactions 5.8%
and 7.7%; fever 1.9% and 2.5%; Nervous system disorders: headache
5.4% and 5.4%; insomnia 4.5% and 5.4%; dizziness 2.2% and 2.0%;
Skin/subcutaneous disorders: rash 4.3% and 3.8%; pruritus 2.8% and
3.8%; Diagnostic investigations: abnormal liver function tests 3.0% and
1.6%; elevated CPK 2.8% and 1.8%; Infections: fungal infections 2.6%
and 3.2%; urinary tract infection 2.4% and 0.5%; Vascular disorders:
hypotension 2.4% and 1.4%; hypertension 1.1% and 2.0%; Renal/urinary
disorders: renal failure 2.2% and 2.7%; Blood/lymphatic disorders: anemia 2.1% and 2.3%; Respiratory disorders: dyspnea 2.1% and 1.6%;
Musculoskeletal disorders: limb pain 1.5% and 2.0%; arthralgia 0.9% and
2.2%. *Comparators included vancomycin (1 g IV q12h) and anti-staphylococcal semi-synthetic penicillins (ie, nafcillin, oxacillin, cloxacillin, flucloxacillin; 4 to 12 g/day IV in divided doses). The incidence (%) of adverse
events that occurred in r5% of patients organized by system organ class
(SOC), in either CUBICIN 6 mg/kg (N=120) or comparator† (N=116) treatment groups in the S. aureus bacteremia/endocarditis study were as follows:
Infections and infestations: 65 (54.2%) and 56 (48.3%); urinary tract
infection NOS 8 (6.7%) and 11 (9.5%); osteomyelitis NOS 7 (5.8%) and 7
(6.0%); sepsis NOS 6 (5.0%) and 3 (2.6%); bacteraemia 6 (5.0%) and 0
(0%); pneumonia NOS 4 (3.3%) and 9 (7.8%); Gastrointestinal disorders:
60 (50.0%) and 68 (58.6%); diarrhoea NOS 14 (11.7%) and 21 (18.1%);
vomiting NOS 14 (11.7%) and 15 (12.9%); constipation 13 (10.8%) and
14 (12.1%); nausea 12 (10.0%) and 23 (19.8%); abdominal pain NOS 7
(5.8%) and 4 (3.4%); dyspepsia 5 (4.2%) and 8 (6.9%); loose stools 5
(4.2%) and 6 (5.2%); gastrointestinal haemorrhage NOS 2 (1.7%) and 6
(5.2%); General disorders and administration site conditions: 53 (44.2%)
and 69 (59.5%); oedema peripheral 8 (6.7%) and 16 (13.8%); pyrexia 8
(6.7%) and 10 (8.6%); chest pain 8 (6.7%) and 7 (6.0%); oedema NOS 8
(6.7%) and 5 (4.3%); asthenia 6 (5.0%) and 6 (5.2%); injection site erythema 3 (2.5%) and 7 (6.0%); Respiratory, thoracic, and mediastinal disorders: 38 (31.7%) and 43 (37.1%); pharyngolaryngeal pain 10 (8.3%)
and 2 (1.7%); pleural effusion 7 (5.8%) and 8 (6.9%); cough 4 (3.3%) and
7 (6.0%); dyspnoea 4 (3.3%) and 6 (5.2%); Skin and subcutaneous tissue
disorders: 36 (30.0%) and 40 (34.5%); rash NOS 8 (6.7%) and 10 (8.6%);
pruritus 7 (5.8%) and 6 (5.2%); erythema 6 (5.0%) and 6 (5.2%); sweating
increased 6 (5.0%) and 0 (0%); Musculoskeletal and connective tissue
disorders: 35 (29.2%) and 42 (36.2%); pain in extremity 11 (9.2%) and 11
(9.5%); back pain 8 (6.7%) and 10 (8.6%); arthralgia 4 (3.3%) and 13
(11.2%); Psychiatric disorders: 35 (29.2%) and 28 (24.1%); insomnia 11
(9.2%) and 8 (6.9%); anxiety 6 (5.0%) and 6 (5.2%); Nervous system
disorders: 32 (26.7%) and 32 (27.6%); headache 8 (6.7%) and 12
(10.3%); dizziness 7 (5.8%) and 7 (6.0%); Investigations: 30 (25.0%) and
33 (28.4%); blood creatine phosphokinase increased 8 (6.7%) and 1
(<1%); Blood and lymphatic system disorders: 29 (24.2%) and 24
(20.7%); anaemia NOS 15 (12.5%) and 18 (15.5%); Metabolism and nutrition disorders: 26 (21.7%) and 38 (32.8%); hypokalaemia 11 (9.2%) and
15 (12.9%); hyperkalaemia 6 (5.0%) and 10 (8.6%); Vascular disorders:
21 (17.5%) and 20 (17.2%); hypertension NOS 7 (5.8%) and 3 (2.6%);
hypotension NOS 6 (5.0%) and 9 (7.8%); Renal and urinary disorders:
18 (15.0%) and 26 (22.4%); renal failure NOS 4 (3.3%) and 11 (9.5%);
renal failure acute 4 (3.3%) and 7 (6.0%). †Comparator: vancomycin (1 g
IV q12h) or anti-staphylococcal semi-synthetic penicillin (ie, nafcillin,
oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), each with initial low-dose
gentamicin. The following events, not included above, were reported as
possibly or probably drug-related in the CUBICIN-treated group: Blood
and Lymphatic System Disorders: eosinophilia (1.7%), lymphadenopathy
(<1%), thrombocythaemia (<1%), thrombocytopenia (<1%); Cardiac
Disorders: atrial fibrillation (<1%), atrial flutter (<1%), cardiac arrest
(<1%); Ear and Labyrinth Disorders: tinnitus (<1%); Eye Disorders: vision
blurred (<1%); Gastrointestinal Disorders: dry mouth (<1%), epigastric
discomfort (<1%), gingival pain (<1%), hypoaesthesia oral (<1%); Infections and Infestations: candidal infection NOS (1.7%), vaginal candidiasis
(1.7%), fungaemia (<1%), oral candidiasis (<1%), urinary tract infection
fungal (<1%); Investigations: blood phosphorous increased (2.5%), blood
alkaline phosphatase increased (1.7%), INR ratio increased (1.7%), liver
function test abnormal (1.7%), alanine aminotransferase increased (<1%),
aspartate aminotransferase increased (<1%), prothrombin time prolonged
(<1%); Metabolism and Nutrition Disorders: appetite decreased NOS
(<1%); Musculoskeletal and Connective Tissue Disorders: myalgia (<1%);
Nervous System Disorders: dyskinesia (<1%), paraesthesia (<1%); Psychiatric Disorders: hallucination NOS (<1%); Renal and Urinary Disorders:
proteinuria (<1%), renal impairment NOS (<1%); Skin and Subcutaneous
Tissue Disorders: heat rash (<1%), pruritus generalized (<1%), rash
vesicular (<1%). In Phase 3 studies of community-acquired pneumonia
(CAP), the death rate and rates of serious cardiorespiratory adverse events
were higher in CUBICIN-treated patients than in comparator-treated
patients. These differences were due to lack of therapeutic effectiveness of
CUBICIN in the treatment of CAP in patients experiencing these adverse
events (see INDICATIONS AND USAGE). The incidence of decreased
renal function based on creatinine clearance levels in CUBICIN 6 mg/kg
(N=120) and comparator† (N=116) was as follows: Days 2 to 4, 2/96
(2.1%) and 6/90 (6.7%); Days 2 to 7, 6/115 (5.2%) and 16/113 (14.2%);
Day 2 to End of Therapy, 13/118 (11.0%) and 30/114 (26.3%). †Comparator: vancomycin (1 g IV q12h) or anti-staphylococcal semi-synthetic penicillin (ie, nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), each with
initial low-dose gentamicin. Post-Marketing Experience The following
adverse reactions have been reported with CUBICIN in worldwide postmarketing experience. Because these events are reported voluntarily from
a population of unknown size, estimates of frequency cannot be made and
causal relationship cannot be precisely established. Immune System Disorders: anaphylaxis; hypersensitivity reactions, including pruritus, hives,
shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia. Musculoskeletal System: rhabdomyolysis; some reports
involved patients treated concurrently with CUBICIN and HMG-CoA reductase inhibitors.
OVERDOSAGE In the event of overdosage, supportive care is advised with
maintenance of glomerular filtration. Daptomycin is slowly cleared from the
body by hemodialysis (approximately 15% recovered over 4 hours) or peritoneal dialysis (approximately 11% recovered over 48 hours). The use of
high-flux dialysis membranes during 4 hours of hemodialysis may increase
the percentage of dose removed compared with low-flux membranes.
DOSAGE The recommended dosage of CUBICIN (daptomycin for injection)
in adult patients is as follows: Creatinine clearance (CLCR ) r30 mL/min:
4 mg/kg once every 24 hours (cSSSI) or 6 mg/kg once every 24 hours
(S. aureus bloodstream infections); Creatinine clearance (CLCR ) <30 mL/
min, including hemodialysis or CAPD: 4 mg/kg once every 48 hours (cSSSI)
or 6 mg/kg once every 48 hours (S. aureus bloodstream infections).
3985072607
CUBICIN is a registered trademark of
Cubist Pharmaceuticals, Inc.
©2003–2007 Cubist Pharmaceuticals, Inc.
SCHIZOPHRENIA: A REVIEW OF TREATMENTS
Affective flattening: restricted emotional expression
Akathisia: uncontrollable motor restlessness
Alogia: restricted speech
Avolition: lack of goal-directed behavior
Dystonia: abnormal muscle tone, e.g., rigidity
Pseudoparkinsonism: drug-induced syndrome
resembling parkinsonism
Researchers continue to explore the roles that neurotransmitters other than dopamine, such a serotonin and
acetylcholine, might play in schizophrenia.1
TREATMENT
Owing to the complex nature of schizophrenia, treatment typically involves both pharmacologic and nonpharmacologic therapies.
Nonpharmacologic Therapies
Although nonpharmacologic interventions may be perceived as treatment modalities that cannot change the
biochemistry of schizophrenia, they can help patients
learn how to cope with their illness. Fostering healthy
relationships, maintaining employment, learning from
others who struggle with mental illness, and participating in cognitive behavioral therapy can all be
effective components of a patient’s treatment.5
A 2-year randomized study compared the effect of
integrated treatment versus standard treatment in
547 newly diagnosed schizophrenia patients. Standardtreatment patients were offered access to a community
mental-health center and received minimal home visits; integrated-treatment patients received home visits
from an assigned assertive community-treatment team
member and were offered family treatment sessions and
social-skills training. Both arms were offered antipsychotic medications. Patients in the integrated-treatment arm showed clinically significant improvement
in positive and negative symptoms and substance abuse,
but no improvement in depression or suicidal behavior. The integrated-treatment group had a statistically
significant decrease in hospital stays during the first
year, but the difference was not significant at 2 years.
Finally, the mean antipsychotic dose for patients in the
integrated-treatment arm was significantly lower.6 This
trial illustrates that psychiatric care has a positive impact
on a patient’s life when pharmacotherapy is augmented
with lifestyle coaching and family involvement.
Pharmacotherapy
Most patients with schizophrenia require chronic treatment with medications to control symptoms and achieve
remission. Once a patient attains a satisfactory clinical response, the regimen should continue indefinitely.
First-line medication options include first- and secondgeneration antipsychotics.1
First-Generation Antipsychotics (FGAs): FGAs, also
known as conventional or typical antipsychotics, work
via dopamine receptor antagonism.1 TABLE 2 includes
a list of FGAs. This class of antipsychotics is associated with movement disorders, including extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Symptoms of EPS include akathisia, dystonia, and
pseudoparkinsonism (see TABLE 1). Akathisia can be
treated either by lowering the antipsychotic dosage or
with benzodiazepines or centrally acting beta-blockers such as propranolol; dystonia and pseudoparkinsonism can be treated with anticholinergic agents such
as benztropine or diphenhydramine.1 TD, which typically presents as abnormal orofacial movements, develops in 30% of patients on long-term FGAs. Unlike
EPS, TD cannot be treated with medications, and it
may be irreversible even after the offending antipsychotic is discontinued.1
Second-Generation Antipsychotics (SGAs): Whereas
FGAs work primarily as dopamine-2 receptor antagonists, the mechanisms are much broader for SGAs (also
known as atypical antipsychotics). In addition to having an antagonistic effect on dopamine, SGAs also
antagonize norepinephrine and serotonin receptors
(TABLE 2). Aripiprazole has a unique mechanism of
action involving mixed dopaminergic agonism and
antagonism in addition to antagonism of serotonergic
receptors.1
Owing to serotonergic antagonism, SGAs are not
associated with high rates of EPS, with the exception
of aripiprazole, which causes akathisia in approximately
10% of patients. 7 Although patients taking SGAs
usually do not experience movement-disorder issues,
SGAs come with new risks that may negatively affect
patient adherence. Clozapine and olanzapine are
associated with metabolic syndrome, specifically weight
gain, diabetes, and dyslipidemia; other atypical antipsychotics, however, offer minimal to no risk of these
metabolic effects. 8 Clozapine also carries a risk of
seizures, anticholinergic effects, hypersalivation, myocarditis, and agranulocytosis.9 The incidence of agranulocytosis in patients taking clozapine is 0.39%, and the
incidence of death from agranulocytosis is 0.012%.10
The FDA requires all providers prescribing clozapine
to be registered with the Clozaril National Registry.
Absolute neutrophil counts must be monitored weekly
for 6 months when therapy is initiated or adjusted, and
continuously throughout the course of therapy.1 Risperidone and paliperidone are associated with hyperprolactinemia, leading to acute adverse events such as galac-
HS-5
U.S. Pharmacist • November 2009 • www.uspharmacist.com
H E A LT H S Y S T E M S E D I T I O N
Table 1
Glossary of Some
Schizophrenia Symptoms
SCHIZOPHRENIA: A REVIEW OF TREATMENTS
H E A LT H S Y S T E M S E D I T I O N
Table 2
Dosing of Conventional and Atypical Antipsychotics
Drug Name
Starting Daily Dose
Target Daily Dose or Range
Schedule
Chlorpromazine (Thorazine)
50-100 mg
300-1,000 mg
3 times dailya
Fluphenazine (Prolixin)
5 mg
5-20 mg
3 times dailya
Haloperidol (Haldol)
2-5 mg
2-20 mg
1-3 times dailya
Perphenazine (Trilafon)
4-8 mg
16-64 mg
3 times dailya
Thiothixene (Navane)
4-10 mg
15-20 mg
2-3 times dailya
Trifluoperazine (Stelazine)
4-10 mg
5-20 mg
Twice dailya
Aripiprazole (Abilify)
10-15 mg
10-15 mg
Once daily
Clozapine (Clozaril)
12.5-25 mg
300-450 mg
1-2 times daily
Iloperidone (Fanapt)
2 mg
12-24 mg
Twice dailya
Olanzapine (Zyprexa)
5-10 mg
20 mg
Once daily
Paliperidone (Invega)
6 mg
6 mg
Once daily
Risperidone (Risperdal)
2 mg
2-8 mg
1-2 times dailya
Quetiapine IR (Seroquel IR)
50 mg
300-400 mg
2-3 times daily
Quetiapine XR (Seroquel XR)
300 mg
400-800 mg
Once daily
Ziprasidone (Geodon)
40 mg
40-160 mg
Twice daily, with food
Fluphenazine decanoate
(Prolixin Decanoate)
12.5-25 mg IM
every 1-3 wk
6.25-50 mg IM
every 2-4 wk
Every 1-3 wk
Haloperidol decanoate
(Haldol Decanoate)
25-50 mg IM
every 2-4 wk
50-200 mg IM
every 2-4 wk
Every 3-4 wk
Risperidone (Risperdal Consta)
12.5 mg IM every 2 wk
25 mg IM every 2 wk
Every 2 wk
Conventional Antipsychotics (FGAs)
Atypical Antipsychotics (SGAs)
Long-Acting Depot Injections
a
The total daily dose of most antipsychotics can be administered once daily if tolerated. Exceptions are clozapine, quetiapine, and
ziprasidone, which likely will require multiple daily doses to control symptoms.
FGA: first-generation antipsychotic; IM: intramuscularly; SGA: second-generation antipsychotic.
Source: Reference 22.
torrhea (spontaneous flow of milk from nipple), amenorrhea (absence of menses), and sexual dysfunction.
Osteoporosis may be a long-term effect of hyperprolactinemia.9,11
Both conventional and atypical agents, particularly
haloperidol, chlorpromazine, iloperidone, thioridazine,
and ziprasidone, are associated with prolongation of
the QTc interval, with the last two agents having the
highest incidence.9,12,13 The incidence of QTc prolongation with these agents is approximately twice that
of a healthy population not taking antipsychotics.14
Providers must always consider the side effects of antipsychotics and discuss them with their patients prior to
prescribing.
There is very little literature supporting the idea that
SGAs are more effective than FGAs. A number of metaanalyses have been published comparing the efficacy
of the two classes, as have meta-analyses comparing various SGAs with one another, but no conclusions have
been made about the comparative efficacy of the various agents.9,15,16 Both CUtLASS (Cost Utility of the
Latest Antipsychotic Drugs in Schizophrenia Study)
and CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) showed that atypical antipsychotics
offer no benefit over conventional antipsychotics; however, CATIE 2 concluded that clozapine may have an
advantage over other atypical antipsychotics in treatment-refractory patients.17-19 Clozapine’s benefit may
be a result of the increase in provider interaction due
to monitoring for agranulocytosis.20
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U.S. Pharmacist • November 2009 • www.uspharmacist.com
SCHIZOPHRENIA: A REVIEW OF TREATMENTS
H E A LT H S Y S T E M S E D I T I O N
• Atypical antipsychotic
Stage 1
Stage 2
Stage 3
Stage 4
• Atypical or conventional antipsychotic
• Not the same atypical from stage 1
• Clozapine
• May try earlier if history of recurrent suicidality, violence,
or substance abuse
• Clozapine plus
• Conventional or atypical antipsychotic or ECT
will improve adherence. Exceptions to
this are clozapine, quetiapine, and
ziprasidone, which probably will require
multiple daily doses to control symptoms. Finally, treatment with multiple
antipsychotics should be considered a
last resort and avoided if at all possible, as it often provides no additional
efficacy and increases the risk of intolerable side effects.
In general, FGAs are more affordable than SGAs, with perphenazine and
fluphenazine costing more than other
FGAs. Currently, the only generic SGAs
are clozapine and risperidone. Cost
should be a major consideration when
choosing an antipsychotic, with a preference for FGAs if a patient can tolerate them.
• Trial of single atypical or conventional agent not tried in
stages 1 and 2
Other Medications: Whereas antipsychotics remain the primary pharmacologic treatment for schizophrenia, a
• Combination therapy, such as atypical plus conventional antipsychotic;
number of other medications may be
combination of atypical and/or conventional antipsychotics plus ECT;
used to augment them. One such class
or
conventional
or
atypical
antipsychotic
plus
mood
stabilizer
Stage 6
is the mood stabilizers, which often
are used in patients experiencing increased
agitation or aggression. Overall, patients
Source: Reference 29. Adapted with permission of the Texas Department of State
with schizophrenia are not violent;
Health Services.
however, episodes in which positive
ECT: electroconvulsive therapy.
symptoms are exacerbated may lead to
Figure 1. Algorithm for the treatment of schizophrenia. A patient should progress
increased agitation. 3 During such
to the next stage if he or she experiences a partial response or nonresponse to
instances, mood stabilizers may be benthe current stage.
eficial. In a meta-analysis of 11 studies comparing antipsychotic monotherImprovements in sleep disturbance and agitation apy with lithium augmentation, more patients receiving
may be seen in the first 2 days of antipsychotic ther- lithium had a clinically significant response, with a
apy; however, the full effect may not be seen for 6 to number needed to treat of 8.23 Two small studies have
8 weeks. If the patient reports no symptom relief in 2 compared antipsychotic monotherapy with carbato 4 weeks, either the antipsychotic dose should be mazepine augmentation; in these studies, patients on
carbamazepine showed clinically significant overall
increased or a new agent should be selected.1,21
Recommended doses of FGAs and SGAs are given global improvement. 24 Similarly, there is only limin TABLE 2.22 These doses have been suggested by the ited evidence to support the use of augmentation thermanufacturers of the respective agents; however, apy with valproate, including a single small study showpractitioners often prescribe outside of the recom- ing less agitation in the valproate augmentation group
mended range. While this often is unavoidable in treat- versus the antipsychotic monotherapy group.25 A metament-resistant patients, the practice may result in adverse analysis of five studies evaluating the efficacy of antipsyevents and limited additional efficacy. Also, many chotic augmentation with lamotrigine showed that
patients probably will not require the higher end of 20% to 30% of clozapine-resistant patients with
the dosing range for FGAs. Specifically, patients schizophrenia had a clinically significant improvement
experiencing their first psychotic break will likely respond when lamotrigine was added.26 In a randomized, douto much lower doses of antipsychotics and be more ble-blind, placebo-controlled study of patients with
sensitive to adverse events than a patient in a more schizophrenia, the addition of topiramate resulted in
advanced stage of schizophrenia.21 Additionally, it should a reduction of both positive and negative symptoms
be noted that the total daily dose of most antipsychotics compared with patients on antipsychotic monothercan be administered once daily if tolerated, and this apy.27 Mood stabilizers have great potential for the
Stage 5
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U.S. Pharmacist • November 2009 • www.uspharmacist.com
SCHIZOPHRENIA: A REVIEW OF TREATMENTS
ADHERENCE
A number of studies have been designed to measure
patient adherence to antipsychotics compared with
other medications, but the results are difficult to interpret. This is primarily because each study defines and
measures nonadherence differently. A meta-analysis
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treatment of schizophrenia. Am J Psychiatry. 2009;166:152-163.
16. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60:553-564.
of adherence studies reported that patients take an average of 58% of their prescribed antipsychotic doses
(range 24%-90%). The meta-analysis found that patients
take medications for physical ailments an average of
76% of the time (range 60%-92%), implying that
adherence to antipsychotics may be lower than adherence to other medications.30 Some barriers to care in
patients with schizophrenia include stigma about mental illness, lack of access to care, and fragmentation of
services.5 A pharmacist can help a patient overcome
these barriers through education and identification of
patient-assistance programs when financial issues arise.
Additionally, the pharmacist may recommend the use
of long-acting depot antipsychotic injections to improve
adherence to medication therapy. Recommended doses
of depot antipsychotics are given in TABLE 2.
CONCLUSION
Despite the fact that there is no cure for schizophrenia, providing patients with guideline-based treatments
supported by primary literature will afford the best
opportunity for controlling the symptoms of their illness. The process of choosing appropriate medications
and monitoring for appropriate adverse reactions should
be facilitated by a pharmacist whenever possible.
17. Jones PB, Barnes TRE, Davies L, et al. Randomized controlled trial
of the effect on quality of life of second- and first-generation antipsychotic drugs on schizophrenia: Cost Utility of the Latest Antipsychotic
Drugs in Schizophrenia Study (CUtLASS I). Arch Gen Psychiatry.
2006;63:1079-1087.
18. Lieberman JA, Stroup TS, McEvoy JP, et al, for the Clinical
Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators.
Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.
19. McEvoy JP, Lieberman JA, Stroup TS, et al, for the CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and
risperidone in patients with chronic schizophrenia who did not respond
to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:
600-610.
20. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60:82-91.
21. APA Practice Guidelines. Lehman AF, Lieberman JA, Dixon LB, et
al. Practice guideline for the treatment of patients with schizophrenia.
2nd ed. www.psychiatryonline.com/pracGuide/loadGuidelinePdf
.aspx?file=Schizophrenia2e_Inactivated_04-16-09. Accessed October 13,
2009.
22. Micromedex Healthcare Series [Intranet database]. Greenwood Village, CO: Thomson Healthcare. Accessed October 13, 2009.
23. Leucht S, Kissling W, McGrath J. Lithium for schizophrenia.
Cochrane Database Syst Rev. 2007;(3):CD003834.
24. Leucht S, Kissling W, McGrath J. Carbamazepine for schizophrenia.
Cochrane Database Syst Rev. 2007;(3):CD001258.
25. Schwarz C, Volz A, Li C, Leucht S. Valproate for schizophrenia.
Cochrane Database Syst Rev. 2008;(3):CD004028.
26. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in
clozapine-resistant schizophrenia: a systematic review and meta-analysis.
Schizophr Res. 2009;109:10-14.
27. Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled
clinical trial. J Psychopharmacol. 2009;23:157-162.
28. Volz A, Khorsand V, Gillies D, Leucht S. Benzodiazepines for
schizophrenia. Cochrane Database Syst Rev. 2007;(1):CD006391.
29. Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication
Algorithm Project antipsychotic algorithm for schizophrenia: 2006
update. J Clin Psychiatry. 2007;68:1751-1762.
30. Cramer JA, Rosenheck R. Compliance with medication regimens for
mental and physical disorders. Psychiatr Serv. 1998;49:196-201.
HS-9
U.S. Pharmacist • November 2009 • www.uspharmacist.com
H E A LT H S Y S T E M S E D I T I O N
treatment of schizophrenia, but more research is needed.
Benzodiazepines have been studied for their benefits in augmenting antipsychotics. Although the studies have been small, they have shown some advantage
over antipsychotic monotherapy in treating agitation
in schizophrenia. This effect is short-lived, however,
with a return of symptoms within 1 hour of a benzodiazepine dose.28
One of the most straightforward algorithms for
the treatment of schizophrenia was published by the
Texas Department of State Health Services (FIGURE 1).
This algorithm is based on evidence when available,
and expert consensus where no evidence exists. If a
patient fails trials of two stages of this algorithm with
no appreciable improvement in symptoms, the diagnosis of schizophrenia should be re-evaluated, and
the possibility of co-occurring substance abuse should
be considered.29
H E A LT H S Y S T E M S E D I T I O N
© JUPITERIMAGES
Prophylactic Therapies in
Traumatic Brain Injury
Management
T
raumatic brain injury (TBI), defined as a strong
impact to the head or a penetrating head injury
that alters the function of the brain, affects the
lives of approximately 1.4 million people in the United
States each year.1 TBI currently accounts for an estimated 1.1 million emergency department admissions
and 50,000 deaths annually. Individuals at highest risk
for TBI are young children 6 months to 4 years old,
males between the ages of 15 and 30 years, elderly individuals (aged 75 years or older), and certain military
personnel. According to the CDC, the leading causes
of TBI include falls (28%), motor vehicle crashes (20%),
events in which a person is struck by or against an
object (19%), and assaults (11%).1
blast wounds are the result of a combination of blunt
and penetrating injuries.
In addition to identifying the mechanism of
injury, TBI is also separated into either primary or secondary injury.2 A primary injury occurs at the time of
injury and directly damages neuronal tissue. Resultant lesions from a primary injury are either focal, where
the injury is in a localized area of the brain, or diffuse, in which the injury is large and widespread. The
secondary injury that occurs from TBI is not initially
seen; instead it is the result of a normal physiological
response to the primary injury, such as tissue hypoxia,
that develops over a period of time from hours to
months following the primary injury.2
For decades, the concentration of TBI management
Types of Injuries
was on maintaining the control of intracranial pressure
To appropriately treat and provide care to patients (ICP) and cerebral perfusion pressure. As will be diswith TBI, it is important to understand the mecha- cussed, the focus of TBI management no longer resides
nism and pathophysiology behind the injury. There in one central area; instead, managing all aspects of
are three key mechanisms of injury—blunt, pene- TBI are now important areas of therapeutic decision
trating, and blast, which are further
making. Building upon the 2007
Jennifer Confer, PharmD
divided into primary or secondary
Guidelines for the Management of
Critical Care Clinical Specialist
injuries.2 Blunt injuries are the most
Severe Traumatic Brain Injury, this
Cabell Huntington Hospital
Clinical Assistant Professor, West Virginia
common cause of TBI and are frearticle will focus on prophylactic
University School of Pharmacy
quently the result of motor vehicle
therapies currently being used and
Huntington, West Virginia
(i.e., automobile, motorcycle, pedesrecommended in patients with TBI
Jon Wietholter, PharmD
trian) crashes, falls, sports-related
(TABLE 1).
Internal Medicine Clinical Specialist
injuries, and assaults. Penetrating
Cabell Huntington Hospital
Prophylactic Steroids
injuries result when any sharp or
Clinical Assistant Professor, West Virginia
Beneficial effects of corticosteroids
blunt object penetrates the scalp or
University School of Pharmacy
in TBI were originally discovered in
skull (e.g., gunshot wounds). Lastly,
Huntington, West Virginia
HS-10
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Fentanyl transdermal system should
ONLY be used in patients who are already
receiving opioid therapy, who have
demonstrated opioid tolerance, and
who require a total daily dose at least
equivalent to fentanyl transdermal system
25 mcg/hr. Patients who are considered
opioid-tolerant are those who have been
taking, for a week or longer, at least 60 mg
of morphine daily, or at least 30 mg of oral
oxycodone daily, or at least 8 mg of oral
hydromorphone daily or an equianalgesic
dose of another opioid.
Because serious or life-threatening
hypoventilation could occur, fentanyl
transdermal system is contraindicated:
• in patients who are not opioid-tolerant
• in the management of acute pain or in
patients who require opioid analgesia
for a short period of time
• in the management of postoperative
pain, including use after out patient
or day surgeries (e.g., tonsillectomies)
• in the management of mild pain
• in the management of intermittent
pain [e.g., use on an as needed basis
(prn)]
The safety of fentanyl transdermal system
has not been established in children under
2 years of age. Fentanyl transdermal
system should be administered to children
only if they are opioid-tolerant and 2 years
of age or older (see PRECAUTIONS:
Pediatric Use).
Patients using fentanyl transdermal system
should avoid exposure to external heat
sources, such as heating pads, hot tubs,
long hot baths, and sunbathing. An increase
in body temperature may result in a sudden
and possible dangerous rise in their body
fentanyl level. Fentanyl transdermal
system may cause death from overdosage;
therefore, it is important for healthcare
professionals, patients and caregivers to
know the signs of fentanyl overdose, which
can include trouble breathing and extreme
sleepiness. Fentanyl transdermal system
should be stored in a safe place and
kept out of the reach of children. Used,
unneeded or defective fentanyl patches
should be safely disposed of by folding
the sticky side of the patch together
(until it sticks to itself) and flushing it
down the toilet.
The most common adverse events reported
in clinical trials were fever, nausea, vomiting,
constipation, dry mouth, somnolence,
confusion, asthenia, and sweating.
Please see adjacent Brief Summary
of Prescribing Information, including
BOXED WARNING.
In the management of persistent, moderate to severe chronic pain that requires
continuous, around-the-clock opioid administration for
an extended period of time and cannot be managed by other means*
Why Take A Chance With
Other Fentanyl Patches?
One patch can cause burns.
This matrix patch contains aluminum in its backing, which can
overheat during a magnetic resonance imaging (MRI) scan and
burn the patient who is wearing it.
Other patches can leak.
They contain a reservoir of fentanyl gel that can leak and cause
potentially life-threatening complications.
Mylan FENTANYL is the first marketed
fentanyl patch designed to avoid the
risks associated with burns and leaks.
The Mylan FENTANYL TRANSDERMAL
SYSTEM CII has no aluminum or other
metals in its backing. Also important
to patient safety, Mylan Fentanyl has a
proprietary matrix design without a
liquid, gel-filled reservoir that can leak.
It is an innovative solution in transdermal
drug delivery.
*Other means include non-steroidal analgesics, opioid combination products, or immediate-release opioids.
©2009 Mylan Pharmaceuticals Inc. MYNFEN031
No metal. No burns. No leaks.
FENTANYL TRANSDERMAL SYSTEM
BRIEF SUMMARY: Please see package insert for full prescribing information.
FOR USE IN OPIOID-TOLERANT PATIENTS ONLY
Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl.
Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and
oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory
depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the
patches (fentanyl transdermal system) may be a particular target for abuse and diversion.
Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that:
• requires continuous, around-the-clock opioid administration for an extended period of time, and
• cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or
immediate-release opioids
Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who
have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr. Patients who are considered opioid-tolerant are those who have been taking, for a
week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of
oral hydromorphone daily or an equianalgesic dose of another opioid.
Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated:
• in patients who are not opioid-tolerant
• in the management of acute pain or in patients who require opioid analgesia for a short period of time
• in the management of postoperative pain, including use after out patient or day surgeries (e.g., tonsillectomies)
• in the management of mild pain
• in the management of intermittent pain [e.g., use on an as needed basis (prn)]
(See CONTRAINDICATIONS for further information.)
Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers should be aware that
serious or life-threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period.
The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as
ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone,
amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil)
may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug
effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal
system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage
adjustments should be made if warranted (see CLINICAL PHARMACOLOGY: Drug Interactions, WARNINGS,
PRECAUTIONS and DOSAGE AND ADMINISTRATION in full prescribing information for further information). The
safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl
transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or
older (see PRECAUTIONS: Pediatric Use in full prescribing information).
Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid-tolerant patients may lead to fatal respiratory depression. Overestimating the
fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal
overdose with the first dose. Due to the mean elimination half-life of 17 hours of fentanyl transdermal system,
patients who are thought to have had a serious adverse event, including overdose, will require monitoring and
treatment for at least 24 hours.
Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. This
risk should be considered when administering, prescribing, or dispensing fentanyl transdermal system in
situations where the healthcare professional is concerned about increased risk of misuse, abuse or diversion.
Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse
(including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be
assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients
receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. Patients at
increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations;
however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction.
Fentanyl transdermal system patches are intended for transdermal use (on intact skin) only. Do not use a
fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.
Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat
sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water
beds, while wearing the system. Avoid taking hot baths or sunbathing. There is a potential for temperaturedependent increases in fentanyl released from the system resulting in possible overdose and death. Patients
wearing fentanyl transdermal systems who develop fever or increased core body temperature due to
strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose
should be adjusted if necessary.
INDICATIONS AND USAGE: Fentanyl transdermal system is indicated for management of persistent, moderate to severe
chronic pain that:
• requires continuous, around-the-clock opioid administration for an extended period of time, and
• cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or
immediate-release opioids
Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have
demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system
25 mcg/hr (see DOSAGE AND ADMINISTRATION in full prescribing information). Patients who are considered
opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least
30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.
Because serious or life-threatening hypoventilation could result, fentanyl transdermal system is contraindicated
for use on an as needed basis (i.e., prn), for the management of postoperative or acute pain, or in patients who are not
opioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS).
An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior
to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case,
initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal
anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World
Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy,
or the American Pain Society.
Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.
Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at
increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or
alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be
appropriately treated with modified-release opioid formulations; however these patients will require intensive
monitoring for signs of misuse, abuse, or addiction.
CONTRAINDICATIONS: Because serious or life-threatening hypoventilation could occur, fentanyl transdermal
system is contraindicated:
• in patients who are not opioid-tolerant
• in the management of acute pain or in patients who require opioid analgesia for a short period of time
• in the management of postoperative pain, including use after out-patient or day surgeries (e.g., tonsillectomies)
• in the management of mild pain
• in the management of intermittent pain [e.g., use on an as needed basis (prn)]
• in situations of significant respiratory depression, especially in unmonitored settings where there is a lack
of resuscitative equipment
• in patients who have acute or severe bronchial asthma
Fentanyl transdermal system is contraindicated in patients who have or are suspected of having paralytic ileus.
Fentanyl transdermal system is contraindicated in patients with known hypersensitivity to fentanyl or any
components of this product.
WARNINGS:
Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use a fentanyl
transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.
The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl
transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older
(see PRECAUTIONS: Pediatric Use in full prescribing information).
Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of
comparable potency. Use in non-opioid-tolerant patients may lead to fatal respiratory depression.
Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication
can result in fatal overdose with the first dose. The mean elimination half-life of fentanyl transdermal system
is 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require
monitoring for at least 24 hours after fentanyl transdermal system removal since serum fentanyl concentrations
decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal.
Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuous
administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and
in the detection and management of hypoventilation including the use of opioid antagonists.
All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal system
application site and surrounding area to direct external heat sources, such as heating pads or electric blankets,
heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should
be advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases in
fentanyl released from the system resulting in possible overdose and death.
Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately
one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl
released from the system and increased skin permeability. Patients wearing fentanyl transdermal systems who
develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side
effects and the fentanyl transdermal system dose should be adjusted if necessary.
Death and other serious medical problems have occurred when people were accidentally exposed to fentanyl
transdermal system. Examples of accidental exposure include transfer of a fentanyl transdermal system from an
adult’s body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver’s
skin to the medication in the patch while the caregiver was applying or removing the patch.
Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than
indicated may cause choking or overdose that could result in death.
Misuse, Abuse and Diversion of Opioids
Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion.
Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when
prescribing or dispensing fentanyl transdermal system in situations where the physician or pharmacist is concerned
about an increased risk of misuse, abuse or diversion.
Fentanyl transdermal system has been reported as being abused by other methods and routes of administration.
These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could
result in overdose and deaths (see WARNINGS and DRUG ABUSE AND ADDICTION).
Concerns about abuse, addiction and diversion should not prevent the proper management of pain. However,
all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid
analgesic products carries the risk of addiction even under appropriate medical use.
Healthcare professionals should contact their state professional licensing board or state controlled substances
authority for information on how to prevent and detect abuse or diversion of this product.
Hypoventilation (Respiratory Depression): Serious or life-threatening hypoventilation may occur at any time during
the use of fentanyl transdermal system especially during the initial 24 to 72 hours following initiation of therapy and
following increases in dose.
Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is
removed, hypoventilation may persist beyond the removal of fentanyl transdermal system. Consequently, patients
with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until
respiration has stabilized.
The use of concomitant CNS active drugs requires special patient care and observation.
Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyl
transdermal system. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following
large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress
respiration.
Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses).
Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
This makes overdoses involving drugs with sedative properties and opioids especially dangerous.
Fentanyl transdermal system should be used with extreme caution in patients with significant chronic obstructive
pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia,
hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of fentanyl
transdermal system may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid
analgesics should be considered, and opioids should be employed only under careful medical supervision at the
lowest effective dose.
Chronic Pulmonary Disease: Because potent opioids can cause serious or life-threatening hypoventilation, fentanyl
transdermal system should be administered with caution to patients with preexisting medical conditions predisposing
them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to
the point of respiratory failure.
Head Injuries and Increased Intracranial Pressure: Fentanyl transdermal system should not be used in patients who
may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased
intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head
injury. Fentanyl transdermal system should be used with caution in patients with brain tumors.
Interactions with other CNS Depressants: The concomitant use of fentanyl transdermal system with other central
nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g.,
benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause
respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined
therapy is contemplated, the dose of one or both agents should be significantly reduced.
Interactions with Alcohol and Drugs of Abuse: Fentanyl may be expected to have additive CNS depressant effects
when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Interactions with CYP3A4 Inhibitors: The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such
as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone,
amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may
result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and
may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4
inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made
if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY: Drug Interactions in full prescribing information,
PRECAUTIONS, and DOSAGE AND ADMINISTRATION in full prescribing information for further information).
PRECAUTIONS: General: Fentanyl transdermal system should not be used to initiate opioid therapy in patients who
are not opioid-tolerant. Children converting to fentanyl transdermal system should be opioid-tolerant and 2 years of
age or older (see BOX WARNING).
Page 1 of 3
Patients, family members and caregivers should be instructed to keep patches (new and used) out of the reach
of children and others for whom fentanyl transdermal system was not prescribed. A considerable amount of active
fentanyl remains in fentanyl transdermal system even after use as directed. Accidental or deliberate application or
ingestion by a child or adolescent will cause respiratory depression that could result in death.
Cardiac Disease: Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with
bradyarrhythmias.
Hepatic or Renal Disease: Insufficient information exists to make recommendations regarding the use of fentanyl
transdermal system in patients with impaired renal or hepatic function. If the drug is used in these patients, it should
be used with caution because of the hepatic metabolism and renal excretion of fentanyl.
Use in Pancreatic/Biliary Tract Disease: Fentanyl transdermal system may cause spasm of the sphincter of Oddi and
should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like fentanyl
transdermal system may cause increases in the serum amylase concentration.
Tolerance: Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of
drugs, and may develop at different rates for different effects.
Physical Dependence: Physical dependence is a state of adaptation that is manifested by an opioid specific
withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the
drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some
or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia,
mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia,
vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be
abruptly discontinued (see DOSAGE AND ADMINISTRATION: Discontinuation of Fentanyl Transdermal System in full
prescribing information).
Ambulatory Patients: Strong opioid analgesics impair the mental or physical abilities required for the performance of
potentially dangerous tasks, such as driving a car or operating machinery. Patients who have been given fentanyl
transdermal system should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug.
Information for Patients: Patients and their caregivers should be provided with a Medication Guide each time
fentanyl transdermal system is dispensed because new information may be available.
Patients receiving fentanyl transdermal system should be given the following instructions by the physician:
1. Patients should be advised that fentanyl transdermal systems contain fentanyl, an opioid pain medicine
similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone.
2. Patients should be advised that each fentanyl transdermal system may be worn continuously for 72 hours, and
that each patch should be applied to a different skin site after removal of the previous transdermal patch.
3. Patients should be advised that fentanyl transdermal system should be applied to intact, nonirritated, and
nonirradiated skin on a flat surface such as the chest, back, flank, or upper arm. Additionally, patients should
be advised of the following:
• In young children or persons with cognitive impairment, the patch should be put on the upper back to lower
the chances that the patch will be removed and placed in the mouth.
• Hair at the application site should be clipped (not shaved) prior to patch application.
• If the site of fentanyl transdermal system application must be cleansed prior to application of the patch,
do so with clear water.
• Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its
characteristics.
• Allow the skin to dry completely prior to patch application.
4. Patients should be advised that fentanyl transdermal system should be applied immediately upon removal from the
sealed package and after removal of the protective liner. Additionally the patient should be advised of the following:
• The fentanyl transdermal system should not be used if the seal is broken or the patch is cut, damaged, or
changed in any way.
• The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds,
making sure the contact is complete, especially around the edges.
• The patch should not be folded so that only part of the patch is exposed.
5. Patients should be advised that the dose of fentanyl transdermal system or the number of patches applied to
the skin should NEVER be adjusted without the prescribing healthcare professional’s instruction.
6. Patients should be advised that while wearing the patch, they should avoid exposing the fentanyl transdermal
system application site and surrounding area to direct external heat sources, such as:
• heating pads,
• electric blankets,
• sunbathing,
• heat or tanning lamps,
• saunas,
• hot tubs or hot baths, and
• heated water beds, etc.
7. Patients should also be advised of a potential for temperature-dependent increases in fentanyl release from the
patch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased body
temperature due to strenuous exertion while wearing the patch should contact their physician.
8. Patients should be advised that if they experience problems with adhesion of the fentanyl transdermal system,
they may tape the edges of the patch with first aid tape. If problems with adhesion persist, patients may
overlay the patch with a transparent adhesive film dressing (e.g., Bioclusive® or Askina®Derm).
9. Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to a
different skin site.
10. Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush down
the toilet used fentanyl transdermal systems after removal from the skin.
11. Patients should be advised that fentanyl transdermal system may impair mental and/or physical ability
required for the performance of potentially hazardous tasks (e.g., driving, operating machinery).
12. Patients should be advised to refrain from any potentially dangerous activity when starting on fentanyl
transdermal system or when their dose is being adjusted, until it is established that they have not been
adversely affected.
13. Patients should be advised that fentanyl transdermal system should not be combined with alcohol or other CNS
depressants (e.g., sleep medications, tranquilizers) because dangerous additive effects may occur, resulting
in serious injury or death.
14. Patients should be advised to consult their physician or pharmacist if other medications are being or will be
used with fentanyl transdermal system.
15. Patients should be advised of the potential for severe constipation.
16. Patients should be advised that if they have been receiving treatment with fentanyl transdermal system and
cessation of therapy is indicated, it may be appropriate to taper the fentanyl transdermal system dose, rather
than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms.
17. Patients should be advised that fentanyl transdermal system contains fentanyl, a drug with high potential
for abuse.
18. Patients, family members and caregivers should be advised to protect fentanyl transdermal system from theft
or misuse in the work or home environment.
19. Patients should be instructed to keep fentanyl transdermal system in a secure place out of the reach of
children due to the high risk of fatal respiratory depression.
20. Patients should be advised that fentanyl transdermal system should never be given to anyone other than the
individual for whom it was prescribed because of the risk of death or other serious medical problems to that
person for whom it was not intended.
21. Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person,
they should immediately take the patch off, wash the exposed area with water and seek medical attention for
the accidentally exposed individual.
22. When fentanyl transdermal system is no longer needed, the unused patches should be removed from their
pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.
23. Women of childbearing potential who become, or are planning to become pregnant, should be advised to
consult a physician prior to initiating or continuing therapy with fentanyl transdermal system.
24. Patients should be informed that accidental exposure or misuse may lead to death or other serious medical
problems.
Drug Interactions: Agents Affecting Cytochrome P450 3A4 Isoenzyme System: Fentanyl is metabolized mainly
via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when
fentanyl transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadministration with
agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system. The concomitant use
of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin,
clarithromycin, nelfanivir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole,
fasamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which
could increase or prolong adverse drug effects and may cause fatal respiratory depression. Patients receiving
fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time,
and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY: Drug
Interactions in full prescribing information, WARNINGS, and DOSAGE AND ADMINISTRATION in full prescribing
information for further information).
Central Nervous System Depressants: The concomitant use of fentanyl transdermal system with other central
nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g.,
benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory
depression, hypotension, and profound sedation, or potentially result in coma or death. When such combined therapy
is contemplated, the dose of one or both agents should be significantly reduced.
MAO Inhibitors: Fentanyl transdermal system is not recommended for use in patients who have received MAOI within
14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Studies in animals to evaluate the carcinogenic
potential of fentanyl HCl have not been conducted. There was no evidence of mutagenicity in the Ames Salmonella
mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation
test, and the human lymphocyte and CHO chromosomal aberration in vitro assays.
The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate
experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via
continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study,
female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for
14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both
studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone
produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hr
patch on a mg/m2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in
rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.
Pregnancy: Teratogenic Effects: Pregnancy Category C: No epidemiological studies of congenital anomalies in
infants born to women treated with fentanyl during pregnancy have been reported.
The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models.
Published literature reports that administration of fentanyl (0, 10, 100, or 500 mcg/kg/day) to pregnant female
Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of
teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on
a mg/m2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats
from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the
0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.
Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous
infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses
at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no
evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately
3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis).
There are no adequate and well controlled studies in pregnant women. Fentanyl transdermal system should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Chronic maternal treatment with fentanyl during pregnancy has been associated with
transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in
newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected
in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient
neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female
Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of
pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male
and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals
demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and
transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose
and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis.
Labor and Delivery: Fentanyl readily passes across the placenta to the fetus; therefore, fentanyl transdermal system
is not recommended for analgesia during labor and delivery.
Nursing Mothers: Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended for
use in nursing women because of the possibility of effects in their infants.
Pediatric Use: The safety of fentanyl transdermal system was evaluated in three open-label trials in 291 pediatric
patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/hr and higher were used
by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic
dose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than
60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical
trials. Approximately 90% of the total daily opioid requirement (fentanyl transdermal system plus rescue medication)
was provided by fentanyl transdermal system.
Fentanyl transdermal system was not studied in children under 2 years of age.
Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age
or older (see DOSAGE AND ADMINISTRATION in full prescribing information and BOX WARNING).
To guard against accidental ingestion by children, use caution when choosing the application site for fentanyl
transdermal system (see DOSAGE AND ADMINISTRATION in full prescribing information) and monitor adhesion of the
system closely.
Geriatric Use: Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N = 4)
indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60. The relevance
of these findings to fentanyl transdermal system is unknown at this time.
Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in
nontolerant patients, or when opioids are given in conjunction with other agents that depress respiration.
Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they
may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see DOSAGE AND
ADMINISTRATION in full prescribing information).
ADVERSE REACTIONS: In post-marketing experience, deaths from hypoventilation due to inappropriate use of
fentanyl transdermal system have been reported (see BOX WARNING and CONTRAINDICATIONS).
Premarketing Clinical Trial Experience: Although fentanyl transdermal system use in postoperative or acute pain
and in patients who are not opioid-tolerant is CONTRAINDICATED, the safety of fentanyl transdermal system was
originally evaluated in 357 postoperative adult patients for 1 to 3 days and 153 cancer patients for a total of 510
patients. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl
transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl
transdermal system for more than 1 year.
Hypoventilation was the most serious adverse reaction observed in 13 (4%) postoperative patients and in 3 (2%) of
the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients.
Various adverse events were reported; a causal relationship to fentanyl transdermal system was not always
determined. The frequencies presented here reflect the actual frequency of each adverse effect in patients who
received fentanyl transdermal system. There has been no attempt to correct for a placebo effect, concomitant use of
Page 2 of 3
other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials.
Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in Table 1;
similar reactions were seen in the 357 postoperative patients.
In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 291 patients with
chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients
were treated for ) 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five
patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months.
There was no apparent pediatric-specific risk associated with fentanyl transdermal system use in children as young
as 2 years old when used as directed. The most common adverse events were fever (35%), vomiting (33%), and
nausea (24%).
Adverse events reported in pediatric patients at a rate of * 1% are presented in Table 1.
TABLE 1: ADVERSE EVENTS (at rate of ≥ 1%)
Adults (N = 380) and Pediatric (N = 291) Clinical Trial Experience
Body System
Body as a Whole
Cardiovascular
Digestive
Nervous
Respiratory
Skin and Appendages
Urogenital
Adults
Abdominal pain*, headache*, fatigue*,
back pain, fever, influenza-like symptoms*,
accidental injury, rigors
Arrhythmia, chest pain
Nausea**, vomiting**, constipation**,
dry mouth**, anorexia*, diarrhea*,
dyspepsia*, flatulence
Somnolence**, insomnia, confusion**,
asthenia**, dizziness*, nervousness*,
hallucinations*, anxiety*, depression*, euphoria*,
tremor, abnormal coordination, speech disorder,
abnormal thinking, abnormal gait,
abnormal dreams, agitation, paresthesia,
amnesia, syncope, paranoid reaction
Dyspnea*, hypoventilation*, apnea*,
hemoptysis, pharyngitis*, hiccups,
bronchitis, rhinitis, sinusitis,
upper respiratory tract infection*
Sweating**, pruritus*, rash, application site
reaction – erythema, papules,
itching, edema
Urinary retention*, micturition disorder
Pediatrics
Pain*, headache*, fever,
syncope, abdominal pain,
allergic reaction, flushing
Hypertension, tachycardia
Nausea**, vomiting**,
constipation*, dry mouth,
diarrhea
Somnolence*, nervousness*,
insomnia*, asthenia*,
hallucinations, anxiety,
depression, convulsions,
dizziness, tremor, speech
disorder, agitation, stupor,
confusion, paranoid reaction
Dyspnea, respiratory
depression, rhinitis, coughing
Pruritus*, application site
reaction*, sweating increased,
rash, rash erythematous, skin
reaction localized
Urinary retention
*Reactions occurring in 3% to 10% of fentanyl transdermal system patients
**Reactions occurring in 10% or more of fentanyl transdermal system patients
The following adverse effects have been reported in less than 1% of the 510 adult postoperative and cancer
patients studied:
Cardiovascular: bradycardia
Digestive: abdominal distention
Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility
Respiratory: stertorous breathing, asthma, respiratory disorder
Skin and Appendages, General: exfoliative dermatitis, pustules
Special Senses: amblyopia
Urogenital: bladder pain, oliguria, urinary frequency
Post-Marketing Experience: Adults: The following adverse reactions have been reported in association with the
use of fentanyl transdermal system and not reported in the premarketing adverse reactions section above:
Body as a Whole: edema
Cardiovascular: tachycardia
Metabolic and Nutritional: weight loss
Special Senses: blurred vision
Urogenital: decreased libido, anorgasmia, ejaculatory difficulty
DRUG ABUSE AND ADDICTION: Fentanyl transdermal system contains a high concentration of fentanyl, a potent
Schedule II opioid agonist. Schedule II opioid substances, which include hydromorphone, methadone, morphine,
oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Fentanyl, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.
The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse
and diversion.
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors
influencing its development and manifestations. It is characterized by behaviors that include one or more of the
following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction
is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency
calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated
“loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact
information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among
drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be
aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence. In addition,
abuse of opioids can occur in the absence of true addiction and is characterized by misuse for nonmedical
purposes, often in combination with other psychoactive substances. Since fentanyl transdermal system may be
diverted for nonmedical use, careful record keeping of prescribing information, including quantity, frequency, and
renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper
dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Fentanyl transdermal systems are intended for transdermal use (to be applied on the skin) only. Do not use a
fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.
OVERDOSAGE: Clinical Presentation: The manifestations of fentanyl overdosage are an extension of its
pharmacologic actions with the most serious significant effect being hypoventilation.
Treatment: For the management of hypoventilation, immediate countermeasures include removing the fentanyl
transdermal system and physically or verbally stimulating the patient. These actions can be followed by
administration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation following an
overdose may be longer than the effects of the narcotic antagonist’s action (the half-life of naloxone ranges from
30 to 81 minutes). The interval between IV antagonist doses should be carefully chosen because of the possibility
of renarcotization after system removal; repeated administration of naloxone may be necessary. Reversal of the
narcotic effect may result in acute onset of pain and the release of catecholamines.
Always ensure a patent airway is established and maintained, administer oxygen and assist or control
respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate body
temperature and fluid intake should be maintained.
If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed
with appropriate parenteral fluid therapy.
Page 3 of 3
MYLAN®
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
REVISED JUNE 2008 BS:FTS:R16
READER INPUT FORM
U.S. PHARMACIST
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Which two articles in this issue did
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HS-14
U.S. Pharmacist • November 2009 • www.uspharmacist.com
TRAUMATIC BRAIN INJURY
Prophylaxis
Category 2007 Guideline Recommendations
Recommended Dosages for Prophylaxis
Steroid
Steroids do not improve outcome or lower ICP
in severe TBI and are not recommended for TBI
Steroid prophylaxis should not be given to patients
who present with severe TBI
Infection
There is no support for the use of prolonged
antibiotics for systemic infection prophylaxis in
intubated TBI patients
Infection prophylaxis should not be routinely
prescribed for patients with severe TBI. If the patient
does require antibiotics for an infection that presents,
choice of medication and dosage should be made appropriately
based on local susceptibility and resistance patterns
Venous
thromboembolism
The use of compression stockings for VTE
prophylaxis should be placed for patients with
severe TBI, unless lower extremity injuries
prevent their use. Pharmacologic therapies with
either LMWH or UFH should also be initiated
in patients with no contraindications
Heparin: 5,000 units SQ every 8 h
Dalteparin: 5,000 units SQ once daily
Enoxaparin: 30 mg SQ twice daily (or 40 mg SQ once daily)
Fondaparinux: 2.5 mg SQ once daily (for patients ≥50 kg)
LMWH should not be given to patients with
CrCl <30 mL/min
Seizure
Early antiseizure prophylaxis is typically initiated
in patients with phenytoin. Although valproate
may have a comparable effect to phenytoin
for early seizures, this is not a recommended,
FDA-labeled use for this medication. Antiseizure
prophylaxis given later than 1 wk following
TBI is not recommended
Early: Phenytoin 10-20 mg/kg IV bolus, followed by
5-6 mg/kg/day IV in 3 divided doses (can be switched
to oral when patient can tolerate at an equivalent dose)
Late: Routine seizure prophylaxis later than 1 wk
following TBI is not recommended
CrCl: creatinine clearance; ICP: intracranial pressure; LMWH: low-molecular-weight heparin; SQ: subcutaneously; TBI: traumatic brain
injury; UFH: unfractionated heparin; VTE: venous thromboembolism.
Source: References 5, 7, 10, 14.
the 1960s. At that time, corticosteroids were thought
to be favorable through a significant reduction in brain
edema, a decrease of cerebrospinal fluid production,
and the lessening of free radical production. Since then,
there have been numerous clinical studies examining
the role that corticosteroids play in neurological procedures, as well as in TBI. In 1976, two trials were conducted comparing low- and high-dose glucocorticoids in patients with severe TBI.3,4 Results of these
trials demonstrated favorable response to high-dose
glucocorticoid groups and favorable dose-related effects
on mortality. Successively, in the 1980s and 1990s,
there were further trials that evaluated clinical outcomes in patients with TBI, ICP, or both. None of
the studies demonstrated a sizeable benefit in using
glucocorticoids in those patients.5
More recently, in 2004, the CRASH (Corticosteroid
Randomization After Significant Head Injury) trial
authors described the results of an international randomized, controlled trial in patients with TBI using
high-dose methylprednisolone (2-g IV methylprednisolone followed by 0.4 mg/h for 48 h) or placebo.6
The study was concluded early due to an interim
analysis that demonstrated a harmful effect of methylprednisolone, particularly with regard to mortality. The
authors thus concluded that although the cause of
increase in mortality was unclear, the detrimental effects
were not different among groups of patients further
classified by injury severity.
In general, the use of prophylactic corticosteroids is
not recommended at this time for improving patient
outcomes or reducing ICP/edema in patients with TBI.5
Furthermore, it is concluded that high-dose methylprednisolone may be correlated with an increase in
mortality. Due to the results of recent trials, there is
little interest in pursuing further research in this area
at this time.
Infection Prophylaxis
With an increased incidence of mechanical ventilation
and other invasive aspects of patient monitoring and
treatment, patients with TBI are at a significantly
increased likelihood of developing infections. The issue
of infection prophylaxis has been evaluated by numerous sources and has revolved around different possibilities of infection development.
One possible infection source is through the insertion of ICP devices. The incidence of ICP device infection can range from less than 1% to 27%.7 Even with
these striking infection rates, there are conflicting data
HS-15
U.S. Pharmacist • November 2009 • www.uspharmacist.com
H E A LT H S Y S T E M S E D I T I O N
Table 1
Current Dose Recommendations for Prophylaxis Based on
2007 Guidelines for the Management of Severe Traumatic Brain Injury
TRAUMATIC BRAIN INJURY
H E A LT H S Y S T E M S E D I T I O N
concerning what the appropriate prophylactic measures
should contain for patients with TBI. Most studies cited
by the 2007 guidelines evaluating prophylactic antibiotic usage in patients with external ventricular drainage
have shown no difference in infection rates. Additionally, one study showed that patients receiving bacitracin
flushes experienced a significantly higher infection
rate than those without prophylactic measures.7
Prophylactic antibiotic use in patients with TBI have
shown no meaningful reduction in nosocomial infections.7 In addition, an increase in serious gram-negative infections was noted in this population. The guidelines also cite data showing an increase in resistant or
gram-negative nosocomial pneumonias. This was seen
when prophylactic antibiotics were given for longer than
48 hours in general trauma patients. In contrast, one
study showed a decrease in pneumonias when prophylactic antibiotics were given to patients with TBI. No
difference in mortality was noted, so it is difficult to
assess the usefulness of this therapeutic avenue.7
Since publication of the 2007 guidelines, one further study in patients with TBI has been completed.8
This study retrospectively evaluated the use of antibiotic prophylaxis in patients with ICP monitor implantation. Of the 155 patients included in the analysis,
only two developed CNS infections, and these were
both in the group that received prophylactic antibiotics. Additionally, both complications from infections
and multidrug resistant infections were significantly
increased in the group that received antibiotics.
In summary, there are currently no convincing
data to support infection prophylaxis in patients with
TBI, especially in light of data suggesting that prophylaxis might predispose patients to more severe infections when infections would arise.7,8 To be fair, there
is a relative lack of data to give any definitive statement on the use of prophylactic antibiotics, but at this
time this practice cannot be supported.
Venous Thromboembolism Prophylaxis
Venous thromboembolism (VTE) is a topic that is very
pertinent to patients with TBI, as they are at an increased
risk of developing blood clots due to their typically
persistent immobile state. The development of deep
vein thrombosis (DVT) in patients with TBI who do
not receive prophylaxis is as high as 25%.9 However,
there remains some uncertainty about the appropriateness of VTE prophylaxis due to the questionable safety
of anticoagulation in patients who have TBI. Mechanical means of VTE prophylaxis such as sequential compression devices seem to carry less risk in patients with
TBI, but concomitant lower limb injuries can prevent
their use in some patients. Per the 2007 guidelines,
mechanical VTE prophylaxis is recommended in all
severe patients with TBI who have no contraindications to usage, such as an intracranial bleed.10
Concerning pharmacologic options, the guidelines
suggest that low-molecular-weight heparin (LMWH)
or low-dose unfractionated heparin (UFH) should be
used in addition to mechanical means of VTE prophylaxis when no contraindications to LMWH or UFH
exist. It is important to note, however, that the guidelines do not elicit a preferred agent, dosage, or timing
of pharmacologic prophylaxis and also warn of the
increased risk of intracranial hemorrhage expansion.10
Three studies have been published since the guidelines on pharmacologic VTE prophylaxis in patients
with TBI.11-13 A 2007 prospective study evaluated the
use of dalteparin in trauma patients in which 23%
were patients with TBI.11 These patients received prophylactic dalteparin (5,000 units SQ once daily) if
there was no active or progressing bleed on CT scan.
No patients developed or had increased intracranial
bleeding after initiation of dalteparin, while only 3.9%
of patients had evidence of DVT and 0.8% had evidence of pulmonary embolism. A second prospective study published in 2008 evaluated the use of
enoxaparin (30 mg SQ twice daily) in patients with
TBI. 12 Progressive hemorrhagic injury was seen in
3.4% of the TBI population, with 67% of those patients
having clinically insignificant hemorrhagic changes.
In addition, one patient died from a potential side
effect from enoxaparin usage. The authors of these
two studies concluded that enoxaparin and dalteparin
are safe options in patients with TBI and that both
agents have a relatively low risk of significant bleeding complications.11,12
A retrospective study published in 2009 looked at
a comparison of the risk of DVT in patients with
and without TBI utilizing either LMWH or UFH
(doses not specified).13 This study showed a three- to
fourfold increase in DVTs in patients with TBI using
relative risks with 95% confidence intervals. The highest rate was noted when prophylaxis was started greater
than 48 hours after insult.
In summary, it is currently acceptable to recommend mechanical and pharmacologic VTE prophylaxis in patients with TBI that have no contraindications to usage.10-13 The evidence is shifting in favor
of quick initiation of prophylactic agents regardless of
product selection. However, the breakpoint for deciding between mechanical and pharmacologic choices
or agents is still unknown and should be a course of
future study.
Seizure Prophylaxis
Posttraumatic seizure (PTS) is a common occurrence
in patients with TBI. These seizures are broken into
two groups: early (within 7 days of injury) and late
(after 7 days). Certain risk factors have been shown
to place patients with TBI at increased risk for PTS.
These risk factors include: Glasgow Coma Score (a
HS-16
U.S. Pharmacist • November 2009 • www.uspharmacist.com
TRAUMATIC BRAIN INJURY
REFERENCES
1. Langlois JA, Rutland-Brown W, Thomas KE. Traumatic Brain Injury in
the United States: Emergency Department Visits, Hospitalizations, and Deaths.
Atlanta, GA: Centers for Disease Control and Prevention, National Center
for Injury Prevention and Control; 2006.
2. Nolan S. Traumatic brain injury: a review. Crit Care Nurs Q.
2005;28:188-194.
3. Faupel G, Reulen HJ, Muller D, et al. Double-blind study on the effects
of steroids on severe closed head injury. In: Pappius HM, Feindel W, eds.
Dynamics of Brain Edema. New York, NY: Springer-Verlag; 1976:337-343.
4. Gobiet W, Bock WJ, Liesgang J, et al. Treatment of acute cerebral edema
with high dose of dexamethasone. In: Beks JW, Bosch DA, Brock M, eds.
Intracranial Pressure III. New York, NY: Springer-Verlag; 1976:231-235.
5. Brain Trauma Foundation, American Association of Neurological
Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the
management of severe traumatic brain injury. XV. Steroids. J Neurotrauma.
2007;24(suppl 1):S91-S95.
6. Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10,008 adults with clinically significant
head injury (MRC CRASH trial): randomised placebo-controlled trial.
Lancet. 2004;364:1321-1328.
7. Brain Trauma Foundation, American Association of Neurological
Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the
management of severe traumatic brain injury. IV. Infection prophylaxis.
J Neurotrauma. 2007;24(suppl 1):S26-S31.
8. Stoikes NF, Magnotti LJ, Hodges TM, et al. Impact of intracranial pressure monitor prophylaxis on central nervous system infections and bacterial
prophylaxis developed late PTS, while only 13% of
patients who did not receive prophylaxis developed
late PTS. While the retrospective data were not statistically significant, the prospective data were even
more striking. A significant difference was noted in
the prospective group, where 39% of patients treated
with antiseizure prophylaxis developed late PTS, while
none of the patients who were not treated with antiseizure prophylaxis developed late PTS. However, phenobarbital is not commonly used in the U.S. in this
regard because of its adverse-effect profile and multiple drug interactions, and because more appropriate
antiepileptic selections are available; therefore,
results must not be generalized too drastically.
In summary, current literature including the 2007
guidelines indicates that the incidence of early PTS
appears to be reduced with the addition of prophylactic antiseizure medications.14 However, there is currently no evidence to indicate that prophylactic antiseizure medications alter mortality or incidence of
late PTS, and it is still unknown whether or not this
course of therapeutic prophylaxis is currently benefitting patients.
Conclusion
Traumatic brain injury can be overwhelming and distressing to both patients and their family members. In
addition to the emotional and social impacts that accompany TBI, it is important to identify and deliver prompt
attention to the physical needs of the patient. Prophylactic medications play an important role in patients
with TBI, yet as of now many categories lack definitive data to direct appropriate therapeutic choices. Future
studies are needed to clarify this important issue in
the management of patients with this condition.
multi-drug resistance. Surg Infect (Larchmt). 2008;9:503-508.
9. Denson K, Morgan D, Cunningham R, et al. Incidence of venous
thromboembolism in patients with traumatic brain injury. Am J Surg.
2007;193:380-384.
10. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. V. Deep vein thrombosis prophylaxis.
J Neurotrauma. 2007;24(suppl 1):S32-S36.
11. Cothren CC, Smith WR, Moore EE, Morgan SJ. Utility of once-daily
dose of low-molecular-weight heparin to prevent venous thromboembolism
in multisystem trauma patients. World J Surg. 2007;31:98-104.
12. Norwood SH, Berne JD, Rowe SA, et al. Early venous thromboembolism prophylaxis with enoxaparin in patients with blunt traumatic brain
injury. J Trauma. 2008;65:1021-1027.
13. Reiff DA, Haricharan RN, Bullington NM, et al. Traumatic brain injury
is associated with the development of deep vein thrombosis independent of
pharmacological prophylaxis. J Trauma. 2009;66:1436-1440.
14. Brain Trauma Foundation, American Association of Neurological
Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the
management of severe traumatic brain injury. XIII. Antiseizure prophylaxis.
J Neurotrauma. 2007;24(suppl 1):S83-S86.
15. Jones KE, Puccio AM, Harshman KJ, et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus.
2008;25:E3.
16. Formisano R, Barba C, Buzzi MG, et al. The impact of prophylactic
treatment on post-traumatic epilepsy after severe traumatic brain injury.
Brain Injury. 2007;21:499-504.
HS-19
U.S. Pharmacist • November 2009 • www.uspharmacist.com
H E A LT H S Y S T E M S E D I T I O N
neurological scale used to assess level of consciousness)
less than 10; cortical contusion; depressed skull fracture; subdural, intracerebral, and epidural hematoma;
penetrating head wound; or seizure within 24 hours
after injury.14
Phenytoin and valproate sodium have been studied in the prevention of early and late PTS. One
study cited by the 2007 guidelines showed a significant reduction in early PTS without showing any significant effect on late PTS or survival with the use of
phenytoin.14 In contrast, a randomized, double-blind
study showed no early or late PTS benefit by using
phenytoin. Valproate sodium has shown a similar rate
of early PTS reduction when compared to phenytoin.
However, a trend toward higher mortality in the valproate sodium group was noted and could be cause for
concern.14
Since the publication of the guidelines, there have
been two pertinent studies completed regarding seizure
prophylaxis.15-16 The first, a study from 2008, compared the incidence of seizures in patients with TBI
when randomized to either phenytoin or levetiracetam.15
Results indicated that there was no significant difference in seizure incidence. However, patients receiving
levetiracetam showed increased incidence of electroencephalogram (EEG) abnormalities. An EEG was indicated if patients displayed persistent coma, decreased
mental status, or clinical signs of seizures.
The second study evaluated the incidence of late
PTS in patients with TBI who did or did not receive
antiseizure prophylaxis upon initial presentation. 16
This study was carried out in Italy, with phenobarbital being one of the main agents used in antiseizure
prophylaxis. Interestingly, in the retrospective portion
of the study, 29% of patients who received antiseizure
H E A LT H S Y S T E M S E D I T I O N
Newly Approved mTOR
Inhibitors for the Treatment of
Metastatic Renal Cell Carcinoma
© JUPITERIMAGES
T
about 30% of these patients will have disease recurrence.
Surgery is a good choice for patients with advanced
disease, benefiting quality of life by reducing pain or
bleeding, and sometimes even improving survival.4
For many years, immunotherapy with the biologic
response modifiers interleukin-2 (IL-2) and interferonalpha (IFN-A) has been the mainstay of systemic treatment for metastatic disease. Treatment with these agents
alone or in combination yields a median survival of 12
to 17.5 months.3 High-dose IL-2, which was FDAapproved in 1992 for advanced RCC, provides durable
complete response in a small fraction of patients. Conventional chemotherapy yields response rates of less than
10% and often is used in a palliative context. High-dose
nonmyeloablative chemotherapy followed by allogeneic
stem-cell transplantation remains experimental.2,4
Targeted therapies have been developed to interfere
with intracellular signaling, tumor-cell proliferation,
differentiation, and angiogenesis. The small-molecule
tyrosine kinase (TK) inhibitors bind to receptor TKs
(RTKs) located on cell-surface growth factor receptors
(GFRs), thereby inhibiting tumor growth.2 Sorafenib,
which was approved in 2005 for advanced RCC, inhibits multiple intracellular and cell-surface kinases, including Raf; vascular endothelial GFR types 1 to 3 (VEGFR
1-3); platelet-derived GFR (PDGFR)Diana Hey Cauley, PharmD, BCOP
beta; the stem cell factor receptor (c-kit);
Clinical Pharmacy Specialist,
Fms-like TK-3 (Flt3); and glial cell
Genitourinary Medical Oncology
line–derived neurotrophic factor recepDivision of Pharmacy, University of Texas
tor (RET).4,5 Sunitinib, approved for
M.D. Anderson Cancer Center
advanced RCC in 2006, also inhibits
Houston, Texas
he American Cancer Society has estimated that
57,760 new cases of kidney cancer and 12,980
deaths due to kidney cancer will occur in the
United States in 2009. Included in these statistics are
renal cell carcinoma (RCC) and transitional cell carcinoma
of the renal pelvis. Kidney cancer is one of the 10 most
common types of cancer in men and women, with men
at higher risk than women. The overall lifetime risk of
developing kidney cancer is approximately 1 in 75 (1.34%).1
RCC constitutes 90% of kidney cancers, and the peak
incidence is in the sixth decade of life. The histology is
primarily clear cell carcinoma (85%); the remaining 15%
comprises papillary, chromophobe, and collecting-duct
carcinomas. The incidence of RCC is increasing, and
about 30% of patients present with metastatic disease.
Risk factors include smoking, hypertension, obesity,
cystic kidney disease, and genetic abnormalities. One
genetic abnormality is the mutation of the von HippelLindau tumor-suppressor gene often seen in clear-cell
carcinomas.2
Patients with metastatic RCC have an estimated 10%
survival rate at 5 years. A prognostic model to predict
survival was developed to stratify patients into low-risk
(no risk factors), intermediate-risk (1-2 risk factors), and
poor-risk categories (>2 risk factors).2 See TABLE 1 for
predictors of short survival.3
Current Treatment Options
Surgery is an important option for
patients with RCC. Localized disease
can be cured with surgery; unfortunately,
HS-20
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NDC#s are prominently
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Strength is highlighted in
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Products with multiple
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Bar Coded with a
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800.729.9991 • www.tevausa.com
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INHIBITORS FOR METASTATIC RENAL CELL CARCINOMA
H E A LT H S Y S T E M S E D I T I O N
Figure 1. mTOR signaling pathway.
mTOR: mammalian target of rapamycin; PI3K:
phosphoinositide 3-kinase.
multiple kinases, including VEGFR 1–3, PDGFR-alpha
and -beta, c-kit, Flt3, colony-stimulating factor receptor
type 1, and RET.4,6
Bevacizumab is a monoclonal recombinant humanized
antibody that binds to and neutralizes circulating VEGF
ligand, which prevents activation of the kinase VEGFR.2
It was FDA-approved in July 2009 in combination with
IFN-A for patients with metastatic RCC. Clinical trials
also demonstrate activity as single-agent therapy.4
Mammalian Target of Rapamycin (mTOR) Pathway
Three primary signaling pathways associated with RTKs
are currently identified in cancer cells. One of them is
the phosphoinositide 3-kinase (PI3K)/Akt/mTOR protein
cascade (FIGURE 1); the other two are the protein kinase
C family and the Ras/mitogen-activated protein kinase
cascades. Activation of RTK leads to stepwise activation
of PI3K, then Akt, and then mTOR, directly promoting
tumor growth. The mutation and overexpression of RTK,
as well as growth receptors, are common in RCC.7
Table 1
Predictors of Short Survival
Risk Factors
Description
LDH level
>1.5 × ULN
HB
<LLN
Corrected serum calcium level
>10 mg/dL
Interval from original diagnosis
to start of systemic treatment
<1 yr
Karnofsky performance score
≤70
Number of metastatic sites
≥2
HB: hemoglobin; LDH: lactate dehydrogenase; LLN: lower limit
of normal; ULN: upper limit of normal.
Source: Reference 3.
mTOR regulates essential signal-transduction pathways,
tying growth stimuli to cell-cycle progression.7 It also
integrates signals involving nutrient availability, energy
status, and stress.8 There are two multiprotein complexes
(mTORCs): mTORC-1 and mTORC-2. mTORC-1 is
rapamycin-sensitive; mTORC-2 is rapamycin-insensitive.7
The mTOR pathway is important with regard to
glucose and lipid metabolism. Interruption of the pathway by mTOR inhibitors increases the frequency of
hyperglycemia and hyperlipidemia.7
mTOR Inhibitors
Rapamycin, also known as sirolimus, originally was
developed as an antifungal drug, but it was initially
used as an immunosuppressive agent in transplant
patients because it inhibits T-cell proliferation after
activation.9 In Europe, rapamycin also is used to prevent
restenosis after percutaneous coronary interventions.
Rapamycin was not studied for its anticancer activity
until the late 1990s, when it was identified as the first
mTOR inhibitor.7
To inhibit mTOR, rapamycin must bind to an abundant intracellular binding protein, FKBP-12; the
drug:FKPB-12 complex binds at the rapamycin binding
domain.8 The result of mTOR inhibition is cell-growth
arrest, decreased protein synthesis, and reduced growth
signaling. Rapamycin decreases the activity of mTORC-2
with sustained exposure.7
Rapalogues, or rapamycin derivatives, which were
developed later, include temsirolimus and everolimus.
The primary difference between the rapalogues is their
pharmacokinetic and pharmacologic properties.7 Temsirolimus was created by adding an ester to a rapamycin
carbon, and adding an ether created everolimus; the result
was increased solubility and bioavailability.8 Notably, the
rapalogues do not induce immunosuppression, as is seen
with rapamycin.7,9
Temsirolimus
Temsirolimus, also known as CCI-779, is an IV-administered mTOR kinase inhibitor. The dosing is 25 mg
once weekly as a 30- to 60-minute infusion. To prevent
a hypersensitivity reaction, the patient should receive
diphenhydramine 25 mg or 50 mg, or a similar antihistamine, about 30 minutes before the start of each dose.
The dose should be held in the event of low neutrophil
or platelet counts or severe adverse reactions.3,10
Temsirolimus binds to FKBP-12, forms a complex,
and inhibits mTOR signaling. The agent inhibits cell
division, halts growth signaling, and reduces hypoxia
inducible factor (HIF-1 and HIF-2 alpha) and VEGF
expression.3,10 It is hydrolyzed to the active metabolite
sirolimus, which also likely inhibits mTOR. Temsirolimus
has a terminal half-life of 12 to 15 hours; that of sirolimus is 40 to 50 hours.8 Temsirolimus is metabolized
hepatically via CYP450 3A4. Drug interactions can occur
HS-22
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Lilly is committed to meeting the ever-changing needs of our hospital customers.
And this commitment drives us to continue working on more innovations for the future.
HI59949
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INHIBITORS FOR METASTATIC RENAL CELL CARCINOMA
H E A LT H S Y S T E M S E D I T I O N
The dose of everolimus may also be reduced
to 5 mg in the presence of moderate hepatic
impairment or severe adverse events. The
mean half-life is about 30 hours. There
Outcome
Temsirolimus
Temsirolimus
IFN-A
are six main metabolites of everolimus;
Measure
Arm
+ IFN-A Arm
Arm
they are 100 times less potent than the
Median OS
10.9 mo
8.4 mo
7.3 mo
parent compound. Grapefruit juice should
Median PFS
5.5 mo
4.7 mo
3.1 mo
be avoided.11
Phase I and II studies established the
Clinical benefita
32.1%
28.1%
15.5%
safety
and efficacy of everolimus admina
Proportion of patients with objective response or stable disease for ≥24 wk.
istered on a daily oral dosing schedule.
IFN-A: interferon-alpha; OS: overall survival; PFS: progression-free survival.
They also demonstrated disease stabilizaSource: Reference 3.
tion or tumor reduction in metastatic
with strong inducers and inhibitors, so these medications RCC.4,7,9,12 Responding to the need for active cancer
should be avoided. If coadministration is unavoidable, medications after traditional agents have failed, a phase
the dose of temsirolimus should be increased to 50 mg III study investigated the role of everolimus in second- or
when given with a strong CYP450 3A4 inducer and third-line dosing.12
Motzer and colleagues conducted a phase III trial in
reduced to 12.5 mg when given with a strong inhibitor.2
Grapefruit juice should be avoided because it may increase 410 patients with metastatic clear cell RCC assigned in
sirolimus levels. Use temsirolimus with caution in patients a 2-to-1 ratio to two treatment arms: oral everolimus 10
with hypersensitivity to polysorbate 80.10
mg daily plus best supportive care or placebo plus best
Phase I and II clinical trials determined that temsiro- supportive care.12 Patients had to have progressed by or
limus 25 mg IV could be given safely on a weekly basis within 6 months of stopping sunitinib, sorafenib, or both
and had promising activity in RCC. Researchers also drugs; previous therapy with bevacizumab, IL-2, or IFN-A
found that patients with treatment-refractory, poor- was allowed. At progression, placebo patients could
prognosis RCC who were receiving temsirolimus had a transition to active open-label everolimus treatment for
median overall survival of 8.2 months versus 4.9 months ethical reasons. At the second interim safety analysis, the
for IFN-A.7 Subsequently, Hudes and colleagues conducted study was halted early because the prolongation in proa phase III trial comparing three treatment arms in 626 gression-free survival (PFS) was greater than expected.
patients with metastatic RCC: temsirolimus 25 mg IV See TABLE 3 for results.12,13 The crossover from placebo
weekly; temsirolimus 15 mg IV weekly with IFN-A at to everolimus at disease progression would likely confound
3 to 6 MU subcutaneously (SC) three times weekly; and the median overall survival data for the everolimus group;
IFN-A 3 to 18 MU SC three times weekly. Patients had therefore, the endpoint was not reached.12
In a follow-up to the phase III everolimus study,
to be treatment-naïve and have at least three predictors
researchers collected 4.5 months of additional blinded
of short survival.3 See TABLE 2 for results.3
Dose reductions and delays were least common in the data for a total of 416 patients. The results of this study
temsirolimus single-agent arm.3 The FDA approved demonstrated persistence of PFS prolongation.13
In March 2009, the FDA approved everolimus for
temsirolimus for metastatic RCC in May 2007. As a
result of the phase II and III trials, temsirolimus is now the treatment of advanced RCC after failure of treatment
favored as first-line treatment for patients with poor- with sunitinib or sorafenib.11 The drug also is FDAapproved as a medical device as a component of the
prognosis metastatic RCC.9
everolimus-eluting coronary stent system for coronary
Everolimus
artery disease.14 Everolimus is approved in Europe as an
Everolimus, also known as RAD001, is an orally admin- immunosuppressant for the prevention of solid organ
istered mTOR kinase inhibitor. It forms a complex with transplant rejection.9
the intracellular protein FKBP-12 and inhibits the mTOR
kinase. Everolimus reduces cell proliferation, cell growth, Adverse Events
angiogenesis, and glucose uptake, and it inhibits HIF-1 The primary adverse-events profile of the mTOR inhibitors includes hyperglycemia, hypercholesterolemia, and
expression and reduces VEGF expression.7,8,11
Everolimus is administered once daily as a 10-mg hyperlipidemia. This reflects the blockade of mTOR, the
tablet, at the same time every day, with or without food. primary signaling conduit for insulin and insulin growth
It is metabolized hepatically via CYP450 3A4. Drug factor. Other common adverse events for temsirolimus
interactions with CYP450 3A4 inducers and inhibitors and everolimus include fatigue, stomatitis, diarrhea,
should be avoided. If treatment with a strong CYP450 hypophosphatemia, low red blood cells and platelets, and
inducer cannot be avoided, the dose of everolimus may peripheral edema. These adverse events are commonly
be increased from 10 mg to 20 mg in 5-mg increments. reversible upon treatment discontinuation. Less common
Table 2
Temsirolimus Phase III Study Results
HS-24
U.S. Pharmacist • November 2009 • www.uspharmacist.com
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INHIBITORS FOR METASTATIC RENAL CELL CARCINOMA
H E A LT H S Y S T E M S E D I T I O N
Table 3
Everolimus Phase III Study Resultsa
Outcome
Measure
Everolimus + Best
Supportive Care
Placebo + Best
Supportive Care
Median PFS
4.9 mo
1.9 mo
Median OS
Not reached
8.8 mo
Patients with PR
1%
0%
Patients with stable disease
63%
32%
Patients with progressive disease
19%
46%
a
active treatment and for 3 months after
the final dose. Women taking everolimus
should use contraception while receiving
active treatment and for 8 weeks after
the final dose.10,11
Patients being treated with mTOR
inhibitors should not receive live vaccines.
Patients should also avoid close contact
with individuals who have received live
vaccines.10,11
Investigational Combination Studies
The goal of combining different therapies
is to achieve greater efficacy. Strategies
often involve combining agents with
different mechanisms of action and sideeffect profiles. Investigational combinations in phase I
and II studies include bevacizumab with either everolimus or temsirolimus; other studies are examining
temsirolimus with sorafenib or IFN-A.4,8 Certain combinations require up-front dose reductions, such as
temsirolimus with sorafenib, or are not safe, such as
temsirolimus with sunitinib.15
Including 4.5-mo follow-up.
OS: overall survival; PFS: progression-free survival; PR: partial response.
Source: References 12, 13.
symptoms are renal insufficiency, interstitial pneumonitis, and low white blood cells.8
Fatigue is experienced by more than 50% of patients
taking mTOR inhibitors. About 10% have dose-limiting
fatigue to the degree of warranting dose reduction.9
Hyperglycemia is experienced by more than 50% of
treated patients. Owing to the rising incidence of obesity
and metabolic syndrome, it is important to identify these
adverse events quickly. Up to 10% of patients develop
severe symptoms and require medical intervention with
an oral hypoglycemic agent or SC insulin. Regular monitoring of triglycerides is recommended, with early dietary
interventions for minor elevations and initiation of a
lipid-lowering agent for levels exceeding 500 mg/dL.
Severe hypertriglyceridemia is associated with acute
pancreatitis.9
Impairment of renal function and interstitial pulmonary fibrosis are rare but important events. Serum creatinine should be monitored regularly. The pulmonary
fibrosis is often steroid-responsive and frequently fully
reversible. If symptoms of progressive dyspnea or lung
infiltrates are present, the dose may be reduced or the
treatment discontinued.9
Both temsirolimus and everolimus are classified as
pregnancy category D. Men and women receiving
temsirolimus should use contraception while receiving
REFERENCES
1. American Cancer Society. Detailed Guide: Kidney Cancer.
What are the key statistics for kidney cancer?
www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_
are_the_key_statistics_for_kidney_cancer_22.asp?sitearea=.
Accessed July 25, 2009.
2. Reeves DJ, Liu CY. Treatment of metastatic renal cell carcinoma. Cancer Chemother Pharmacol. 2009;64:11-25.
3. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus,
interferon alfa, or both for advanced renal-cell carcinoma. N
Engl J Med. 2007;356:2271-2281.
4. Basso M, Cassano A, Barone C. A survey of therapy for
advanced renal cell carcinoma. Urol Oncol. Epub July 6,
2009. www.urologiconcology.org/article/S10781439(09)00142-2/abstract [registration required]. Accessed
July 20, 2009.
5. Nexavar (sorafenib) package insert. Wayne, NJ: Bayer
Cost
The average wholesale price (AWP) of the temsirolimus
injection kit 25 mg IV weekly is $1,499, or $5,996 per
month. The respective monthly AWPs of everolimus 5
mg and 10 mg orally daily are $6,400 and $6,700. The
manufacturers offer assistance programs for eligible
patients. Prior authorization often is required for these
high-cost medications.
Summary
There are two recently approved novel mTOR inhibitors
with activity in metastatic RCC. Temsirolimus is FDAapproved for first-line treatment of metastatic RCC and
is favored for poor-prognosis patients. Everolimus is
FDA-approved for second-line treatment of metastatic
RCC after sunitinib or sorafenib failure. These agents
provide a valuable choice for providers and patients with
limited treatment options.
HealthCare Pharmaceuticals, Inc; February 2009.
6. Sutent (sunitinib) package insert. New York, NY: Pfizer
Labs; July 2009.
7. Wysocki P. mTOR in renal cell cancer: modulator of
tumor biology and therapeutic target. Expert Rev Mol Diagn.
2009;9:231-241.
8. Hudes GR. Targeting mTOR in renal cell carcinoma.
Cancer. 2009;115(suppl 10):2313-2320.
9. Dasanu CA, Clark BA III, Alexandrescu DT. mTORblocking agents in advanced renal cancer: an emerging therapeutic option. Expert Opin Investig Drugs. 2009;18(2):
175-187.
10. Torisel (temsirolimus) injection package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc; September 2008.
11. Afinitor (everolimus) package insert. East Hanover, NJ:
Novartis Pharmaceuticals Corp; March 2009.
12. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of
everolimus in advanced renal cell carcinoma: a double-blind,
randomised, placebo-controlled phase III trial. Lancet.
2008;372:449-456.
13. Kay A, Motzer R, Figlin R, et al. Updated data from a
phase III randomized trial of everolimus (RAD001) versus
PBO in metastatic renal cell carcinoma (mRCC). Proc Am
Soc Clin Oncol. 2009. Abstract 278 [presented at 2009
ASCO Genitourinary Cancers Symposium].
14. FDA. XIENCE™ V everolimus eluting coronary stent
on the over-the-wire (OTW) or rapid exchange (RX) stent
delivery systems–P070015.
www.fda.gov/medicaldevices/productsandmedicalprocedures/
deviceapprovalsandclearances/recently-approveddevices/
ucm074025.htm. Accessed July 15, 2009.
15. Sosman J, Puzanov I. Combination targeted therapy in
advanced renal cell carcinoma. Cancer. 2009;115(suppl
10):2368-2375.
HS-26
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H E A LT H S Y S T E M S E D I T I O N
Nutrition and
Clinical Depression
In-Service Primers
OVERVIEW
Research results in
the emerging area
of nutritional
neuroscience point
to a link between
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hile the connection
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people see the connection
between nutrition and depression. This is because depression is
more typically thought of as
either biochemicaly based or
emotionally rooted. It is now
proven that nutrition can play a
key role in the onset, as well as
severity and duration, of depression. Nutritional neuroscience is
an emerging discipline that is
shedding light on the link
between nutritional factors and
human cognition, behavior, and
emotions.1
There are two types of depression. Behavioral depression or
“the blues” results from various
causes, and most people experience it at some point in their
lives. Clinical depression, on the
other hand, is much more serious. It is usually caused by a
chemical imbalance in the brain
and requires medical attention.2
Nutrition plays an important
role in every aspect of well-being,
and improper nutrition can lead
to poor bodily function. There
are many reports that people with
clinical depression also suffer
from malnutrition. The dietary
habits of the general population
in the United States and many
Asian countries reveal that people
are often deficient in many nutrients, especially essential amino
acids, vitamins, minerals, and
omega-3 fatty acids. People who
are depressed often lose all sense
Manouchehr Saljoughian, PharmD, PhD,
Alta Bates Summit Medical Center,
Department of Pharmacy,
Berkeley, California
W
of self and stop eating and caring.
Food alone cannot prevent
depression, but poor nutrition
makes the body incapable of
healing itself. Supplements containing amino acids have been
found to reduce symptoms of
depression, as they are converted
to neurotransmitters, which in
turn alleviate depression and
other mental health problems.3
Since most antidepressant prescription drugs have side effects,
it is possible that some patients
who are not being observed by
psychiatrists will skip taking their
medications. Such noncompliance can put patients at a higher
risk for committing suicide or
being hospitalized. An alternate
and effective way for psychiatrists
to circumvent noncompliance is
to familiarize themselves with
alternative or complementary
nutritional therapies. Psychiatrists
can recommend doses of dietary
supplements based on efficacious
studies and adjust the doses based
on the results obtained by closely
observing the changes in the
patient.4
If a person with depression
suffers from loss of sleep, clinicians will either increase the
amount of amino acids in their
diet or add iron for loss of
appetite. There are foods that
should be included in the diet of
a person with clinical depression.
Meat and amino acids such as
phenylalanine, tryptophan,
choline, and tyrosine—which
help the nervous system function
properly—should be added to the
HS-28
U.S. Pharmacist • November 2009 • www.uspharmacist.com
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NUTRITION AND CLINICAL DEPRESSION
H E A LT H S Y S T E M S E D I T I O N
diet. Choline and tryptophan can
be found in many freshwater fish,
and tyrosine can be found in
cheese.5 Foods that should be
avoided are alcohol and caffeine.
Alcohol acts as a central nervous
system depressant, which makes
the situation worse, and caffeine
interferes with sleep and promotes nervousness.
Signs and
Symptoms of Depression
Many people attribute the feelings induced by depression to
other causes such as inability to
handle stress, social stigma, and
alcoholism. However, depression
is not difficult to spot, and specific signs and symptoms exhibited by a person are helpful in
identifying its presence (see
TABLE 1). 6
Brain Biochemical Imbalance
Neurotransmitters are the natural
biochemicals that facilitate communication between brain cells.
These substances control our
emotions, memory, moods,
behavior, sleep, and learning abilities. Neurotransmitters are manufactured in the brain from the
amino acid precursors we receive
from food. Without adequate
amino acid conversion, sufficient
amounts of neurotransmitters are
not produced.7 Alcohol destroys
these essential precursor amino
acids, which is probably why
alcoholics seem so emotionally
down and depressed.
The two major neurotransmitters involved in preventing
depression are serotonin (from
the amino acid L-tryptophan)
and norepinephrine (from the
amino acids L-phenylalanine and
L-tyrosine). It is interesting that
the depressive symptoms exhibited indicate which amino acids
are lacking: If the symptoms are
sleeplessness, anxiety, or irritability, then L-tryptophan is low; if
the symptoms are lethargy,
Table 1
Signs of Depression
•
Indecisiveness
•
Continual fatigue and lethargy
•
Loss of appetite or binge eating
•
Withdrawal from daily activities
•
Inability to concentrate
•
Lack of motivation and
unresponsiveness to people
•
Feeling helpless, immobilized
•
Sleeping too much; using sleep
to escape reality
•
Insomnia, particularly earlymorning insomnia
•
Lack of response to good news
•
Ongoing anxiety
•
An “I don’t care” attitude
•
Easily upset or angered
•
Listening to mood music
persistently
•
Self-destructive behavior
Source: Reference 6.
fatigue, sleeping too much, or
feelings of immobility, L-tyrosine
or L-phenylalanine is lacking.7
Conversion of Amino
Acids to Neurotransmitters
The amino acid tyrosine, found
in large amounts in cheese, has
an amazing effect on depression.
Tyrosine is a nonessential amino
acid that is synthesized in the
body from phenylalanine. As a
building block for several important brain chemicals, tyrosine is
needed to make epinephrine,
norepinephrine, serotonin, and
dopamine, all of which work to
regulate mood. Tyrosine also aids
in the production of melanin
(the pigment responsible for hair
and skin color) and in the function of organs responsible for
making and regulating hormones, including the adrenal,
thyroid, and pituitary glands.
Tyrosine is also involved in the
synthesis of enkephalins, substances that have pain-relieving
effects in the body. 8
Low levels of tyrosine have
been associated with low blood
pressure, low body temperature,
and an underactive thyroid.
Because tyrosine binds to free
radicals, it is considered a mild
antioxidant. Thus, tyrosine may
be useful for individuals who
have been exposed to harmful
chemicals (such as from smoking) and radiation. The usual
dose is 3 to 6 g per day, taken on
an empty stomach. Vitamins B6
and C need to be taken to facilitate the conversion of tyrosine to
norepinephrine.8
An alternative to tyrosine is
the amino acid L-phenylalanine,
which can also be converted into
norepinephrine. L-phenylalanine
is converted to a substance called
2-phenylethylamine (2-PEA). Low
brain levels of 2-PEA are also
responsible for some depression.
2-PEA is converted to tyrosine,
which then converts to norepinephrine. L-phenylalanine is a
better start than tyrosine, but if it
causes the brain to race due to
the formation of 2-PEA, the
patient should start with tyrosine.
A disadvantage to taking Lphenylalanine is its slight potential for raising blood pressure.
There is also some evidence
that excess L-phenylalanine can
cause headaches, insomnia, and
irritability. For these reasons, it is
important to start with a low
dose. L-phenylalanine doses can
range from 500 mg to 1,500 mg
daily and should be taken on an
empty stomach.8
The FDA prohibited the manufacture and sale of tryptophan
in the United States in the fall of
1980. Although the FDA continues to enunciate its concern
about the use of L-tryptophan as
a single product and related compounds such as L-5-hydroxytryptophan, the agency does not prohibit the marketing of dietary
supplements that contain lower
HS-30
U.S. Pharmacist • November 2009 • www.uspharmacist.com
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Baxter, Committed to a Safer Healthcare Environment, and the distinctive product label design are trademarks of Baxter International Inc.
Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111085 03/09
NUTRITION AND CLINICAL DEPRESSION
H E A LT H S Y S T E M S E D I T I O N
doses of L-tryptophan. 5-hydroxytryptophan (a direct precursor to
serotonin) has been offered as an
alternative. The amino acid tryptophan is the precursor for serotonin and it is found in large
amounts in milk and turkey (see
TABLE 2). Serotonin controls
mood, sleep, sexual ability,
appetite, and pain threshold.
Increasing serotonin can lift
depression and end insomnia.8
Prostaglandin E1
and Depression
Another biochemical cause of
depression is a genetic inability to
manufacture enough
prostaglandin E1 (PGE1), an
important brain metabolite
derived from essential fatty acids
(EFAs). The problem is the result
of an inborn deficiency in omega6 essential fatty acids. Alcohol
stimulates temporary production
of PGE1 and lifts the depression.
When drinking is stopped, PGE1
levels fall again and depression
returns. To banish it, the patients
turn again to alcohol. Thus, a
downward spiral toward alcoholism begins.
During the past 15 years,
researchers have found that if
they restore the PGE1 levels to
normal range in patients suffering from alcoholism, they can
eliminate both the depression
and the need to drink for relief.
Research shows
that nutritional
deficiencies in
brain chemistry
can result in
depression, anger,
hopelessness, and
paranoia.
This can be achieved with a substance called gamma-linolenic
acid, which can be easily converted to PGE1. 9
The Effect of Nutrition
Research shows that nutritional
deficiencies in brain chemistry
can result in depression, anger,
hopelessness, and paranoia. This
is because the connection
Table 2
Important Points About Tryptophan
•
Tryptophan alone will not be converted to serotonin. To ensure that it is
properly used, you must also take vitamins C and B6.
•
Tryptophan is converted to niacin before its final conversion into serotonin.
If your body is deficient in niacin, the tryptophan you take will supply you
with niacin, not serotonin. For this reason, it is a good idea to take a Bcomplex vitamin daily. This will give you both vitamin B6 and niacin and
allow the tryptophan to be converted to serotonin.
•
Unlike serotonin, tryptophan (or more accurately, its breakdown product 5hydroxytryptophan, or 5-HTP) can pass through the blood–brain barrier.
Thus, supplementation of tryptophan would appear to be a simple and natural alternative to selective serotonin reuptake inhibitor drugs.
•
Since it is not stored in the body, tryptophan cannot accumulate to toxic
levels. Taking high doses of supplements containing tryptophan, however,
can produce some side effects such, as drowsiness, increased blood pressure, and bad dreams.
between depression and vitamin
and mineral deficiencies is often
missed. A closer look at the diet
of patients suffering from
depression indicates that their
nutrition is far from adequate.
They make poor food choices
and frequently select foods that
contribute to depression. 10
The B-complex vitamins are
essential to mental and emotional
well-being. They cannot be stored
in our bodies, so we depend
entirely on our daily diet to supply them. B vitamins are
destroyed by alcohol, refined sugars, nicotine, and caffeine. Continued vitamin C deficiency
causes chronic depression,
fatigue, and vague ill health, and
insufficient amounts of minerals
also cause mental problems. The
relationship between vitamins B
and C and minerals and depression is shown in TABLE 3.
Carbohydrates
Carbohydrates, or polysaccharides,
play an important role in the
structure and function of an
organism. In humans, they have
been found to affect mood and
behavior. Food rich in carbohydrates triggers the release of
insulin in the body. Insulin facilitates the release of blood sugar
into the cells, where it can be used
for energy, and simultaneously
triggers the entry of tryptophan to
the brain. Tryptophan in the brain
affects neurotransmitter levels.
Consumption of diets low in
carbohydrates tends to precipitate
depression, since the production of
the brain chemicals serotonin and
tryptophan, which promote the
feeling of well-being, is reduced. It
is suggested that low glycemic
index (GI) foods such as some
fruits and vegetables, whole grains,
and pasta are more likely to provide a moderate but lasting effect
on brain chemistry, mood, and
energy level than the high GI
foods.10
HS-32
U.S. Pharmacist • November 2009 • www.uspharmacist.com
NUTRITION AND CLINICAL DEPRESSION
Vitamin Bs
•
•
•
•
•
•
•
Vitamin B1 (thiamine): Deficiencies trigger depression and irritability and
can cause neurologic and cardiac disorders among alcoholics.
Vitamin B2 (riboflavin): Adequate riboflavin may be required for cognitive
function. Riboflavin has been reported to improve depression scores in
patients taking TCA drugs.
Vitamin B3 (niacin): Depletion causes anxiety, depression, apprehension,
and fatigue.
Vitamin B5 (pantothenic acid): Symptoms of deficiency are fatigue, chronic
stress, and depression. Vitamin B5 is needed for hormone formation and
for the uptake of amino acids and the brain chemical acetylcholine, which
combine to prevent certain types of depression.
Vitamin B6 (pyridoxine): Deficiency can disrupt formation of neurotransmitters. Vitamin B6 is a coenzyme needed for conversion of tryptophan to
serotonin and of phenylalanine and tyrosine to norepinephrine.
Folic acid (B9): Folate and MTHF work best together by helping to regulate
the neurotransmitters that affect depression.
Vitamin B12: This vitamin controls blood levels of the amino acid homocysteine. Elevated levels of this substance appear to be linked with heart disease and, possibly, depression and Alzheimer’s disease.
Vitamin C
Continued vitamin C deficiency causes chronic depression, fatigue, and vague
ill health.
Minerals
Deficiencies in a number of minerals can also cause mental problems.
• Calcium: Depletion affects the central nervous system. Low levels of calcium cause nervousness, apprehension, irritability, and numbness.
• Zinc: Deficiencies result in lack of appetite and lethargy. When zinc is low,
copper in the body can increase to toxic levels, resulting in paranoia and
fearfulness. Zinc also protects the brain cells against the potential damage
caused by free radicals.
• Iron: Depression is often a symptom of chronic iron deficiency. Other
symptoms include general weakness, exhaustion, lack of appetite, and
headaches.
• Manganese: This metal is needed for proper use of the B-complex vitamins
and vitamin C. Since it also plays a role in amino acid formation, a deficiency may contribute to depression resulting from low levels of the neurotransmitters serotonin and norepinephrine. Manganese also helps stabilize
blood sugar and prevent hypoglycemic mood swings.
• Potassium: Depletion is frequently associated with depression, tearfulness,
weakness, and fatigue. A 1981 study found that depressed patients were
more likely than controls to have decreased intracellular potassium.
Decreased brain levels of potassium have also been found on autopsy of
suicides. Potassium levels can be boosted by using one teaspoon of Morton’s Lite-Salt every day.
• Magnesium: Symptoms of deficiency include confusion, apathy, loss of
appetite, weakness, and insomnia.
• Selenium: Low selenium intake is associated with lowered mood status.
Intervention studies with selenium with other patient populations reveal
that selenium improves mood and diminishes anxiety.
MTHF: methyltetrahydrofolate; TCA: tricyclic antidepressant.
Source: References 11-14.
Proteins and Amino Acids
Many of the neurotransmitters in
the brain are made from amino
acids. Proteins are made up of
amino acids and are important
building blocks of life. As many
as 12 amino acids are manufactured in the body and the
remaining eight (essential amino
acids) must be supplied through
diet. A high-quality protein diet
contains all of the essential amino
acids. Foods rich in high-quality
protein include meat, milk and
other dairy products, and eggs.
Plant proteins in beans, peas, and
grains may be low in one or two
essential amino acids.
Protein intake and in turn the
individual amino acids can affect
the brain function and mental
health. The neurotransmitter
dopamine is made from the
amino acid tyrosine, and the neurotransmitter serotonin is made
from tryptophan. If there is a
lack of either of these amino
acids, there will lack of neurotransmitter synthesis, which is
associated with low mood and
aggression in patients. The excessive buildup of amino acids may
also lead to brain damage and
mental retardation. For example,
excessive amounts of phenylalanine in individuals with the disease called phenylketonuria can
cause brain damage and mental
retardation.10
Omega-3 Fatty Acids
The brain is one of the organs
with the highest level of lipids
(fats). Brain lipids are composed
of fatty acids and are a major
part of its membranes. It has
been estimated that gray matter
contains 50% fatty acids that are
polyunsaturated in nature (about
33% belong to the omega-3 family) and hence are supplied
through the diet. In one of the
first experimental demonstrations
of the effect of nutrients on the
structure and function of the
HS-33
U.S. Pharmacist • November 2009 • www.uspharmacist.com
H E A LT H S Y S T E M S E D I T I O N
Table 3
Effects of Vitamins and Minerals on Depression
NUTRITION AND CLINICAL DEPRESSION
H E A LT H S Y S T E M S E D I T I O N
brain, the omega-3 fatty acid
alpha-linolenic was found to
have a major role. An important
trend has been observed from the
findings of some recent studies
that lowering plasma cholesterol
by diet and medications might
increase depression. Among the
significant factors involved are
the quantity and ratio of omega6 and omega-3 polyunsaturated
fatty acids (PUFAs) that affect
serum lipids and alter the biochemical and biophysical properties of cell membranes. It has
been hypothesized that sufficient
long-chain PUFAs, especially
DHA, may decrease the development of depression.15
The glycerophospholipids in
the brain consist of a high proportion of PUFAs derived from
the essential fatty acids, linoleic
acid, and alpha-linolenic acid.
The main PUFAs in the brain
are DHA, derived from the
omega-3 fatty acid alphalinolenic acid, arachidonic acid,
and docosatetraenoic acid, both
derived from the omega-6 fatty
acid and linoleic acid. Experimental studies have also
revealed that diets lacking
omega-3 PUFAs lead to considerable disturbance in neural
function. 16
REFERENCES
1. Shaheen Lakhan SE, Vieira KF. Nutritional
therapies for mental disorders. Nutr J. 2008;7:2.
2. National Institute of Mental Health. Depression. Bethesda, MD: US Department of Health
and Human Services; 2000 [reprinted September
2002].
3. Bourre JM. Effect of nutrients (in food) on the
structure and function of the nervous system:
update on dietary requirements for brain, part 1:
nicronutrients. J Nutr Health Aging. 2006;
10:377-385.
4. Massimo CM, Ferrara A, Boscati L, et al.
Plasma and platelet amino acid concentrations in
patients affected by major depression and under
Fluvoxamine treatment. Neuropsychobiology.
1998;37:124-129.
5. Shaw K, Turner J, Del Mar C. Tryptophan and
5-hydroxytryptophan for depression. Cochrane
Database of Systematic Reviews. 2002;1:article
CD003198.
6. Rush AJ. The varied clinical presentations of
major depressive disorder. J Clin Psychiatry.
2007;68:4-10.
Age, Depression, and CAM
Anorexia in the elderly may play
an important role in precipitating depression, either by reducing food intake directly or in
response to such adverse factors
as age-associated reductions in
sensory perception (taste and
smell), poor dentition, use of
multiple prescription drugs, and
depression. Currently, to tackle
the problem of depression, many
people are following the complementary and alternative medicine (CAM) interventions. CAM
therapies are defined by the
National Center for Complementary and Alternative Medicine as “a group of diverse medical and health systems,
practices, and products that are
not considered to be a part of
conventional medicine.”17 Mental health professionals need to
be aware that it is likely that a
fair number of their patients
with bipolar disorder might use
CAM interventions. Some clinicians judge these interventions
to be attractive and safe alternatives or adjuncts to conventional
psychotropic medications.
Current research in psychoneuroimmunology and brain
biochemistry indicates the possibility of communication path7. Firk C, Markus CR. Serotonin by stress interaction: a susceptibility factor for the development
of depression? J Psychopharmacol. 2007;21:
538-544.
8. Ruhe HG, Mason NS, Schene AH. Mood is
indirectly related to serotonin, norepinephrine
and dopamine levels in humans: a meta-analysis
of monoamine depletion studies. Mol Psychiatry.
2007;12:331-359.
9. Horrobin DF, Manku MS. Possible role of
prostaglandin E1 in the affective disorders and in
alcoholism. Br Med J. 1980;280(6228):
1363-1366.
10. Bourre JM. Effect of nutrients (in food) on
the structure and function of the nervous system:
update on dietary requirements for brain, part 1:
micronutrients. J Nutr Health Aging.
2006;10:377-385.
11. Abou-Saleh MT, Coppen A. Folic acid and
the treatment of depression. J Psychosom Res.
2006;61:285-287.
12. Levenson CW. Zinc, the new antidepressant?
Nutr Rev. 2006;6:39-42.
13. Eby GA, Eby KL. Rapid recovery from major
ways that can provide a clearer
understanding of the association
between nutritional intake, the
central nervous system, and
immune function, thereby influencing an individual’s psychological health status. These findings
may lead to greater acceptance of
the therapeutic value of dietary
intervention among health practitioners and health care providers
in addressing depression and
other psychological disorders.18
The Safety of
Vitamin Supplements
Vitamin C and the B-complex
vitamins, discussed above, are all
water soluble; therefore, they
cannot accumulate in the body
or be stored for future use.
Amounts above and beyond current nutritional needs are
excreted through urine. As a
result, there is little danger of
overdosing. Unlike water-soluble
vitamins, lipid-soluble vitamins
and minerals can be stored in
body tissues. For therapeutic
doses of these compounds, the
advice of a qualified nutrition
consultant is required. Do not
exceed the recommended therapeutic doses, since accumulation
of certain minerals in the body
can be dangerous. 19
depression using magnesium treatment. Med
Hypotheses. 2006;67:362-370.
14. Benton D. Selenium intake, mood and other
aspects of psychological functioning. Nutr Neurosci. 2002;5:363-374.
15. Bourre JM. Dietary omega-3 fatty acids and
psychiatry: mood, behavior, stress, depression,
dementia and aging. J Nutr Health Aging.
2005;9:31-38.
16. Sinclair AJ, Begg D, Mathai M, Weisinger
RS. Omega-3 fatty acids and the brain: review of
studies in depression. Asia Pac J Clin Nutr.
2007;16:391-397.
17. Roberts SB. Energy regulation and aging:
recent findings and their implications. Nutr Rev.
2000;58:91-97.
18. Andreescu C, Mulsant BH, Emanuel JE.
Complementary and alternative medicine in the
treatment of bipolar disorder: a review of the evidence. J Affect Disord. May 2, 2008 [Epub ahead
of print].
19. Eritsland J. Safety considerations of polyunsaturated fatty acids. Am J Clin Nutr.
2000;71:197S-201S.
HS-34
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Progressive
Supranuclear Palsy
PARKINSON’S-LIKE SYMPTOMS
Difficulty looking up
without extending
the neck or
difficulty climbing
up and down stairs
may signal this
condition.
P
Disability develops in PSP
patients within 3 to 5 years of
diagnosis; death usually occurs
within 10 years of symptom
onset, often secondary to infection (e.g., pneumonia) or other
complications of immobility.2,6,7
Advance directives, such as a living will or durable power of attorney (see Reference 8), should be
prepared by patients diagnosed
with PSP so that they have the
opportunity to indicate the type
of medical treatment they wish to
receive as part of their end-of-life
care plan.6,8
Mary Ann E. Zagaria, PharmD, MS, CGP
Senior Care Consultant Pharmacist and
President of MZ Associates, Inc.
Norwich, New York
www.mzassociatesinc.com
Recipient of the Excellence in Geriatric Pharmacy
Practice Award from the Commission for
Certification in Geriatric Pharmacy
Pathophysiology
and Diagnosis
While PD is slowly progressive
and primarily involves the substantia nigra, patients with PSP
show a degeneration of neurons
that occurs in the basal ganglia—
the part of the brain that helps
coordinate and ensure smooth
body movements—and in the
brain stem, the part of the brain
that controls vital body functions
(e.g., breathing, heart rate, swallowing) and eye movements.1,6 In
addition, neurofibrillary tangles
are detected (containing abnormal
tau protein), and strokes (lacunar)
may occur in the basal ganglia
and deep white matter.1
According to Schneider and
Mandelkow, neurofibrillary tangles are a hallmark of Alzheimer’s
and other neurodegenerative diseases (e.g., PSP, Pick’s disease,
frontotemporal dementia, and
parkinsonism linked to chromosome 17) referred to as
rogressive supranuclear
palsy (PSP) is an uncommon neurodegenerative disorder often misdiagnosed, most
frequently as Parkinson’s disease
(PD).1,2 Although PSP is less
common than PD, both are characterized by progressive loss of
selected neurons in certain areas
of the brain, which causes disease.3,4 Approximately 4% of
patients experiencing parkinsonian symptoms have PSP.2 Few clinicians are proficient at recognizing the nonclassic presentations
of PSP and also at treating it.5
Pharmacists should be aware of
this distinct condition with an
unknown cause, also known as
Steele-Richardson-Olszewski syndrome. Although PSP usually
strikes individuals after age 50
years, some patients can develop
signs in their fourth decade.1,2
tauopathies, since neurofibrillary
tangles are composed of intracellular aggregates of the microtubule-associated protein tau.9
While the mechanisms underlying
tau-mediated neurotoxicity are
not well understood, neurodegeneration and neuronal dysfunction
are associated with pathologic
hyperphosphorylation and aggregation of tau.9 A shared characteristic of PD and PSP is the presence of Lewy bodies (abnormal
intracytoplasmic inclusion
deposits), although Lewy bodies
are found in a minority of PSP
cases.3
Diagnosis of PSP is clinical, by
history and physical examination.2
Neuroimaging is not required for
diagnosis since findings are not
specific.2
Signs and Symptoms
A core feature of PSP is known as
vertical supranuclear gaze palsy,
where the voluntary vertical gaze
is impaired; this causes difficulty
looking up or down without
extending or flexing the neck, or
difficulty climbing up and down
stairs, and may be the first noticeable symptom of the disease.1,2
Shortly after onset of the disorder,
patients present with postural
instability, causing gait unsteadiness and falls (typically backward).2,3 A staring, astonished
appearance may be caused by
retraction of the upper eyelids.2
Other findings (TABLE 1) may
include dysphagia and dysarthria
with emotional lability
(pseudobulbar palsy). Emotional
20
U.S. Pharmacist • November 2009 • www.uspharmacist.com
PROGRESSIVE SUPRANUCLEAR PALSY
lability (with a propensity to
laugh or cry easily) is referred to
as pseudobulbar affect.2 Rigidity,
bradykinesia, and dystonic neck
extension may be present, and
language functions resemble those
evident in PD (i.e., speech may
become incomprehensible, repetitive/babbling, or mute).1-3,7 While
only occasional, a subtle resting
tremor may be present.2
Deficits, similar to those secondary to multiple strokes, occur
in a progressive and usually rapid
fashion.2 In terms of the patient’s
cognition, mental slowing, executive dysfunction (i.e., impairment
of volitional activities such as
planning, organizing, self-awareness, self-regulation, and initiation of action), and memory
impairment (less severe than in
Alzheimer’s disease) occur.1,3,6
Later in the disease, depression
and dementia are common, causing some individuals to experience sleep disturbances, agitation,
and irritability.2,3 Eventually, most
PSP patients require a wheelchair
and a feeding tube.7
Upon initially seeing a patient
with symptoms of PSP, pharmacists may recognize symptoms
that resemble drug-induced
pseudoparkinsonism, most commonly seen with the use of firstgeneration antipsychotic agents of
the phenothiazine (e.g., chlorpromazine), thioxanthene (e.g., thiothixene), or butyrophenone (e.g.,
haloperidol) classes. Based on the
parkinsonian signs and symptoms
and considering that the core
symptom of vertical supranuclear
gaze palsy is not always present in
the early stage of PSP, it is not
difficult to understand how this
disease may be misdiagnosed as
PD, especially since diagnosis is
determined clinically and not by
any substantiating diagnostic test.
Schmidt et al note the most
important features that characterize and differentiate PSP from
other parkinsonian syndromes as
Table 1
Potential Symptoms of Progressive
Supranuclear Palsy
•
•
•
•
•
•
•
•
•
•
•
Loss of voluntary eye movements; particular difficulty with vertical movements,
referred to as vertical supranuclear gaze palsy; inability to fix gaze on a stationary
or moving object (square wave jerks). Reflexive eye movements are unaffected
Other ophthalmic signs and symptoms include blurred vision, diplopia, photophobia, burning, tearing, and upper eyelid retraction
Postural instability causing falls (specifically a tendency to fall backward)
Bradykinesia
Muscular rigidity with progressive dyskinetic movements due to disordered
tonicity of muscle (e.g., dystonic neck extension); subtle resting tremor
(usually absent)
Pseudobulbar palsy: difficulty swallowing (dysphagia) and speech disturbance
(dysarthria) with emotional lability
Cognitive impairment (e.g., mental slowing, executive dysfunction, memory
impairment)
Sleep disturbances (insomnia or hyposomnia)
Agitation, irritability, disinhibition
Depression (late in course)
Dementia (eventually occurs)
Source: References 1-3, 6, 7, 16.
the following: 1) supranuclear
gaze palsy; 2) postural instability;
3) pseudobulbar palsy; and 4)
cognitive disturbances.10 Litvan
et al indicate that which specifically differentiates PSP from
other diseases: 1) PSP from PD is
unstable gait, absence of tremordominant disease, and absence of
a response to levodopa; 2) PSP
from diffuse Lewy body disease is
supranuclear vertical gaze palsy,
gait instability, and the absence
of delusions; 3) PSP from Pick’s
disease is postural instability; 4)
PSP from multiple system atrophy
is supranuclear vertical gaze
palsy and increased age at symptom onset; and 5) PSP from corticobasal degeneration is gait
abnormality, severe upward gaze
palsy, bilateral bradykinesia, and
absence of alien limb
syndrome. 11
Significant autonomic dysfunction may be seen in patients with
PSP as well as in patients with
PD.10 According to Schmidt et al,
the parasympathetic cardiovascular
system appears to be involved to a
similar extent in patients with PD
and patients with PSP, as compared to sympathetic cardiovascular dysfunction, which is more
frequent and severe in patients
with PD but can also be seen in
patients with PSP.10
Treatment
PSP is an incurable condition.
Treatment is supportive and far less
effective than that for Parkinson’s
disease.2 The treatment of PSP
remains unsatisfactory, since only
occasionally do levodopa,
dopamine agonists (TABLE 2),
amantadine, or amitriptyline partially relieve rigidity.1,2 It is presumed that the reason PSP is not
responsive to dopamine replacement or dopamine agonist therapies is that dopamine receptors
are decreased as a result of postsynaptic damage beyond pathological changes seen in PD.12 Symptomatic treatment with drugs and
other therapies should be targeted
at reducing morbidity and
improving quality of life (e.g.,
depression can be treated with
21
U.S. Pharmacist • November 2009 • www.uspharmacist.com
PROGRESSIVE SUPRANUCLEAR PALSY
selective serotonin reuptake
the short-term effects of
Table 2
inhibitors).5,7 Pharmacists
coenzyme Q10 in PSP.15
should note that prior to
Dopamine Agonists Used in the Results indicated significant
initiating any treatment, the Treatment of Parkinson’s Diseasea changes in the occipital lobe
and a consistent trend in the
overall benefit-to-risk ratio
Apomorphine (Apokyn)
basal ganglia.15 Coenzyme Q
to the individual patient
Bromocriptine
(Parlodel)
10 treatment compared to
must be considered.
Pramipexole (Mirapex)
placebo showed clinical
Due to adverse effects
Ropinirole (Requip, Requip XL)
improvement according to
associated with dopamine
b
Rotigotine transdermal (Neupro [DSC])
the PSP rating scale and the
agonists—including nausea,
a
Refer to manufacturer’s prescribing information for comFrontal Assessment Battery;
hypotension, confusion, and
plete dosing guidelines.
although the improvement
hallucinations—their utility
b
Currently unavailable in the United States.
was slight, it was noted as
is severely limited.4 A
Source: References 4, 14, 17.
recently published reassesssignificant.15 The researchers
concluded that since coenzyme Q
ment of risks and benefits of
the central nervous system effects
10 appears to improve cerebral
dopamine agonists in PD has
of amantadine; the use of two
energy metabolism in PSP, longrevealed the occurrence of increas- divided daily doses may minimize
ingly recognized adverse effects
this effect.14 In patients with renal term treatment might have a disimpairment, amantadine requires
ease-modifying, neuroprotective
such as lower extremity edema,
renal dosing based on estimated
effect.15
daytime somnolence, impulse
13
creatinine clearance. Monitoring
control disorders, and fibrosis.
The antiviral agent amantaparameters for amantadine therapy Conclusion
dine was accidentally discovered
include renal function, Parkinson’s In PSP, neurodegenerative
changes take place in the brain
to have an antiparkinsonism
symptoms, mental status, and
stem, basal ganglia, and elseaction (e.g., increasing release of
blood pressure.14
Nonpharmacologic measures
where; neurofibrillary tangles are
dopamine among other effects).4
Adverse effects associated with
introduced early in the course of
present. While PSP continues to
amantadine therapy include rest- disease may include weighted
be an underrecognized disorder
lessness, agitation, confusion,
walking aids or wheelchairs to pre- and is often misdiagnosed, it can
and hallucinations; high doses
vent falls, and adaptive eyeglasses
be differentiated from other akimay result in an acute toxic psy(e.g., bifocals, prisms) to improve
netic rigid syndromes such as
chosis.4 Peripheral edema, ortho- vision.2 Also important in the
PD.5 Diagnosis of this debilitating
static hypotension, urinary reten- early stage of the illness is the
disorder is clinical and treatment is
tion, dry mouth, and livedo
introduction of physical therapy,
supportive. Risks associated with
reticularis (i.e., red to blue skin
occupational therapy, and speech
potential adverse effects of treatdiscoloration on the limbs and
therapy as supportive measures.2
ment should be considered in the
trunk that intensifies upon expo- Thus far, surgical approaches to
formulation of an individualized
PSP have proven ineffective.5
sure to cold) may also occur.1,4
pharmaceutical care plan. Early
The geriatric patient populaA randomized, placebo-condiscussion about end-of-life issues
tion may be more susceptible to
trolled trial in Germany looked at is advised.
REFERENCES
1. Beers MH, Porter RS, Jones TV, et al. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:1885.
2. Progressive Supranuclear Palsy. In: Beers MH, Jones
TV, Berkwits M, et al, eds. The Merck Manual of Geriatrics. Updated June 2006.
www.merck.com/mkgr/mmg/sec6/ch46/ch46d.jsp.
Accessed October 19, 2009.
3. Craft S, Cholerton B, Reger M. Aging and cognition:
what is normal? In: Hazzard WR, Blass JP, Halter JB, et
al, eds. Principles of Geriatric Medicine and Gerontology.
5th ed. New York, NY: McGraw-Hill, Inc; 2003:13551372.
4. Howland RD, Mycek MJ. Pharmacology. 3rd ed.
Philadelphia, PA: Lippincott Williams & Wilkins;
2006:91-101.
5. Lubarsky M, Juncos JL. Progressive supranuclear palsy:
a current review. Neurologist. 2008 Mar;14(2):79-88.
6. Beers MH, Jones TV, Berkwits M, et al, eds. The
Merck Manual of Health & Aging. Whitehouse Station,
NJ: Merck Research Laboratories; 2004:367-369.
7. Chand P, Litvan I. Progressive supranuclear palsy and
corticobasal degeneration: similarities and differences.
Future Neurol. May 2008. www.medscape.com/viewarticle/578084. Accessed October 21, 2009.
8. Zagaria ME. The dying patient: choices, control, and
communication. U.S Pharm. 2009;34(10):32-34.
9. Schneider A, Mandelkow E. Tau-based treatment
strategies in neurodegenerative diseases. Neurotherapeutics.
2008;5(3):443-457.
10. Schmidt C, Herting B, Prieur S, et al. Autonomic
dysfunction in patients with progressive supranuclear
palsy. Mov Disord. 2008;23(14):2083-2089.
11. Litvan I, Campbell G, Mangone CA, et al. Which
clinical features differentiate progressive supranuclear
palsy (Steele-Richardson-Olszewski syndrome) from
related disorders? A clinicopathological study. Brain.
1997;120(pt 1):65-74.
12. Nelson MV, Berchou RC, LeWitt PA. Parkinson’s disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New
York, NY: McGraw-Hill, Inc; 2005:1075-1088.
13. Antonini A, Tolosa E, Mizuno Y, et al. A reassment of
risks and benefits of dopamine agonists in Parkinson’s disease. Lancet Neurol. 2009;8:929-937.
14. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage
Handbook. 14th ed. Hudson, OH: Lexi-Comp, Inc;
2009.
15. Stamelou M, Reuss A, Pilatus U, et al. Short-term
effects of coenzyme Q10 in progressive supranuclear
palsy: a randomized, placebo-controlled trial. Mov Disord.
2008;23(7):942-949.
16. Dorland’s Pocket Medical Dictionary. 28th ed. Elsevier
Saunders; 2009.
17. My Epocrates. Version 1.0. Updated October 6,
2009.
22
U.S. Pharmacist • November 2009 • www.uspharmacist.com
FDA Fast Facts
New Leukemia
Treatment Fast Tracked
The FDA approved ofatumumab (Arzerra) for
treating patients with
chronic lymphocytic
leukemia (CLL), a blood
and bone marrow cancer.
Ofatumumab was
approved using the accelerated approval process for
patients with CLL whose
cancer is uncontrolled by
other types of chemotherapy. The effectiveness of
the drug was evaluated in
59 patients with CLL
whose disease no longer
responded to the available
therapies. CLL, which
arises from B cells found
in the body’s immune system, mainly afflicts
patients older than 50
years, killing about 4,400
people each year.
“The approval of
Arzerra illustrates FDA’s
commitment to using the
accelerated approval
process to approve drugs
for patients who have
limited therapeutic
options,” said Richard
Pazdur, MD, director of
the Office of Oncology
Drug Products in the
FDA’s Center for Drug
Evaluation and Research.
The manufacturer, GlaxoSmithKline, is currently
conducting a clinical trial
to verify that ofatumumab added to standard chemotherapy delays
CLL progression.
Marketing of Illegal
Opioids Halted
The FDA warned four
FDA Marks AIDS Program Milestone
The U.S. Department of Health and Human Services (HHS) marked the
recent approval of the 100th antiretroviral drug in association with the
President’s Emergency Plan for AIDS Relief (PEPFAR), which is designed
to prevent HIV/AIDS and to treat and care for patients and those
affected by the disease worldwide. The PEPFAR program is a joint effort
involving the FDA and other HHS agencies, the State Department’s
Office of the U.S. Global AIDS Coordinator, the U.S. Department of
Defense, other federal agencies, host country governments, and other
international partners. “This milestone exemplifies the dedication, caring,
and hard work of all who strive to better the lives of those infected with
or affected by HIV/AIDS,” said HHS Secretary Kathleen Sebelius.
Drug products used in PEPFAR receive a tentative approval and cannot be approved for marketing in the United States due to current patents
and marketing exclusivity, yet the drugs must meet the same manufacturing, safety, and efficacy standards required for marketing in this country.
As of October 6, 2009, more than 100 products had been assessed by the
FDA as part of the PEPFAR program and either fully or tentatively
approved. Of these, 29 were new products, 71 were versions of drugs
approved in the U.S., and 22 were new combinations or regimens not
previously authorized in the U.S. In 2008, PEPFAR provided almost $1.6
billion in support of HIV/AIDS treatment programs.
companies that they
must stop marketing
unapproved codeine sulfate tablets, opioid analgesics used to treat pain.
These particular products have not received
FDA approval, and the
agency has no evidence
that they are safe and
effective. Another manufacturer, Roxane Laboratories, markets approved
codeine sulfate tablets,
and the FDA does not
expect a shortage in the
supply of these drugs.
The products and the
manufacturers and distributors that received
the warning letters are:
Codeine Sulfate Tablets,
30 mg, 60 mg (Lehigh
Valley Technologies Inc.,
Allentown, Pennsylva-
nia); Codeine Sulfate
Tablets, 30 mg, 60 mg
(Cerovene Inc., Valley
Cottage, New York);
Codeine Sulfate Tablets,
30 mg (Dava International Inc., Fort Lee,
New Jersey); and
Codeine Sulfate Tablets,
30 mg, 60 mg (Glenmark Generics Inc.
USA, Mahwah, New Jersey). Companies receiving the warning letters
have 15 days to give the
FDA a plan to discontinue marketing the
unapproved drugs.
New Web Page
Details Disposal
Instructions
The FDA launched a
Web page for consumers
with information on
24
U.S. Pharmacist • November 2009 • www.uspharmacist.com
how to dispose of certain drugs, including
high-potency opioids
and other potentially
harmful controlled substances. The FDA recommends that these
medicines be disposed of
by flushing them down
the sink or toilet to keep
them away from children and others. Medicines not listed should
be thrown away in the
household trash after
mixing them with some
unpalatable substance,
such as coffee grounds,
and sealing them in a
bag or other container.
Another option is to dispose of them through
drug take-back programs, federal and state
law permitting.
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So Many Options,
So Little Difference
in Efficacy
What Is the Appropriate
Antidepressant?
© JUPITERIMAGES
ncertainty is high when it comes to selecting What Is Depression?
the appropriate antidepressant for patients diag- Depression can be a chronic or recurrent mental disnosed with major depressive disorder (MDD), order that presents with several symptoms such as
not only because studies have reported no differences in depressed mood, loss of interest or pleasure, feelings
efficacy between agents, but also because only 11% to of guilt, disturbed sleep or appetite, low energy, and
30% of patients will reach remission with initial treat- difficulty thinking.7 Depression can lead to substanment, even after a year.1,2 This consequently has led clin- tial impairment in an individual’s ability to take care
icians to practice in a trial-and-error fashion to treat of everyday responsibilities. Depression can also lead to
depression.3 Furthermore, the last major revision of the suicide, a tragedy accounting for the loss of about
Diagnostic and Statistical Manual of Mental Disorders 850,000 lives worldwide every year.7
(DSM-IV-TR) was produced in 2000.4 In 2005, a guideline watch was published to review important safety con- Prevalence and At-Risk Populations
cerns that had emerged about some agents, such as There are an estimated 121 million people worldwide
nefazodone, as well as to review two new antidepressants affected with depression.7 In 2000, depression was the
approved that year, escitalopram and duloxetine.5 Revi- fourth leading contributor to the global burden of dission and update of the DSM-IV-TR (DSM-V manuscript) ease among all diseases, and by 2020 it is anticipated
is not due until May 2012. Therefore, there is need for that it will rise to the number-two leading contributor
an up-to-date review to assist clinicians in deciding on to the global burden of disease, second only to heart
the appropriate agents to treat individual patients.
disease.7
Populations at higher risk for developing depression
The 2007 Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) study attempted to develop and include women, people between the ages of 24 and 45
evaluate feasible treatment strategies to improve clinical years, and those with first-degree relatives with depresoutcomes for patients with treatment-resistant depres- sion. Women are at increased risk for depression until
sion who were identified with a current major depressive their 50s, and their lifetime risk is two times greater than
episode.6 Specifically, STAR*D aimed to determine which men’s. People between the ages of 24 and 45 years
of several treatments is the most effective “next step” for experience the highest rate of depression. Finally, firstpatients who do not reach remission with an initial or degree relatives of depressed patients are 1.5 to 3 times
subsequent treatment or who cannot tolerate the treat- more likely to experience depression than others.4,8
ment. The overall results of this study demonstrated that
pharmacologic differences between psychotropic medi- Pathophysiology and
cations did not translate into substantial clinical differ- Pharmacotherapy Rationale
Biological and psychosocial causes have been hypothences, although tolerability differed.6
The purpose of this article is to review treatment evi- esized in an attempt to describe the pathophysiology of
dence available in the literature in
depression. Pharmacologic agents will
Rochette DeLucia, PharmD, MS
order to provide a quick reference that Marjorie
target the biological causes linked to
PGY1 Pharmacy Practice Resident
will help clinicians decide on the
dysregulation in the neurotransmitBaptist Medical Center
appropriate agent, taking into conters. This dysregulation is often
Jacksonville, Florida
sideration adverse effects, drug interdescribed as a deficiency in brain neuMichael J. Schuh, PharmD, MBA
actions, and medication safety, as well
rotransmitter levels. Norepinephrine,
Ambulatory Pharmacist, Mayo Clinic
as patient characteristics.
serotonin, and dopamine levels
Jacksonville, Florida
U
26
U.S. Pharmacist • November 2009 • www.uspharmacist.com
WHAT IS THE APPROPRIATE ANTIDEPRESSANT?
Table 1
Selective Serotonin Reuptake Inhibitors
Medications
Initial/Max Dose
Comments
Adverse Effects
Citalopram
(Celexa)
20 mg/60 mg daily
(40 mg max effective)
t1/2 = 35 h; weak CYP2D6 inhibitor; anxiety symptoms
significantly improved compared to other SSRIs
Escitalopram
(Lexapro)
10 mg/20 mg daily
(10 mg max effective)
t1/2 = 35 h; most potent SSRI;
like citalopram, fewer drug interactions
Fluoxetine
(Prozac)
20 mg/80 mg daily
Long t1/2 = 7-15 days; active metabolite norfluoxetine;
potent CYP2D6 inhibitor = drug interactions;
may cause weight loss
Fluvoxamine
(Luvox)
50 mg/300 mg in
divided doses
t1/2 = 16 h adults, 26 h elderly; potent CYP3A4, 2C19,
1A2 inhibitor = most drug interactions; primarily
used to treat OCD and panic disorders
Weight gain,
insomnia,
tremors,
prolonged QT
interval, dizziness,
constipation, dry
mouth, nausea,
lightheadedness,
syncope,
confusion,
agitation, sexual
dysfunction
Paroxetine
(Paxil)
20 mg/60 mg daily
(50 mg max effective)
t1/2 = 26 h; potent CYP2D6 inhibitor; mild affinity for
muscarinic receptors = more anticholinergic side
effects than other SSRIs; sedating
Sertraline
(Zoloft)
50 mg/200 mg daily
t1/2 = 26 h; absorption increases when taken with food;
weak CYP2D6 inhibitor = less potential drug interactions;
more likely than other SSRIs to cause nausea; most
cited reason for d/c
d/c: discontinuation; max: maximum; OCD: obsessive compulsive disorder; SSRI: selective serotonin reuptake inhibitor; t1/2: half-life.
Source: References 4, 10.
may be decreased in patients with depression, thus associating a decreased amount of neurotransmitters with
the disorder. 8 The pharmacotherapy rationale has
been to boost these deficiencies by blocking the reuptake or preventing enzymatic metabolism of neurotransmitters via antidepressants. Overall, these mechanisms
aim at increasing the level of neurotransmitters either
by forcing the neuron to fire more often and produce
more neurotransmitters or by preventing degradation
of the neurotransmitter itself.
Pharmacologic Agents
Several classes of agents are currently available to treat
depression. They include selective serotonin reuptake
inhibitors (SSRIs), tricyclic antidepressants (TCAs),
monoamine oxidase inhibitors (MAOIs), and serotoninnorepinephrine reuptake inhibitors (SNRIs), among
others.
Antidepressants have been associated with an increased
risk of suicidal thinking and suicidality in children, adolescents, and young adults in short-term placebo controlled studies of MDD. Anyone considering the use
of any antidepressant in a child, adolescent, or young
adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in
adults beyond age 24 years, and there was a reduction
in risk with antidepressants compared to placebo in
adults aged 65 years and older. Depression and other
psychiatric disorders are themselves associated with
increased risk of suicide. Patients of all ages who are
started on antidepressant therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.9
Selective Serotonin Reuptake Inhibitors4,10: SSRIs are
considered first-line agents when it comes to treating
patients with depression. These drugs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (TABLE 1). The major adverse effects
of this class include nausea, vomiting, and diarrhea,
which are dose-dependent effects and tend to dissipate
after the first weeks of treatment. In some patients,
SSRIs can cause agitation and sleep disturbances, which
will also dissipate with time. Sexual dysfunction is a
side effect present with all antidepressants, but seems
to be most common with SSRIs.
Serotonin syndrome (i.e., abdominal pain, diarrhea,
sweating, mental status change, renal failure, cardiovascular shock, and possibly death) is a rare adverse effect
of SSRIs. Serotonin syndrome can occur with an increase
in SSRI dose or by taking SSRIs with herbals such as
St. John’s wort or with illicit drugs. Finally, combining
SSRIs with MAOIs can also lead to lethal drug interactions with development of serotonin syndrome. When
clinicians feel the need to switch from one class of agent
to the other, it is suggested that at least five half-lives
elapse between the time the SSRI is stopped and the
MAOI is started.4 Of all agents in the class, fluvoxamine has the highest rate of drug interactions, since it
29
U.S. Pharmacist • November 2009 • www.uspharmacist.com
WHAT IS THE APPROPRIATE ANTIDEPRESSANT?
Table 2
Tertiary and Secondary Amine Tricyclic Antidepressants
Medications
Initial/Max Dose
Comments
Adverse Effects
Amitriptyline (Elavil)
25-75 mg/200 mg daily
5HT > NE
Amoxapine (Asendin)
50 mg bid/400 mg daily
5HT = NE, weak DA
Orthostatic
hypotension,
drowsiness, weight
gain, anticholinergic,
QT prolongation (in
overdose)
Tertiary Amine TCAs
Clomipramine (Anafranil) 25 mg/250 mg daily
5HT > NE
Doxepin (Sinequan)
50-75 mg/300 mg daily
5HT = NE; highly sedating
Imipramine (Tofranil)
50-100 mg/200 mg daily
5HT = NE
Secondary Amine TCAs
Desipramine (Norpramin) 100-200 mg/300 mg daily
NE > 5HT; metabolite of imipramine
Maprotiline (Ludiomil)
25 mg tid/225 mg daily
NE > 5HT
Nortriptyline (Pamelor)
25-50 mg/150 mg daily
NE > 5HT; metabolite of amitriptyline
Same as above, but
with more drowsiness,
somnolence, and weight
gain than tertiary
DA: dopamine; 5HT: serotonin; max: maximum; NE: norepinephrine; TCA: tricyclic antidepressant. Source: References 4, 10.
inhibits several hepatic enzymes such as CYP450 1A2,
2C19, 2C9, 2D6, and 3A4. Fluoxetine follows fluvoxamine’s drug interaction rate closely with inhibition of
CYP 2C9, 2D6, and 3A4. Finally, citalopram and escitalopram have the least drug interactions, since they
inhibit 2D6 enzymes to a lesser extent.
When considering patient characteristics and
safety, SSRIs are safe to use in most patient groups,
including those with preexisting cardiac disease, asthma,
dementia, and hypertension. The elderly, who are particularly prone to orthostatic hypotension as well as
weight loss, may benefit most from using SSRIs since
those agents produce weight gain and lack anticholinergic activity.
Tricyclic Antidepressants4,10: TCAs block norepinephrine
and serotonin reuptake, but they also have affinity for
alpha1, H1, and muscarinic receptors, thus causing anticholinergic adverse effects. There are two subclasses of
agents available within this class, the tertiary and secondary amine TCAs (TABLE 2). The secondary amine
TCAs (desipramine, maprotiline, nortriptyline) have
less affinity for the alpha1, H1, and muscarinic receptors, therefore causing fewer anticholinergic adverse
effects than the tertiary amine TCAs (e.g., amitriptyline, amoxapine, clomipramine, doxepin, imipramine).
The main adverse effects of this class of agents are
orthostatic hypotension, QT prolongation, drowsiness,
dry mouth, blurred vision, constipation, and weight
gain. In general, tertiary amine TCAs have more serotonin activity versus secondary amine TCAs, which have
more norepinephrine activity, thus causing less drowsiness, somnolence, and weight gain.
It is known that TCAs inhibit both CYP 2C19 and
2D6 enzymes.11 They are also metabolized to a lesser
extent by CYP 1A2 and 3A4 enzymes.12 For this reason, although drug–drug interactions with these agents
might not be the primary concern, it is advised to use
caution when combining TCAs with SSRIs, since the
drug plasma level of TCAs has the potential to increase
by up to fourfold, possibly leading to toxic effects.13,14
When considering patient characteristics and
safety, TCAs are contraindicated in some specific cardiac conditions such as patients with a history of arrhythmias, sinus node dysfunction, or conduction defects.
Caution is advised with the elderly, as they are more
sensitive to cholinergic blockade as well as orthostatic
hypotension. Furthermore, individuals also suffering
from dementia will be particularly susceptible to the
toxic effects of muscarinic blockade on memory and
attention span and would generally do best if given
antidepressants with the lowest degree of anticholinergic effects. Finally, caution should be exercised when
considering starting TCAs in patients with suicidal
thoughts due to high lethality risks with overdose.
The lethal dose is only eight times the therapeutic dose,
so if TCAs are ingested in an overdose, they may
block the sinoatrial node in the heart.
Monoamine Oxidase Inhibitors4,10: The MAOIs that
are available include isocarboxazid, phenelzine, selegiline, and tranylcypromine (TABLE 3). Aside from selegiline, which is a selective MAO B inhibitor, all other
agents inhibit both MAO A and B enzymes responsible for serotonin, norepinephrine, and dopamine metabolism
in the brain. Due to severe adverse effects and required
diet restrictions, MAOIs are generally reserved for patients
who have failed other antidepressants.
Hypertensive crisis can occur when patients taking
MAOIs ingest foods containing tyramine, such as beer,
30
U.S. Pharmacist • November 2009 • www.uspharmacist.com
WHAT IS THE APPROPRIATE ANTIDEPRESSANT?
Table 3
Monoamine Oxidase Inhibitors
Medications
Initial/Max Dose
Isocarboxazid (Marplan)
Phenelzine (Nardil)
Selegiline (Emsam)a
Tranylcypromine (Parnate)
Comments
Dietary restrictions: no
10 mg bid/60 mg daily
foods containing tyramine
15 mg tid/90 mg daily
(e.g., beer, wine, aged
6 mg/12 mg (24-h transdermal patch) cheese, soy sauce,
bananas, smoked meat)
30 mg/60 mg (divided doses)
Adverse Effects
HTN crisis: palpitations,
chest pain, muscle rigidity;
5HT syndrome: nausea,
sedation, diaphoresis,
confusion, HTN
a
Selective monoamine oxidase B inhibitor. 5HT: serotonin; HTN: hypertension; max: maximum.
Source: References 4, 10.
wine, aged cheese, and smoked meat. This reaction
presents as an acute onset of severe headache, nausea,
neck stiffness, heart palpitations, chest pain, and confusion. MAOIs can also cause serotonin syndrome. As
mentioned previously, this syndrome most commonly
occurs when MAOIs are taken concomitantly with other
serotonergic agents such as SSRIs or if venlafaxine, an
SNRI, is administered soon after an MAOI. When
patients are switched from an SSRI with a short halflife to an MAOI, it is important that a 2-week washout
period be respected between the discontinuation of the
SSRI and the start of the MAOI. If fluoxetine is the
SSRI, which has a long half-life, the washout period
should be 5 weeks.4 Other adverse effects can occur with
MAOIs such as orthostatic hypotension, weight gain,
sexual dysfunction, and insomnia.
Due to the high rate of drug interactions with these
agents, caution should be used when prescribed to
patients with asthma using sympathomimetic bronchodilators. In patients with hypertension, MAOIs may
induce orthostatic hypotension, especially with concurrent diuretic treatments.
Serotonin-Norepinephrine Reuptake Inhibitors4,10:
The SNRIs such as desvenlafaxine, duloxetine, and venlafaxine may also be used as first-line agents (TABLE 4).
These medications are safer than TCAs, and their adverse
effects are similar to those of SSRIs, including nausea,
vomiting, and sexual dysfunction, as well as elevated
blood pressure.
Venlafaxine has been shown to cause an increase in
blood pressure in 3% to 13% of cases, while desvenlafaxine was reported to cause an increase in blood pressure in only 1% to 2% of cases.10 Thus, it is recommended to avoid using venlafaxine in patients with
uncontrolled hypertension since the agent can exacerbate the condition. Duloxetine has more norepinephrine
activity than both of the aforementioned agents, thus
being useful with physical symptoms such as muscle
aches, headaches, stomach issues, and generalized pain,
often occurring with severely depressed patients. Due
to its effectiveness in pain symptoms, duloxetine has
also been approved for other indications such as fibromyalgia and diabetic peripheral neuropathic pain.15 Finally,
all three agents have more serotonin than norepinephrine
Table 4
Serotonin-Norepinephrine Reuptake Inhibitors
Medications
Initial/Max Dose
Comments
Adverse Effects
Desvenlafaxine
(Pristiq)
50 mg/100 mg
daily (50 mg max
effective dose)
Active metabolite of venlafaxine;
BP elevation reported to be less
common than with venlafaxine
Duloxetine
(Cymbalta)
40 mg/
60 mg daily
t1/2 = 12 h; moderate inhibitor of
CYP2D6; GI adverse effects (nausea,
dry mouth, constipation) are common;
unique beneficial treatment for physical
pain associated with depression
Similar adverse
effects to SSRIs,
except more
incidence of BP
elevation with
SNRIs
Venlafaxine
(Effexor)
25 mg tid/
225 mg daily
5HT > NE at lower doses; NE > 5HT at
higher doses; t1/2 = 11 h; inhibitor of CYP2D6
BP: blood pressure; 5HT: serotonin; GI: gastrointestinal; max: maximum; NE: norepinephrine; SNRI: serotonin-norepinephrine
reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; t1/2: half-life.
Source: References 4, 10.
36
U.S. Pharmacist • November 2009 • www.uspharmacist.com
WHAT IS THE APPROPRIATE ANTIDEPRESSANT?
Table 5
Other Antidepressants
Medications
Initial/Max Dose
Comments
Adverse Effects
Bupropion IR (Wellbutrin)
100 mg bid/
150 mg tid
Contraindicated in patients with anorexia,
bulimia, or seizure disorders
Bupropion SR (Budeprion SR,
Wellbutrin SR, Buproban)
150 mg/
200 mg bid
Bupropion XL (Wellbutrin XL,
Budeprion XL)
150 mg/
450 mg daily
Similar to SSRIs but
with less 5HT adverse
effects such as nausea,
somnolence, and
weight gain; no sexual
dysfunction
NDRIs
Mixed-Action Antidepressants
Mirtazapine (Remeron)
15 mg/
45 mg daily
Blocks alpha2, 5HT2a,c, 5HT3,
and H1 receptors
More weight gain, less
sexual dysfunction,
insomnia
Nefazodone (Serzone)
100 mg bid/
300 mg bid
Blocks 5HT2a and 5HT reuptake;
3A4 inhibitor = many drug
interactions will limit use
Black box warning =
hepatotoxicity
Trazodone (Desyrel)
150 mg/
600 mg daily
Blocks 5HT2 and alpha1 receptors
Too much sedation
limits use
5HT: serotonin; IR: immediate release; max: maximum; NDRI: norepinephrine-dopamine reuptake inhibitor; SR: sustained release;
SSRI: selective serotonin reuptake inhibitor; XL: extended release. Source: References 4, 10.
activity at lower doses and more norepinephrine than
serotonin activity at higher doses, thus having dosedependent adverse effects.
ory impairment, dry mouth, and constipation may occur.
Caution is also advised with trazodone use in men due
to risk of priapism.
Other Antidepressants4,10: Several other antidepressants
are available that differ in their mechanism of action
from the classes of medications described previously.
The norepinephrine-dopamine reuptake inhibitors
(NDRIs) such as bupropion immediate-release (IR)
branded Wellbutrin (also available in long-acting dosage
forms such as Wellbutrin XL, Wellbutrin SR, Budeprion SR, Budeprion XL, and Buproban) may be used
as first-line agents to treat depression (TABLE 5). Their
adverse effects are similar to those of SSRIs, with minimal serotonin effects such as nausea and weight gain
and little or no sexual dysfunction. Bupropion has been
shown to exert beneficial effects on Parkinson’s disease
symptoms in some patients, but it may also induce some
psychotic symptoms, perhaps because of its agonistic
action on the dopaminergic system.16
Finally, there are three more antidepressants with
mixed action available: mirtazapine, nefazodone, and
trazodone (TABLE 5). All three agents block different
serotonin receptors, thus having distinct effects. Mirtazapine causes more weight gain by increasing appetite.
Nefazodone has limited uses because of hepatotoxicity
and CYP3A4 enzyme inhibition, which leads to drug
interactions. Trazodone blocks serotonin receptors to
a great extent, with poor binding to muscarinic receptors. Adverse effects such as sedation, headache, mem-
Conclusion
In general, antidepressant medications have been
shown to be equally efficacious; therefore, medication
choice should be based on adverse effects, drug interactions, safety, and patient preferences. Several algorithms
are available to guide the clinician during the patient’s
treatment, particularly the recently updated Texas Department of State Health Services algorithm for the treatment of MDD (updated July 2008).17 If patients show
partial response, clinicians may choose to increase the
dose, change to an alternative agent, or give a combination of antidepressants. On the contrary, if patients do
not respond or cannot tolerate the drug, switching to
an alternative agent is also appropriate, taking into consideration that therapeutic effects will usually occur
between 4 to 6 weeks, even though adverse effects
might appear after 1 week of treatment.4,17 In addition,
while the adverse effects appear early in treatment, they
generally dissipate after 2 to 3 weeks.4,17 Nonetheless, the
antidepressant that will most likely ensure a patient’s
improvement and safety may be determined, at least partially, by trial and error. Given the difficulty in predicting what medication will be both efficacious for and
tolerated by an individual patient, familiarity with a broad
spectrum of antidepressants is prudent and useful.
References available online at www.uspharmacist.com.
39
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Medications
Used in Opioid
Maintenance
Treatment
F
or the community pharmacist, the ability to aid
in the management of opioid dependence is vital
to closing the gap between treated and untreated
opioid-dependent individuals. In the United States,
approximately 2 million adults are dependent on
heroin or other nonmedically prescribed opioids, yet only
about 14% receive treatment.1,2 In an effort to provide
care to a greater number of patients with dependence or
addiction treatment needs, the Drug Addiction Treatment Act of 2000 (DATA 2000) was passed. DATA 2000
states that physicians who qualify can treat opioid dependence in the office setting with a schedule III, IV, or V
drug that is FDA-approved for this indication.3 In 2002,
buprenorphine (Subutex) and buprenorphine/naloxone
(Suboxone) sublingual tablets were approved for the management of opioid dependence. As the practice of treating opioid dependence expands, pharmacists must become
familiar with this chronic condition and stay up-to-date
with current treatment options for patients on maintenance therapy.
© MEDI-MATION LTD / PHOTO RESEARCHERS, INC
Many characteristics of opioids, especially onset of
action and half-life, contribute to the potential for dependence and to the onset of withdrawal. Withdrawal may
present as anxiety, bone pain, chills, piloerection, sweating, nervousness, nausea, diarrhea, rhinorrhea, or constant yawning. More severe symptoms include hot and
cold flashes, increased blood pressure and pulse, mydriasis, abdominal and muscle cramps, and vomiting. Symptoms continue for 48 to 96 hours after the last dose, but
may persist for weeks to months in some individuals.6 See
TABLE 1 for withdrawal profiles of various opioids.
PHARMACOLOGIC TREATMENT
There are three major approaches to opioid dependence:
opioid detoxification, agonist maintenance, and antagonist maintenance. Opioid detoxification, also known as
medically supervised withdrawal, is utilized mainly to
transition into or out of a maintenance program, over a
very short period of time. In antagonist maintenance,
naltrexone—an opioid antagonist like naloxone—is used.
Unlike naloxone, it can be used orally because of its supeNEUROBIOLOGY OF OPIOID
rior bioavailability. Unfortunately, neither opioid
DEPENDENCE AND WITHDRAWAL
detoxification nor antagonist maintenance has proved to
Over the past 30 years, much has been discovered be as efficacious as agonist maintenance for producing
about opioid dependence that has improved our under- long-term abstinence.7 However, research is being constanding of addiction as a chronic disease. Opioids acti- ducted using novel approaches like rapid detoxification
vate specific opioid receptors (mu, delta, and kappa). Ini- under general anesthesia and subcutaneous naltrexone
tially, when heroin or other short-acting opioids are taken, implantation.8,9
To be an effective option for maintenance treatment,
receptor agonists induce euphoria. Subsequent doses will
quickly produce tolerance—the need for increasingly an agent must be able to do the following: block the
higher doses to induce the same effect—and physical euphoric and sedating effects of dependent opioids; relieve
dependence. Currently, it is believed that tolerance is a the cravings (the major cause of relapse); relieve and
result of a reduction in either the number or the prevent withdrawal symptoms; permit the patient to participate in society; and allow for at least once-daily dosresponsivity of opioid receptors.4,5
Chronic exposure to opioids causes upregulation of the ing.10 The pharmacologic agents that embody these charcyclic adenosine monophosphate signaling pathways in acteristics and have proven their efficacy are buprenorphine,
neurons that are responsible for the
buprenorphine/naloxone, and methadone
Christie Choo, PharmD, BCPS
release of noradrenaline. When the
(see TABLE 2).
Assistant Clinical Professor
inhibitory opioid is no longer present,
College of Pharmacy and Allied Health
Methadone and Levo-Alpha
the firing rates of these neurons are
Professions, St. John’s University
Jamaica, New York
Acetyl Methadol (LAAM)
unopposed and result in adrenergic overClinical Manager–Internal Medicine
activation, which manifests as the con- New York–Presbyterian/Columbia University Methadone, a schedule II controlled
substance, has been the most frequently
stellation of withdrawal symptoms.4,5
Medical Center, New York, New York
40
U.S. Pharmacist • November 2009 • www.uspharmacist.com
OPIOID MAINTENANCE TREATMENT
Table 1
Comparison of Opioid Withdrawal Profiles
Drug
Dose Equivalent to
Methadone 1 mg
Time for Effects
to Wear off
Onset of
Withdrawal
Peak of
Withdrawal
End of
Withdrawal
Fentanyl
Meperidine
Oxycodone
Hydromorphone
Heroin
Morphine
Codeine
Hydrocodone
Methadone
0.01 mg
20 mg
1.5 mg
0.5 mg
1-2 mg
3-4 mg
30 mg
0.5 mg
NA
1h
2-3 h
3-6 h
4-5 h
4h
4-5 h
4h
4-8 h
8-12 h
3-5 h
4-6 h
8-12 h
4-5 h
8-12 h
8-12 h
8-12 h
8-12 h
36-72 h
8-12 h
8-12 h
36-72 h
36-72 h
36-72 h
36-72 h
36-72 h
36-72 h
96-144 h
4-5 days
4-5 days
≈7-10 days
≈7-10 days
7-10 days
7-10 days
≈7-10 days
≈7-10 days
14-21 days
NA: not applicable.
Source: Reference 6.
used medication in opioid treatment programs. Access
to methadone for the treatment of opioid dependence
is available only through DEA-licensed methadone
clinics. LAAM is no longer being produced or marketed because of the increased risk of cardiac death.
Clinical Pharmacology: Both methadone and LAAM
are synthetic mu-opioid receptor agonists, like heroin,
and serve to replace heroin or other opioids’ occupation
of mu-opioid receptors. Methadone also is an N-methylD-aspartate antagonist.
Methadone is a highly fat-soluble drug that is
rapidly and extensively absorbed. The oral suspension
has variable bioavailability (range 36% to 100%) and
reaches its peak effects 1 to 7.5 hours after intake.11
Methadone is a 50:50 racemic mixture. The R-enantiomer has a significantly higher affinity to mu and kappa
receptors. Methadone has an average half-life of 24 hours
(range 13 to 50 hours). Metabolism of the drug occurs
through the CYP450 system—mainly CYP3A4, but also
CYP2B6, CYP2C9, CYP2C19, and CYP2D6. Methadone
is an inhibitor of CYP2D6.12,13
Dosing: In an opioid-naïve patient beginning methadone
maintenance, the first dose should not exceed 40 mg
owing to the risk of death from respiratory depression.
A common starting dose is 20 mg to 30 mg. The
patient usually is monitored for 2 to 4 hours to allow the
methadone to peak. After the first day, additional doses
of 5 mg to 10 mg may be given if withdrawal symptoms persist. The dose may be slowly titrated over the
next couple of weeks to achieve a dose that prevents withdrawal and drug cravings without oversedating or causing other side effects. Most patients can be maintained
on a dose of 60 mg to 120 mg, although some patients
will need doses outside this range.6
For maintenance, methadone should be dispensed to
the patient as a 1-mg/mL solution. Doses of less than
50 mg/day have been associated with increased relapse
rates and less retention in programs.14,15
Side Effects: Because methadone acts upon central opioid receptors, its side-effect profile mirrors that of other
opioids. These effects include sweating, somnolence, dizziness, mild nausea, anorexia, constipation, and pruritus.
The most serious adverse effects are respiratory depression and cardiac arrhythmias. There also have been reports
of increased risk of cardiac death. Patients should be
counseled regarding possible weight gain, sexual dysfunction, and oligomenorrhea or amenorrhea.10,14
Interactions: There are numerous potential drug interactions with methadone (see TABLE 3). Methadone’s drug
interactions occur primarily through inhibition or induction of liver enzymes and changes in protein binding.12,13
No clinically significant protein-binding drug interaction has been reported.
Giving methadone with opioid antagonists, mixed
agonist/antagonists, and partial agonists (i.e., naloxone,
naltrexone, pentazocine, nalbuphine, butorphanol, and
buprenorphine) may precipitate withdrawal. Somnolence
and respiratory depression may be potentiated if methadone
is taken with other opioids.
Buprenorphine and Naloxone
Some of the drawbacks of methadone treatment are
that the drug has increased risks of respiratory depression, death from overdose, QT prolongation, divergence,
and difficult withdrawal. Buprenorphine is a partial agonist that carries fewer risks than methadone.16 Naloxone is formulated in combination with buprenorphine
to decrease the abuse potential: When taken correctly
sublingually, naloxone has no clinical effect because of
poor bioavailability; if injected, however, naloxone precipitates withdrawal.
Pharmacology: Buprenorphine is a synthetic opioid with
partial mu-opioid receptor agonism and kappa-receptor
antagonism. It has a higher affinity for mu-opioid receptors; therefore, it displaces morphine, methadone, and
other full agonists from the receptor site. This partial
41
U.S. Pharmacist • November 2009 • www.uspharmacist.com
KAPIDEX WORKS A
SECOND
SHIFT
TO HELP SHUT DOWN ACID PUMPS
KAPIDEX is the first and only PPI with a
Dual Delayed Release™ (DDR) formulation,
which provides a second release of drug
Mean plasma concentration (in healthy subjects; day 5; ng/mL)1
1200
1000
800
600
400
KAPIDEX
KA
K
A
60 mg
200
KAPIDEX
30 mg
KA
KA
0
0
6
12
18
24
Time (h)
• KAPIDEX 30 mg provided full 24-hour heartburn relief in a majority of symptomatic
non-erosive gastroesophageal reflux disease patients at week 41
• KAPIDEX 60 mg provided consistently high erosive esophagitis healing rates
at week 81
• KAPIDEX offers a safety and tolerability profile similar to lansoprazole1
• KAPIDEX can be taken without regard to food1
KAPIDEX should be swallowed whole. Alternatively, capsules can be opened,
sprinkled on 1 tablespoon of applesauce, and swallowed immediately. While
KAPIDEX can be taken without regard to food, some patients may benefit from
administering the dose prior to a meal if post-meal symptoms do not resolve
under post-fed conditions.
Conclusions of comparative efficacy cannot be drawn from this information.
Indications
KAPIDEX is indicated for healing all grades of erosive esophagitis (EE) for
up to 8 weeks, maintaining healing of EE for up to 6 months, and treating
heartburn associated with symptomatic non-erosive gastroesophageal reflux
disease (GERD) for 4 weeks.
Important Safety Information
KAPIDEX is contraindicated in patients with known hypersensitivity to
any component of the formulation. Hypersensitivity and anaphylaxis have
been reported with KAPIDEX use. Symptomatic response with KAPIDEX
does not preclude the presence of gastric malignancy. Most commonly
reported treatment-emergent adverse reactions (≥2%): diarrhea (4.8%),
abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%),
vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir with
KAPIDEX because atazanavir systemic concentrations may be substantially
decreased. KAPIDEX may interfere with absorption of drugs for which gastric
pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts,
ketoconazole). Patients taking concomitant warfarin may require monitoring
for increases in international normalized ratio (INR) and prothrombin time.
Increases in INR and prothrombin time may lead to abnormal bleeding, which
can lead to serious consequences.
Please see adjacent brief summary of prescribing information for KAPIDEX.
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION
KAPIDEX™ (dexlansoprazole) delayed release capsules
INDICATIONS AND USAGE
KAPIDEX is indicated for:
sTHEHEALINGOFALLGRADESOFEROSIVEESOPHAGITIS%%FORUPTOWEEKS
sMAINTAININGHEALINGOF%%FORUPTOMONTHSAND
sTHETREATMENTOFHEARTBURNASSOCIATEDWITHNONEROSIVEGASTROESOPHAGEAL
REmUXDISEASE'%2$FORWEEKS
CONTRAINDICATIONS
+!0)$%8ISCONTRAINDICATEDINPATIENTSWITHKNOWNHYPERSENSITIVITYTOANY
COMPONENTOFTHEFORMULATION(YPERSENSITIVITYANDANAPHYLAXISHAVEBEEN
REPORTEDWITH+!0)$%8USE [see Adverse Reactions]
WARNINGS AND PRECAUTIONS
Gastric Malignancy
3YMPTOMATIC RESPONSE WITH +!0)$%8 DOES NOT PRECLUDE THE PRESENCE OF
GASTRICMALIGNANCY
ADVERSE REACTIONS
Clinical Trials Experience
4HE SAFETY OF +!0)$%8 WAS EVALUATED IN PATIENTS IN CONTROLLED AND
UNCONTROLLEDCLINICALSTUDIESINCLUDINGPATIENTSTREATEDFORATLEAST
MONTHSANDPATIENTSTREATEDFORONEYEAR0ATIENTSRANGEDINAGEFROM
TOYEARSMEDIANAGEYEARSWITHFEMALE#AUCASIAN
"LACK !SIAN AND OTHER RACES 3IX RANDOMIZED CONTROLLED CLINICAL
TRIALSWERECONDUCTEDFORTHETREATMENTOF%%MAINTENANCEOFHEALED%%AND
SYMPTOMATIC'%2$WHICHINCLUDEDPATIENTSONPLACEBOPATIENTS
ON+!0)$%8MGPATIENTSON+!0)$%8MGANDPATIENTSON
LANSOPRAZOLEMGONCEDAILY
DRUGREACTIONASTHENIACHESTPAINCHILLSFEELINGABNORMALINmAMMATION
MUCOSALINmAMMATIONNODULEPAINPYREXIAHepatobiliary Disorders:BILIARY
COLICCHOLELITHIASISHEPATOMEGALYImmune System Disorders: HYPERSENSI
TIVITY Infections and Infestations: CANDIDA INFECTIONS INmUENZA NASOPHAR
YNGITIS ORAL HERPES PHARYNGITIS SINUSITIS VIRAL INFECTION VULVOVAGINAL
INFECTION Injury, Poisoning and Procedural Complications: FALLS FRACTURES
JOINTSPRAINSOVERDOSEPROCEDURALPAINSUNBURNLaboratory Investigations:
!,0INCREASED!,4INCREASED!34INCREASEDBILIRUBINDECREASEDINCREASED
BLOODCREATININEINCREASEDBLOODGASTRININCREASEDBLOODGLUCOSEINCREASED
BLOOD POTASSIUM INCREASED LIVER FUNCTION TEST ABNORMAL PLATELET COUNT
DECREASEDTOTALPROTEININCREASEDWEIGHTINCREASEMetabolism and Nutrition
Disorders:APPETITECHANGESHYPERCALCEMIAHYPOKALEMIA Musculoskeletal
and Connective Tissue Disorders: ARTHRALGIA ARTHRITIS MUSCLE CRAMPS
MUSCULOSKELETAL PAIN MYALGIA Nervous System Disorders: ALTERED TASTE
CONVULSION DIZZINESS HEADACHES MIGRAINE MEMORY IMPAIRMENT PARES
THESIAPSYCHOMOTORHYPERACTIVITYTREMORTRIGEMINALNEURALGIAPsychiatric
Disorders: ABNORMALDREAMSANXIETYDEPRESSIONINSOMNIALIBIDOCHANGES
Renal and Urinary Disorders: DYSURIA MICTURITION URGENCY Reproductive
System and Breast Disorders: DYSMENORRHEA DYSPAREUNIA MENORRHAGIA
MENSTRUALDISORDER; Respiratory, Thoracic and Mediastinal Disorders:ASPIRA
TION ASTHMA BRONCHITIS COUGH DYSPNOEA HICCUPS HYPERVENTILATION
RESPIRATORY TRACT CONGESTION SORE THROAT Skin and Subcutaneous Tissue
Disorders: ACNE DERMATITIS ERYTHEMA PRURITIS RASH SKIN LESION URTICARIA
Vascular Disorders:DEEPVEINTHROMBOSISHOTmUSHHYPERTENSION
!DDITIONALADVERSEREACTIONSTHATWEREREPORTEDINALONGTERMUNCONTROLLED
STUDY AND WERE CONSIDERED RELATED TO +!0)$%8 BY THE TREATING PHYSICIAN
INCLUDED ANAPHYLAXIS AUDITORY HALLUCINATION "CELL LYMPHOMA CENTRAL
OBESITY CHOLECYSTITIS ACUTE DECREASED HEMOGLOBIN DEHYDRATION DIABETES
MELLITUSDYSPHONIAEPISTAXISFOLLICULITISGASTROINTESTINALPAINGOUTHERPES
!SCLINICALTRIALSARECONDUCTEDUNDERWIDELYVARYINGCONDITIONSADVERSERE ZOSTERHYPERGLYCEMIAHYPERLIPIDEMIAHYPOTHYROIDISMINCREASEDNEUTROPHILS
ACTIONRATESOBSERVEDINTHECLINICALTRIALSOFADRUGCANNOTBEDIRECTLYCOM -#(# DECREASE NEUTROPENIA ORAL SOFT TISSUE DISORDER RECTAL TENESMUS
PAREDTORATESINTHECLINICALTRIALSOFANOTHERDRUGANDMAYNOTREmECTTHE RESTLESSLEGSSYNDROMESOMNOLENCETHROMBOCYTHEMIATONSILLITIS
RATESOBSERVEDINPRACTICE
/THER ADVERSE REACTIONS NOT OBSERVED WITH +!0)$%8 BUT OCCURRING WITH
-OST#OMMONLY2EPORTED!DVERSE2EACTIONS
THERACEMATELANSOPRAZOLECANBEFOUNDINTHELANSOPRAZOLEPACKAGEINSERT
4HE MOST COMMON ADVERSE REACTIONS r THAT OCCURRED AT A HIGHER !$6%23%2%!#4)/.3SECTION
INCIDENCEFOR+!0)$%8THANPLACEBOINTHECONTROLLEDSTUDIESAREPRESENTED
DRUG INTERACTIONS
IN4ABLE
Drugs with pH-Dependent Absorption Pharmacokinetics
Table 2: Incidence of Treatment-Emergent Adverse
+!0)$%8 CAUSES INHIBITION OF GASTRIC ACID SECRETION +!0)$%8 IS LIKELY TO
Reactions in Controlled Studies
SUBSTANTIALLY DECREASE THE SYSTEMIC CONCENTRATIONS OF THE ()6 PROTEASE
Placebo KAPIDEX KAPIDEX KAPIDEX Lansoprazole INHIBITORATAZANAVIRWHICHISDEPENDENTUPONTHEPRESENCEOFGASTRICACIDFOR
ABSORPTIONANDMAYRESULTINALOSSOFTHERAPEUTICEFFECTOFATAZANAVIRAND
30 mg
60 mg
Total
30 mg
THE DEVELOPMENT OF ()6 RESISTANCE 4HEREFORE +!0)$%8 SHOULD NOT BE
(N=896) (N=455) (N=2218) (N=2621) (N=1363)
Adverse Reaction
%
%
%
%
%
COADMINISTEREDWITHATAZANAVIR
$IARRHEA
!BDOMINAL0AIN
.AUSEA
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)TISTHEORETICALLYPOSSIBLETHAT+!0)$%8MAYINTERFEREWITHTHEABSORPTIONOF
OTHERDRUGSWHEREGASTRICP(ISANIMPORTANTDETERMINANTOFORALBIOAVAILABILITY
EGAMPICILLINESTERSDIGOXINIRONSALTSKETOCONAZOLE
Warfarin
#OADMINISTRATIONOF+!0)$%8MGANDWARFARINMGDIDNOTAFFECTTHE
PHARMACOKINETICSOFWARFARINOR).2(OWEVERTHEREHAVEBEENREPORTSOF
INCREASED).2ANDPROTHROMBINTIMEINPATIENTSRECEIVING00)SANDWARFARIN
CONCOMITANTLY)NCREASESIN).2ANDPROTHROMBINTIMEMAYLEADTOABNORMAL
BLEEDING AND EVEN DEATH 0ATIENTS TREATED WITH +!0)$%8 AND WARFARIN
CONCOMITANTLY MAY NEED TO BE MONITORED FOR INCREASES IN ).2 AND
PROTHROMBINTIME
!DVERSE2EACTIONS2ESULTINGIN$ISCONTINUATION
)NCONTROLLEDCLINICALSTUDIESTHEMOSTCOMMONADVERSEREACTIONLEADINGTO
USE IN SPECIFIC POPULATIONS
DISCONTINUATIONFROM+!0)$%8THERAPYWASDIARRHEA
Pregnancy
/THER!DVERSE2EACTIONS
/THER ADVERSE REACTIONS THAT WERE REPORTED IN CONTROLLED STUDIES AT AN Teratogenic Effects
0REGNANCY #ATEGORY " 4HERE ARE NO ADEQUATE AND WELLCONTROLLED STUDIES
INCIDENCEOFLESSTHANARELISTEDBELOWBYBODYSYSTEM
Blood and Lymphatic System Disorders:ANEMIALYMPHADENOPATHYCardiac WITHDEXLANSOPRAZOLEINPREGNANTWOMEN4HEREWERENOADVERSEFETALEFFECTS
Disorders:ANGINAARRHYTHMIABRADYCARDIACHESTPAINEDEMAMYOCARDIAL INANIMALREPRODUCTIONSTUDIESOFDEXLANSOPRAZOLEINRABBITS"ECAUSEANIMAL
INFARCTION PALPITATION TACHYCARDIA Ear and Labyrinth Disorders: EAR PAIN REPRODUCTIONSTUDIESARENOTALWAYSPREDICTIVEOFHUMANRESPONSE+!0)$%8
TINNITUSVERTIGOEndocrine Disorders: GOITEREye Disorders:EYEIRRITATION SHOULDBEUSEDDURINGPREGNANCYONLYIFCLEARLYNEEDED
EYESWELLINGGastrointestinal Disorders: ABDOMINALDISCOMFORTABDOMINAL !REPRODUCTIONSTUDYCONDUCTEDINRABBITSATORALDEXLANSOPRAZOLEDOSESUP
TENDERNESS ABNORMAL FECES ANAL DISCOMFORT "ARRETTS ESOPHAGUS BEZOAR TOMGPERKGPERDAYAPPROXIMATELYFOLDTHEMAXIMUMRECOMMENDED
BOWEL SOUNDS ABNORMAL BREATH ODOR COLITIS MICROSCOPIC COLONIC POLYP HUMANDEXLANSOPRAZOLEDOSE;MG=BASEDONBODYSURFACEAREA;"3!=
CONSTIPATIONDRYMOUTHDUODENITISDYSPEPSIADYSPHAGIAENTERITISERUC REVEALEDNOEVIDENCEOFHARMTOTHEFETUSDUETODEXLANSOPRAZOLE)NADDITION
TATION ESOPHAGITIS GASTRIC POLYP GASTRITIS GASTROENTERITIS GASTROINTESTINAL REPRODUCTION STUDIES PERFORMED IN PREGNANT RATS WITH ORAL LANSOPRAZOLE AT
DISORDERS GASTROINTESTINAL HYPERMOTILITY DISORDERS '%2$ ') ULCERS AND DOSESUPTOMGPERKGPERDAYTIMESTHERECOMMENDEDHUMANDOSE
PERFORATION HEMATEMESIS HEMATOCHEZIA HEMORRHOIDS IMPAIRED GASTRIC BASEDON"3!ANDINPREGNANTRABBITSATORALLANSOPRAZOLEDOSESUPTOMG
EMPTYING IRRITABLE BOWEL SYNDROME MUCUS STOOLS NAUSEA AND VOMITING PERKGPERDAYTIMESTHERECOMMENDEDHUMANDOSEBASEDON"3!REVEALED
ORALMUCOSALBLISTERINGPAINFULDEFECATIONPROCTITISPARESTHESIAORALRECTAL NOEVIDENCEOFIMPAIREDFERTILITYORHARMTOTHEFETUSDUETOLANSOPRAZOLE
HEMORRHAGEGeneral Disorders and Administration Site Conditions:ADVERSE
Nursing Mothers
)TISNOTKNOWNWHETHERDEXLANSOPRAZOLEISEXCRETEDINHUMANMILK(OWEVER
LANSOPRAZOLEANDITSMETABOLITESAREPRESENTINRATMILKFOLLOWINGTHEADMINIS
TRATIONOFLANSOPRAZOLE!SMANYDRUGSAREEXCRETEDINHUMANMILKANDBECAUSE
OFTHEPOTENTIALFORTUMORIGENICITYSHOWNFORLANSOPRAZOLEINRATCARCINOGENICITY
STUDIES[see Carcinogenesis, Mutagenesis, Impairment of Fertility]ADECISION
SHOULD BE MADE WHETHER TO DISCONTINUE NURSING OR TO DISCONTINUE THE DRUG
TAKINGINTOACCOUNTTHEIMPORTANCEOFTHEDRUGTOTHEMOTHER
WERETREATEDORALLYWITHLANSOPRAZOLEATDOSESOFTOMGPERKGPERDAY
ABOUTTOTIMESTHEEXPOSUREONABODYSURFACEMGMBASISOFAKG
PERSON OF AVERAGE HEIGHT M "3! GIVEN THE RECOMMENDED HUMAN
DOSEOFLANSOPRAZOLEMGPERDAY
OVERDOSAGE
4HERE HAVE BEEN NO REPORTS OF SIGNIlCANT OVERDOSE OF +!0)$%8 -ULTIPLE
DOSESOF+!0)$%8MGANDASINGLEDOSEOF+!0)$%8MGDIDNOT
RESULT IN DEATH OR OTHER SEVERE ADVERSE EVENTS $EXLANSOPRAZOLE IS NOT
EXPECTEDTOBEREMOVEDFROMTHECIRCULATIONBYHEMODIALYSIS)FANOVERDOSE
OCCURSTREATMENTSHOULDBESYMPTOMATICANDSUPPORTIVE
4HE POTENTIAL EFFECTS OF DEXLANSOPRAZOLE ON FERTILITY AND REPRODUCTIVE
PERFORMANCEWEREASSESSEDUSINGLANSOPRAZOLESTUDIES,ANSOPRAZOLEATORAL
DOSESUPTOMGPERKGPERDAYTIMESTHERECOMMENDEDLANSOPRAZOLE
HUMAN DOSE BASED ON "3! WAS FOUND TO HAVE NO EFFECT ON FERTILITY AND
REPRODUCTIVEPERFORMANCEOFMALEANDFEMALERATS
PATIENT COUNSELING INFORMATION
CLINICAL PHARMACOLOGY
[see FDA-Approved Patient Labeling in the full prescribing information]
Pharmacodynamics
!NTISECRETORY!CTIVITY
4HEEFFECTSOF+!0)$%8MGNORLANSOPRAZOLEMGNONCE
DAILY FOR lVE DAYS ON HOUR INTRAGASTRIC P( WERE ASSESSED IN HEALTHY
SUBJECTSINAMULTIPLEDOSECROSSOVERSTUDY
Information for Patients
4O ENSURE THE SAFE AND EFFECTIVE USE OF +!0)$%8 THIS INFORMATION AND
INSTRUCTIONS PROVIDED IN THE &$!APPROVED PATIENT LABELING SHOULD BE
DISCUSSEDWITHTHEPATIENT)NFORMPATIENTSOFTHEFOLLOWING
,ANSOPRAZOLE PRODUCED DOSERELATED GASTRIC %#, CELL HYPERPLASIA AND %#,
CELLCARCINOIDSINBOTHMALEANDFEMALERATS[see Clinical Pharmacology].
)NRATSLANSOPRAZOLEALSOINCREASEDTHEINCIDENCEOFINTESTINALMETAPLASIAOF
THEGASTRICEPITHELIUMINBOTHSEXES)NMALERATSLANSOPRAZOLEPRODUCEDA
Pediatric Use
3AFETYANDEFFECTIVENESSOF+!0)$%8INPEDIATRICPATIENTSLESSTHANYEARS DOSERELATEDINCREASEOFTESTICULARINTERSTITIALCELLADENOMAS4HEINCIDENCEOF
THESEADENOMASINRATSRECEIVINGDOSESOFTOMGPERKGPERDAYTO
OFAGEHAVENOTBEENESTABLISHED
TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3!
Geriatric Use
EXCEEDEDTHELOWBACKGROUNDINCIDENCERANGETOFORTHISSTRAIN
)NCLINICALSTUDIESOF+!0)$%8OFPATIENTSWEREAGEDYEARSANDOVER
OFRAT4ESTICULARINTERSTITIALCELLADENOMAALSOOCCURREDINOFRATSTREATED
.O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN
THESEPATIENTSANDYOUNGERPATIENTSANDOTHERREPORTEDCLINICALEXPERIENCE WITHMGLANSOPRAZOLEPERKGPERDAYTIMESTHERECOMMENDEDLANSO
HASNOTIDENTIlEDSIGNIlCANTDIFFERENCESINRESPONSESBETWEENGERIATRICAND PRAZOLEHUMANDOSEBASEDON"3!INAYEARTOXICITYSTUDY
YOUNGERPATIENTSBUTGREATERSENSITIVITYOFSOMEOLDERINDIVIDUALSCANNOTBE )N A MONTH CARCINOGENICITY STUDY #$ MICE WERE TREATED ORALLY WITH
RULEDOUT]
LANSOPRAZOLEDOSESOFMGTOMGPERKGPERDAYTOTIMESTHE
RECOMMENDEDHUMANDOSEBASEDON"3!,ANSOPRAZOLEPRODUCEDADOSE
Renal Impairment
.O DOSAGE ADJUSTMENT OF +!0)$%8 IS NECESSARY IN PATIENTS WITH RENAL RELATEDINCREASEDINCIDENCEOFGASTRIC%#,CELLHYPERPLASIA)TALSOPRODUCED
IMPAIRMENT4HEPHARMACOKINETICSOFDEXLANSOPRAZOLEINPATIENTSWITHRENAL AN INCREASED INCIDENCE OF LIVER TUMORS HEPATOCELLULAR ADENOMA PLUS
IMPAIRMENTARENOTEXPECTEDTOBEALTEREDSINCEDEXLANSOPRAZOLEISEXTENSIVELY CARCINOMA 4HE TUMOR INCIDENCES IN MALE MICE TREATED WITH MG AND
METABOLIZED IN THE LIVER TO INACTIVE METABOLITES AND NO PARENT DRUG IS MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE RECOMMENDED
RECOVEREDINTHEURINEFOLLOWINGANORALDOSEOFDEXLANSOPRAZOLE.
LANSOPRAZOLE HUMAN DOSE BASED ON "3! AND FEMALE MICE TREATED WITH
MG TO MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE
Hepatic Impairment
.ODOSAGEADJUSTMENTFOR+!0)$%8ISNECESSARYFORPATIENTSWITHMILDHEPATIC RECOMMENDED HUMAN DOSE BASED ON "3! EXCEEDED THE RANGES OF BACK
IMPAIRMENT#HILD0UGH#LASS!+!0)$%8MGSHOULDBECONSIDEREDFOR GROUNDINCIDENCESINHISTORICALCONTROLSFORTHISSTRAINOFMICE,ANSOPRAZOLE
PATIENTSWITHMODERATEHEPATICIMPAIRMENT#HILD0UGH#LASS".OSTUDIES TREATMENT PRODUCED ADENOMA OF RETE TESTIS IN MALE MICE RECEIVING TO
HAVEBEENCONDUCTEDINPATIENTSWITHSEVEREHEPATICIMPAIRMENT#HILD0UGH MG PER KG PER DAY TO TIMES THE RECOMMENDED LANSOPRAZOLE
HUMANDOSEBASEDON"3!
#LASS#.
3ERUM'ASTRIN%FFECTS
4HE EFFECT OF +!0)$%8 ON SERUM GASTRIN CONCENTRATIONS WAS EVALUATED IN
APPROXIMATELYPATIENTSINCLINICALTRIALSUPTOWEEKSANDINPATIENTS
FORUPTOTOMONTHS4HEMEANFASTINGGASTRINCONCENTRATIONSINCREASED
FROMBASELINEDURINGTREATMENTWITH+!0)$%8MGANDMGDOSES)N
PATIENTSTREATEDFORMORETHANMONTHSMEANSERUMGASTRINLEVELSINCREASED
DURINGAPPROXIMATELYTHElRSTMONTHSOFTREATMENTANDWERESTABLEFORTHE
REMAINDEROFTREATMENT-EANSERUMGASTRINLEVELSRETURNEDTOPRETREATMENT
LEVELSWITHINONEMONTHOFDISCONTINUATIONOFTREATMENT
+!0)$%8ISAVAILABLEASADELAYEDRELEASECAPSULE
+!0)$%8MAYBETAKENWITHOUTREGARDTOFOOD
+!0)$%8SHOULDBESWALLOWEDWHOLE
s!LTERNATIVELY+!0)$%8CAPSULESCANBEOPENEDANDADMINISTEREDASFOLLOWS
n/PENCAPSULE
n3PRINKLEINTACTGRANULESONONETABLESPOONOFAPPLESAUCE
n3WALLOWIMMEDIATELY
$ISTRIBUTEDBY
%NTEROCHROMAFlN,IKE#ELL%#,%FFECTS
Takeda Pharmaceuticals America, Inc.
4HEREWERENOREPORTSOF%#,CELLHYPERPLASIAINGASTRICBIOPSYSPECIMENS $EERlELD),
OBTAINEDFROMPATIENTSTREATEDWITH+!0)$%8MGMGORMGFOR
530ATENT.OS
UPTOMONTHS
AND
$URINGLIFETIMEEXPOSUREOFRATSDOSEDDAILYWITHUPTOMGPERKGPERDAY
OF LANSOPRAZOLE MARKED HYPERGASTRINEMIA WAS OBSERVED FOLLOWED BY %#, +!0)$%8ISATRADEMARKOF4AKEDA0HARMACEUTICALS.ORTH!MERICA)NCAND
CELLPROLIFERATIONANDFORMATIONOFCARCINOIDTUMORSESPECIALLYINFEMALERATS USEDUNDERLICENSEBY4AKEDA0HARMACEUTICALS!MERICA)NC
!LLOTHERTRADEMARKNAMESARETHEPROPERTYOFTHEIRRESPECTIVEOWNERS
[see Nonclinical Toxicology ]
Ú4AKEDA0HARMACEUTICALS!MERICA)NC
%FFECTON#ARDIAC2EPOLARIZATION
!STUDYWASCONDUCTEDTOASSESSTHEPOTENTIALOF+!0)$%8TOPROLONGTHE &OR MORE DETAILED INFORMATION SEE THE FULL PRESCRIBING INFORMATION FOR
1414cINTERVALINHEALTHYADULTSUBJECTS+!0)$%8DOSESOFMGORMG +!0)$%8 0) 2 *ANUARY OR CONTACT 4AKEDA 0HARMACEUTICALS
DIDNOTDELAYCARDIACREPOLARIZATIONCOMPAREDTOPLACEBO4HEPOSITIVECONTROL !MERICA)NCAT
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0)2"RF*ANUARY
TIMEAVERAGED1414 INTERVALSCOMPAREDTOPLACEBO
c
NONCLINICAL TOXICOLOGY
,,0$
Carcinogenesis, Mutagenesis, Impairment of Fertility
4HECARCINOGENICPOTENTIALOFDEXLANSOPRAZOLEWASASSESSEDUSINGLANSOPRA
ZOLESTUDIES)NTWOMONTHCARCINOGENICITYSTUDIES3PRAGUE$AWLEYRATS
KAPIDEX™ and Dual Delayed Release™ are trademarks of Takeda Pharmaceuticals North America, Inc.,
and are used under license by Takeda Pharmaceuticals America, Inc.
Reference: 1. KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc.
©2009 Takeda Pharmaceuticals North America, Inc.
LPD-00250 6/09 Printed in U.S.A.
OPIOID MAINTENANCE TREATMENT
Table 2
Characteristics of Options for Maintenance Treatment
Buprenorphine and
Buprenorphine/Naloxone
Methadone
Pharmacologic Action
Buprenorphine: partial agonist
Naloxone: full antagonist
Full agonist
Route of Administration
Sublingual
Oral
Dosing
Buprenorphine: 2-32 mg; naloxone:
0.5-8 mg; combination: 4:1 ratio
20-30 mg initially, then 60-120 mg
Administration
Daily to 3 times/wk
Daily
Common Side Effects
Headache, nausea, sweating, rhinitis,
constipation
Cardiac dysrhythmia, hypotension, diaphoresis,
constipation, nausea, vomiting, dizziness,
sedation
Contraindications
Need for ongoing opioid agonists for
pain relief, hypersensitivity
Hypersensitivity
Pregnancy Concerns
Category C; combination not
recommended in pregnancy—replace
with methadone or buprenorphine
Category C; current standard of care in
pregnancy
Accessibility
Physician’s office or opioid
treatment program
Opioid treatment program
Regulatory Concerns
Physician may prescribe only with
DEA-issued registration certificate code;
30-patient census/prescriber, then 100patient census after 1st y; pharmacy
may dispense up to 30-day supply
based on schedule III
Physician may prescribe only to opioiddependent patients for up to 72 h as bridge
to treatment entry; only licensed opioid
treatment programs may dispense; federal
regulations govern dispensing frequency
(e.g., daily, 3 times/wk, wkly)
Insurance Coverage
Specific to type of insurance
Specific to type of insurance
DEA: Drug Enforcement Administration.
Source: Reference 25.
agonism allows buprenorphine to have a ceiling effect on
the opioid effects at higher doses, making it safer in the
event of overdose.
Naloxone is a mu-opioid receptor antagonist with
poor oral bioavailability owing to limited absorption and
extensive first-pass metabolism. It has a rapid onset of
action when given intravenously. Because it has a
higher affinity for mu-opioid receptors than heroin, morphine, or methadone, naloxone displaces these drugs from
receptors and blocks their effects.17
Buprenorphine/naloxone (Suboxone) is available as
a 4:1 fixed combination. Subutex (buprenorphine), a
white tablet, is available in 2-mg and 8-mg strengths;
Suboxone is an orange tablet and is available in 2/0.5mg and 8/2-mg formulations. Buprenorphine is
rapidly absorbed sublingually, and peak effects are reached
90 minutes after administration. Naloxone does not
affect the pharmacokinetics of buprenorphine. The mean
half-life of buprenorphine is 37 hours; that of naloxone is 1.1 hours.18
Dosing: Because buprenorphine displaces the other opioid from mu-receptor sites and induces withdrawal, it
should be initiated only when the patient already has
evident signs of withdrawal; otherwise, the patient might
associate the buprenorphine with withdrawal, thereby
reducing adherence. The buprenorphine/naloxone combination is the drug of choice for initiating therapy in
both U.S. and European guidelines. Buprenorphine may
be started alone at doses of 4 mg to 8 mg or in combination in a 4:1 ratio to naloxone. A second dose of 4
mg may be given in 2 to 4 hours, and the patient may
be given an additional dose of 2 mg to 4 mg to take
home in case of withdrawal within the next 24 hours.
The physician should monitor for buprenorphine-precipitated withdrawal while the patient is in the office.
This is not to be confused with withdrawal from underdosing of buprenorphine, which usually occurs in the
second half of the 24-hour dosing interval.16
The maintenance dose may be achieved by doubling
the dose each day, to a maximum of 24 mg to 32 mg.
If withdrawal symptoms arise at any time during the
24-hour dosing interval, the dose is too low and needs
to be increased. If induction occurs too slowly, the
patient may prematurely terminate treatment. Therefore, it is important for the practitioner to be diligent
in monitoring the patient. When converting to or from
the naltrexone combination, a 1:1 ratio of the buprenorphine dose may be used.16
When the maintenance dose is achieved, buprenor-
46
U.S. Pharmacist • November 2009 • www.uspharmacist.com
OPIOID MAINTENANCE TREATMENT
Table 3
Potential Drug Interactions for
Methadone and Buprenorphine
Interaction
Methadone
Buprenorphine
Increase Effects
of Opioid Substitute
Alcohol
Antidepressants
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline
Anti-infectives
• Ciprofloxacin
• Erythromycin
• Fluconazole
• Ketoconazole
Benzodiazepines
Cimetidine
Alcohol
Antiretrovirals
• Atazanavir
• Indinavir
• Nevirapine
• Ritonavir
• Saquinavir
Benzodiazepines
Fluvoxamine
Ketoconazole
Interactions: Buprenorphine goes through hepatic metabolism via CYP3A4. The drug has the
potential for many of the same interactions as
methadone (see TABLE 3). One dangerous interaction to monitor for is the potentially fatal
interaction with benzodiazepines.19 Concomitant
administration should be avoided. Compared with
methadone, buprenorphine may be a safer choice
in patients receiving antiretrovirals.20
CLINICAL EFFICACY OF METHADONE
VERSUS BUPRENORPHINE
It is well established that both methadone and
buprenorphine are effective for decreasing illicit
drug use. It is worthwhile to consider the results
of studies examining the efficacy of methadone
versus buprenorphine.7
The 2008 Cochrane review determined that
Decrease Effects
Anti-infectives
Carbamazepine
methadone dosed at 60 mg/day to 120 mg/day
of Opioid Substitute • Fusidic acid
Phenobarbital
has superior efficacy compared with buprenor• Rifampin
Phenytoin
Antiretrovirals
Rifampin
phine.21 The specific studies yield varied results.
• Abacavir
One study found less illicit heroin use with
• Amprenavir
buprenorphine than with methadone, but the
• Efavirenz
methadone arm had higher retention rates. 22
• Nevirapine
Another study concluded that high-dose methadone
• Ritonavir
• Saquinavir
had a higher retention rate and less illicit opioid
Barbiturates
use compared with buprenorphine 8 mg.23 A douCarbamazepine
ble-blind, randomized trial comparing an averPhenytoin
age dose of buprenorphine (10 mg/day) versus
Source: References 12, 16.
methadone (70 mg/day) showed a higher retention rate with methadone, but found that the
phine may be administered from every other day to 3 drugs had equal efficacy in reducing illicit heroin use.24
times weekly (e.g., Monday, Wednesday, and Friday) in However, a study from 1992 concluded that buprenororder to increase compliance and patient satisfaction. phine had better retention rates than methadone at 25
Every-4-day regimens have been associated with increased weeks.26 Overall, it is accepted that buprenorphine and
withdrawal symptoms. The daily dose may be doubled methadone have comparable efficacy and that treatment
for every-other-day dosing and also for thrice-weekly dos- should be individualized.
ing, but Friday’s dose would be 2.5 times the daily dose.16
New patients should be advised that sublingual tablets CONCLUSION
must be dissolved under the tongue, as the medication Because of DATA 2000 and ongoing research on opiis much less effective if swallowed.18 No more than two oid dependence, pharmacists must be prepared to face
tablets should be taken at one time, to avoid swallow- an increase in the number of prescriptions being writing them by mistake. Wetting the mouth before placing ten for opioid maintenance treatment. When presented
the tablets under the tongue may help them dissolve with a new prescription, a pharmacist may visit the site
faster. Full absorption may take up to 10 minutes. Patients www.buprenorphine.samhsa.gov to confirm physician
should refrain from smoking for 10 to 15 minutes before eligibility. Pharmacists must monitor and counsel patients
taking the medication, as this seems to help the tablets about withdrawal symptoms and overdose possibilities.
dissolve faster.18
Because buprenorphine is a partial agonist, the risk of
overdose is smaller, and its use in combination with naloxSide Effects: Buprenorphine/naloxone is generally well one further reduces the risk of intravenous abuse. Histolerated. Side effects are associated mainly with buprenor- torically, daily visits to methadone clinics have been the
phine, since naloxone is not readily absorbed. In clinical most frequently utilized method of treating opioid depentrials, the most common adverse effects were headache, dence, but with the current availability of sublingual
withdrawal syndrome, pain, nausea, insomnia, sweating, buprenorphine products, more patients will be able to
rhinitis, constipation, abdominal pain, flulike syndrome, receive treatment in a convenient office-based setting.
and flushing.17
References available online at www.uspharmacist.com.
53
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Generic Trends
Generics Will
Have Modest
Negative Impact on
Hypertension Drug
Market Sales
Through 2018
Despite the generic erosion of many hypertension drug products
expected over the next
decade, it is estimated
that the overall hypertension drug market
will experience only a
modest decline. According to Decision
Resources, a research
and advisory firm for
pharmaceutical and
health care issues, the
market will decrease
1.4% annually through
2013, and thereafter the
annual decline will slow
to 1% through 2018 in
the United States,
France, Germany, Italy,
Spain, the United Kingdom, and Japan.
According to a company report, a major
contributor to the market decline will be an
increase in the generic
availability of antihypertensive agents. For
example, by 2018,
Novartis’s Diovan alone
will lose more than $1
billion in sales beginning next year when the
drug goes off patent.
Other hypertension
drug classes will suffer
as well, including
angiotensin-converting
enzyme inhibitors (ACE
inhibitors), angiotensin
II receptor antagonists,
Hatch-Waxman Act Turns 25
Twenty-five years ago a bill introduced by Senator Orrin Hatch and Rep.
Henry Waxman that would change the generic industry forever was signed
into law at a White House Rose Garden ceremony. While not perfect, the
Hatch-Waxman Act continues to receive accolades from industry observers
and government officials.
“Our industry is proud of how far it has come in the past 25 years,” said
Kathleen Jaeger, president and CEO of the Generic Pharmaceutical Association, commenting on the law. “Today, generic medicines represent 72% of
the total prescriptions dispensed in the U.S., but only 17% of all dollars
spent on prescription drugs. One billion dollars is saved every three days by
using generics. That’s extraordinary savings—far more than anyone predicted or could have even imagined 25 years ago.”
Health and Human Services Secretary Kathleen Sebelius also offered
kudos, particularly in the context of health care reform proposals currently
in front of Congress.
“I think that it’s appropriate this year that as we look at what’s pending
in Congress on health reform that we are also celebrating the quarter century anniversary of the Hatch-Waxman Act, which really began to transform the pharmaceutical industry and made generic drugs much more
widely available to Americans.”
And from the bill’s authors comes admission that they didn’t always see
eye-to-eye from across the aisle, but were able to still produce a bipartisan
piece of legislation that has withstood many challenges over its relatively
short 25-year history.
“Henry and I put our differences aside to work in a bipartisan manner
to get the bill passed,” admits Senator Hatch. “In the end, we passed a bill
that has not only worked well, but has saved consumers, state, and federal
governments billions of dollars.”
“When Senator Hatch and I developed the legislation 25 years ago to
produce generic drugs, we thought that the result of this law would save
perhaps a billion dollars…in reality generic drugs have saved consumer and
businesses, and state and federal governments $734 billion,” said Representative Waxman.
calcium channel blockers, and diuretics.
Mylan Settles
With Pfizer Over
Vfend Generic
Mylan Pharmaceuticals
and Matrix Laboratories
have entered into a settlement and license
agreement with Pfizer
Inc. relating to voricona-
zole tablets, 50 mg and
200 mg, the generic version of Pfizer’s Vfend
Tablets, a triazole antifungal agent.
Mylan’s Matrix was
the first company to
submit a substantially
complete Abbreviated
New Drug Application
containing a Paragraph
IV certification to the
54
U.S. Pharmacist • November 2009 • www.uspharmacist.com
FDA and therefore
believes it will be eligible
for 180 days of marketing exclusivity upon
commercial marketing of
the product.
Pursuant to the agreement, Mylan will have
the right to market
voriconazole tablets in
the U.S. in the first
quarter of 2011.
Providing Affordable and
Innovative Medicine for Healthier Lives
Affordable Medicines
High-quality, low cost generic ANDA alternatives
Innovative Medicines
_ First Indian company to fully develop
an in-house biosimilar
– NCEs for unmet medical needs
– OTCs for a more complete selection
Planning Our Future to
Meet Your Future
– Robust generic pipeline
– Supply chain excellence
– 41 Rx generic product families available
– Rx-to-OTC switches
– Vertically integrated
– Customer focused
Global Presence...Local Focus
Dr. Reddy’s Laboratories, Inc. 3600 Arco Corporate Drive, Charlotte, NC 28273-7104
(866) 733-3952
www.DRREDDYS.com
DRCO / 09/09 R
Generic Trends
“Free Generic Fill”
Provision in Health
Care Reform
Legislation
Applauded by GPhA
“GPhA applauds the
Senate Finance Committee for approving the
‘Free Generic Fill’ provision [in health care
reform legislation],
which would save
patients and the federal
government more than
$6 billion over 10
years,” commented
Kathleen Jaeger, president and CEO of the
Generic Pharmaceutical
Association (GPhA).
The “free generic fill”
provision creates an
exception that would
allow health plan sponsors to encourage beneficiaries to utilize generic
drugs by allowing them
to waive copays as an
incentive to try a generic
drug.
“Clearly, Congress has
recognized that expanding access to generic
medicines is the key to
lowering health care
costs...,” said Jaeger.
Innovative Pharmacy
Benefit Plan
Design Can Optimize
Generic Utilization
Data from research con-
ducted by CVS Caremark
and presented at the
Academy of Managed
Care Pharmacy (AMCP)
Annual Educational Conference showed that innovative pharmacy benefit
plan design can impact
generic utilization. Specifically, the study found
that implementing a $0
copay structure for
generic medications can
be an effective strategy to
increase generic dispensing, with the generic dispensing rate increasing to
60.8% (which represents
a 4.2% increase).
“The data presented at
AMCP illustrate an
example of how we can
work with our plan sponsors to change and optimize participant behavior
in order to achieve
increased generic utilization,” said Jack Bruner,
executive vice president,
CVS Caremark.
Some other data
uncovered by the study
showed that the average
participant cost share for
generic medications
decreased almost 10%
and the average plan cost
per 30 days of therapy
also exhibited a slight
decline, despite the
reduction in generic
copayment rates.
Call for Papers
U.S. Pharmacist is seeking authors to write clinical articles and continuing education lessons on a variety of topics. While we will
entertain all subject matter, we are particularly interested in articles that correspond to our “Editorial Focus” therapeutic areas. The
therapeutic categories and the months for which they are planned are listed below:
Cardiovascular Diseases – February
Endocrinology – June
Gastroenterologic Diseases – December
Infectious Diseases – August
Neurologic Diseases – January
New Drugs – October
Ophthalmology – April
Pain Management – May
Pediatric and Adolescent Health – March
Psychotropics – November
Respiratory Diseases – July
Women’s Health – September
In addition to these topics, we also publish supplements each year
covering oncology and hematology, diabetes, the generic drug
industry, and OTC drugs.
In the majority of cases, articles are peer-reviewed and an honorarium
is offered based on their complexity and length. As a general
guideline, we would like the articles to be approximately 2,500
–2,800 words, including references and tables. Continuing
education lessons should be approximately 6,000 words, including
references, tables, and exam. Prospective authors are urged to
review the “Author Guidelines” on the U.S. Pharmacist Web site
at www.uspharmacist.com.
Interested authors should contact Rob Davidson, Executive Editor
([email protected]), with the topic(s) they would like to cover.
All articles must be original and exclusive to U.S. Pharmacist.
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GST00073
© GREENSTONE LLC 2009
GSP I04
Contemporary Compounding
Ketamine Hydrochloride
10-mg Troches
In lozenge form, this analgesic and anesthetic agent can be
prepared to suit the patient’s individual flavor preference.
G FORMULA
Ketamine Hydrochloride 10-mg Troches
Rx (for 100 troches):
Ingredient
Ketamine hydrochloride
Silica gel
Stevia
Acacia
Citric acid
Flavor
Polyethylene glycol 1450
Method of Preparation:
Calibrate the mold being
used to determine the
amount of polyethylene
glycol (PEG) 1450
needed. Calculate the
quantity of each ingredient for the amount to be
prepared. Accurately
weigh or measure each
ingredient. Melt the PEG
1450 at 50°-55°C. Blend
the powders (ketamine
hydrochloride [HCl], silica gel, stevia, acacia, citric acid) and slowly sprinkle into melted base
while mixing; mix until
uniform. Remove from
heat, add flavor (which
can be based on the
patient’s preference), and
mix well. Pour into
molds and let mixture
cool. Trim (if necessary),
package, and label.
Loyd V. Allen, Jr, PhD
Professor Emeritus, College of
Pharmacy, University of
Oklahoma, Oklahoma City
1g
1g
750 mg
1.65 g
1.2 g
qs
qs
Use: Ketamine HCl
troches have been used
to treat moderate-tosevere pain.
Packaging: Package in
well-sealed, light-resistant
containers.
Labeling: Keep out of the
reach of children. Use
only as directed.
Stability: A beyond-use
date of up to 6 months
may be used for this
preparation.1
Quality Control: Quality-control assessment can
include weight, specific
gravity, active drug assay,
color, texture–surface,
appearance, feel, melting
test, dissolution test,
physical observation, and
physical stability.2
Discussion: Ketamine
HCl (C13H16ClNO.HCl,
MW 274.2), an analgesic
and anesthetic, occurs as
a white, crystalline powder with a slight characteristic odor. ≈1.15 mg is
equivalent to 1 mg ketamine base. It is soluble 1
g in 4 mL water, 14 mL
alcohol, and 60 mL
absolute alcohol.1,3
Silica gel is obtained
by insolubilizing the dissolved silica in sodium
silicate solution. It occurs
as a fine, white, hygroscopic, odorless, amorphous powder with a
usual particle size of 2-10
mu. It is insoluble in
alcohol, other organic
solvents, and water, and
soluble in hot solutions
of alkali hydroxides. It is
used as a desiccant, suspending agent, and viscosity-increasing agent.4
Stevia (honey leaf,
yerba dulce) is a natural
sweetening agent
extracted from the Stevia
rebaudiana Bertoni plant.
Nontoxic and safe, it
occurs as a white, crystalline, hygroscopic powder. It can be used in hot
and cold preparations.5
Acacia (gum acacia,
gum arabic) is the dried
gummy exudate obtained
from some species of the
acacia tree. It is a complex
aggregate of sugars and
58
U.S. Pharmacist • November 2009 • www.uspharmacist.com
hemicelluloses, with MW
from 240,000 to 580,000.
It is used as an emulsifying agent (5%-10% concentration[conc]), pastille
base (10%-30% conc),
suspending agent (5%10% conc), and tablet
binder (1%-5% conc), as
well as in cosmetics and
food products. It should
be preserved when in
aqueous solution, as it is
subject to bacterial or
enzymatic degradation.
Boiling its solution briefly
will inactivate any
enzymes and enhance its
stability. Some substances
that are incompatible with
acacia are cresol, ethanol
(95%), morphine, phenol,
and thymol. Some salts
reduce the viscosity of
aqueous acacia solutions.
Since acacia is negatively
charged in solution, it will
form a coacervate with
positively charged molecules such as those in gelatin. Acacia may coagulate
in the presence of trivalent
salts.6
Citric acid (citric acid
monohydrate,
C6H8O7.H2O) occurs as
colorless or translucent
crystals or as a white, crystalline, efflorescent, odorless powder with a strong,
tart, acidic taste. It is present at about the 5%-8%
Contemporary Compounding
level in lemon juice. In
0.3%-2% concentration,
it is used to improve flavor in liquid formulations
and as a sequestering
agent. It may be used to
prepare effervescent granules and solid and semisolid (chewable) dosage
forms. The hydrated form
may contain up to 8.8%
water, and the pH of a
1% w/v aqueous solution
is ≈2.2. Its density is
REFERENCES
1. USP Pharmacists’ Pharmacopeia. 2nd ed.
Rockville MD: US Pharmacopeial Convention, Inc; 2008:217,775-779,1444.
2. Allen LV Jr. Standard operating procedure for performing physical quality assessment of suppositories, troches, lollipops
and sticks. IJPC. 1999;3:56-57.
1.542 g/mL. The
hydrated form will effloresce and the anhydrous
form will be hygroscopic,
depending upon the
humidity. If stored in air
that is too dry, it may lose
its water if the temperature reaches ≈40°C. Its
melting point is ≈100°C,
but it softens at ≈75°C.
One g is soluble in <1
mL water and 1.5 mL
ethanol. It is incompatible
with potassium tartrate,
alkali and alkaline earth
carbonates, bicarbonates,
acetates, and sulfides. If
included in a syrup formulation, it may induce
sucrose to crystallize.7
PEG 1450 (Carbowax,
polyoxyethylene glycol) is
an addition polymer of
ethylene oxide and water.
At room temperature, it
occurs as a solid or as
white or off-white waxy
3. Sweetman SC, ed. Martindale: The
Complete Drug Reference. 33rd ed. London, England: Pharmaceutical Press (PP);
2002:1262-1263.
4. Owen SC. Colloidal silicon dioxide. In:
Rowe RC, Sheskey PJ, Owen SC, eds.
Handbook of Pharmaceutical Excipients. 5th
ed. Washington, DC: American Pharma-
ceutical Association (APA); 2006:188-191.
5. Reynolds JEF, ed. Martindale: The
Extra Pharmacopoeia. 30th ed. London,
England: PP; 1993:1049.
6. Kibbe AH. Acacia. In: Rowe RC,
Sheskey PJ, Owen SC, eds. Handbook of
Pharmaceutical Excipients. 5th ed. Washington, DC: APA; 2006:1-3.
flakes or powder. Its density ranges from 1.151.21 g/mL; its melting
point is 40°-48°C. It is
soluble in water; miscible
in all ratios with other
PEGs; soluble in acetone,
dichloromethane, ethanol,
and methanol; and
slightly soluble in
aliphatic hydrocarbons
and ether. It is insoluble
in fats, fixed oils, and
mineral oil.8
7. Amidon GE. Citric acid. In: Rowe RC,
Sheskey PJ, Owen SC, eds. Handbook of
Pharmaceutical Excipients. 5th ed. Washington, DC: APA; 2006:185-187.
8. Price JC. Polyethylene glycol. In: Rowe
RC, Sheskey PJ, Owen SC, eds. Handbook of Pharmaceutical Excipients. 5th ed.
Washington, DC: APA; 2006:545-550.
Pharmacologic Management
of Alcohol Dependence
© JUPITERIMAGES
A
lcohol dependence is a serious health concern
that is associated with many long-term consequences. Alcohol dependence not only affects
an individual’s physical health, but also may impact
mental health and social well-being. Alcohol use is common in the American population. According to the
2008 National Survey on Drug Use and Health, more
than 50% of Americans aged 12 and older reported
drinking, 23% reported binge drinking, and 6.9% were
heavy alcohol drinkers.1 The prevalence rate of alcohol abuse or dependence in the United States is estimated at 5% to 14%.1-3
Alcohol dependence is a chronic disorder that may
require maintenance treatment, similar to other medical conditions such as hyperlipidemia and diabetes.4
It is believed that multiple neurotransmitters such as
endogenous opioids, dopamine, serotonin, gammaaminobutyric acid (GABA), and glutamate may be
either directly or indirectly affected by alcohol.4 Risk
factors such as genetics, environmental factors, and cultural attitudes may play a significant role in the
development of alcohol dependence.2
The intent of this article is to review the pharmacologic management of alcohol dependence; therefore
alcohol withdrawal, although a crucial part of treatment, will not be discussed.
Pharmacologic Therapy
The ultimate goals for patients with alcohol dependence are to achieve abstinence and prevent relapse.
Currently, the four pharmacologic agents that may
aid in accomplishing these goals are disulfiram, oral
naltrexone, injectable extended-release naltrexone, and
acamprosate.
sion, arrhythmia, convulsions, respiratory depression,
and myocardial infarction.4-6 The effects of this drug
are sufficiently unpleasant to the patient to serve as a
deterrent to consuming alcohol.
Disulfiram in the absence of alcohol tends to cause
minimal effects; however, drowsiness, metallic aftertaste, and hepatotoxicity may occur.5 Severe cardiovascular disease and concurrent use of metronidazole are
two major contraindications associated with disulfiram.5 It is important not to administer disulfiram until
the patient has abstained from alcohol for at least 12
hours. Furthermore, since disulfiram irreversibly inhibits
ALDH, alcohol consumption must be avoided for 2
weeks after the last dose.5
There is a substantial amount of literature regarding the use of disulfiram for alcohol dependence, but
many of these trials have significant methodologic weaknesses.6,7 Some of the data are inconsistent and may
be conflicting.4,6 A Veterans Administration Cooperative Study assessed 605 subjects assigned to disulfiram 250 mg, disulfiram 1 mg, or placebo. 8 This
study, conducted over 1 year, concluded that there were
no significant between-group differences in abstinence
rates or time to first drink. The study did find, however, that patients receiving disulfiram 250 mg who
ended up drinking reported fewer drinking days compared with the other two groups.8
Disulfiram is still utilized despite the conflicting
data. Disulfiram’s unique mechanism of action may be
a powerful advantage for patients. Disulfiram may help
with drinking outcomes such as reduced drinking days
or frequency; however, other outcomes, such as time
to first drink, abstinence, and alcohol consumption per
unit of time, lack consistent evidence. 4,6 Although
not appropriate for all patients, disulfiram has a place
in therapy for individuals seeking help with cessation
of heavy drinking.
Disulfiram: Disulfiram is an aversion-based treatment
that acts by blocking aldehyde dehyKrina H. Patel, PharmD
drogenase (ALDH). This results in
Assistant Professor
an increase in acetaldehyde levels
Pharmacy Practice
when alcohol is consumed and induces
Nesbitt College of Pharmacy and Nursing
negative effects such as dizziness,
Wilkes University
flushing, nausea, vomiting, hypotenWilkes Barre, Pennsylvania
Naltrexone: Naltrexone is a competitive opioid receptor antagonist.
Endogenous opioids are released in
response to alcohol intake, thereby
60
U.S. Pharmacist • November 2009 • www.uspharmacist.com
PHARMACOLOGIC MANAGEMENT OF ALCOHOL DEPENDENCE
causing alcohol’s acute rewarding properties. Naltrexone’s mechanism of action reduces cravings and also
is likely to minimize the “high” that individuals experience with alcohol intake, which may result in lower
alcohol consumption.7,9-12
Naltrexone’s adverse-effect profile tends to be
mild, but gastrointestinal side effects, headache,
dizziness, anxiety, and decreased appetite may occur.5
Rarely, naltrexone may cause dose-related hepatotoxicity, so frequent monitoring is recommended. Owing
to naltrexone’s mechanism of action, current opiate
treatment may induce withdrawal symptoms, so patients
should be opioid-free for at least 7 to 10 days before
naltrexone is initiated.5
Several studies have concluded that naltrexone is an
effective treatment option for alcohol dependence. In a
12-week, double-blind, placebo-controlled trial, 70 male
patients were treated with naltrexone or placebo.9 Patients
who received naltrexone experienced fewer cravings and
consumed less alcohol. The percentage of patients who
relapsed was significantly less in the naltrexone group
compared with the placebo group (54% vs. 23%). Additionally, 95% of placebo patients who sampled alcohol
relapsed, versus 50% of naltrexone patients.9 Another
trial established that naltrexone was superior to
placebo when outcomes such as number of drinking
days, abstinence rates, relapse rates, and severity of alcohol-related problems were compared.12 This study found
that abstinence rates were higher in the naltrexone group
versus the placebo group (61% vs. 19%).12
There are also some less compelling data regarding
naltrexone. One trial evaluated the use of naltrexone
for 3 months or 12 months in 627 veterans.13 Naltrexone was not significantly better than placebo in decreasing percentage of drinking days or drinks per day,
and it did not improve days to relapse. The trial concluded that the use of naltrexone in this population
base was not supported.13
Overall, naltrexone is an effective treatment option
for patients with alcohol dependence. Based on the literature, naltrexone can help improve outcomes by lessening cravings, decreasing heavy alcohol consumption,
decreasing relapse, and potentially enhancing abstinence rates.7,9-12
Intramuscular (IM) Naltrexone: In 2006, the FDA
approved a long-acting IM formulation of naltrexone.
Previous trials of naltrexone suggested that nonadherence to treatment may be a concern, resulting in
decreased effectiveness and suboptimal treatment outcomes. 10,14 Use of the IM formulation may help
overcome problems with adherence. One concern
regarding this formulation is the potential for injection-site reactions such as cellulitis, hematoma, and
necrosis.5
Several trials support positive outcomes associated
with the use of IM naltrexone. In one multicenter,
randomized, placebo-controlled trial, 315 patients
received either IM naltrexone or placebo.15 The trial,
conducted over 3 months, found that IM naltrexone
significantly improved abstinence rates compared with
placebo (18% vs. 10%), and also prolonged the time
to first drinking day.15 Overall, IM naltrexone appears
to be a safe and effective treatment option that may
be especially beneficial for patients who have adherence problems.16
Acamprosate: In 2004, acamprosate became available
in the U.S. for the treatment of alcohol dependence.
It is hypothesized that acamprosate restores GABA and
glutamate imbalances caused by alcohol intake.5,11 It
also is proposed that acamprosate has some effects on
the N-methyl-D-aspartic acid receptor.11
Some common adverse effects associated with
acamprosate are diarrhea, headache, insomnia, anxiety,
and muscle weakness.5 Patients treated with acamprosate
should try their best to avoid alcohol; however, alcohol
intake does not affect the pharmacokinetics of acamprosate, and therefore no disulfiram-type reaction will
occur.5 In addition, acamprosate may be a safer option
than disulfiram or naltrexone in patients with hepatic
impairment. The drug should be used with caution in
patients with renal impairment, however.5
Currently, there is insufficient U.S. literature strongly
evidencing the effectiveness of acamprosate, although
an adequate amount of European literature supports
its use.17-20 The COMBINE study, conducted in the
U.S., concluded that acamprosate failed to show evidence of efficacy with regard to time to first heavy drink
or abstinent days.17 In another U.S.-based double-blind,
placebo-controlled study, patients received acamprosate
2 g, acamprosate 3 g, or placebo.18 This study found
that percentage of abstinent days did not differ
among treatment groups; however, a post-hoc analysis that controlled baseline covariates and measured
highly motivated patients as a subset found that acamprosate yielded a greater number of abstinent days than
placebo.18
A European meta-analysis of 20 trials suggested that
continuous abstinence rates at 6 months were significantly higher for acamprosate-treated patients versus
patients given placebo (36.1% vs. 23.4%). 19 Data
also indicate that acamprosate confers improved
abstinence rates for up to 48 weeks.20
It is not clear why outcomes associated with acamprosate are inconsistent between the U.S. and European studies. Certain factors, such as the severity of
the alcohol dependence, may be potential reasons. 4
Based on the literature, acamprosate is associated
with an improved rate of complete abstinence and may
have other positive outcomes, such as decreased drinking frequency and rate of relapse.7,18-20 The drug appears
61
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Day 1
Day 2
Day 3
Day 4
Day 5
TAKE Z-PAK® FOR 5 DAYS1 OR...
(azithromycin) 250 mg
TAKE AZITHROMYCIN TO
1 DAY. 1 DOSE.
2
Please see accompanying Zmax brief summary.
Zmax is indicated for mild to moderate acute bacterial
sinusitis in adults due to Haemophilus influenzae, Moraxella
catarrhalis, or Streptococcus pneumoniae and is also indicated
for community-acquired pneumonia due to Chlamydophila
pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae,or
or Streptococcus pneumoniae in adult and pediatric patients
aged 6 months and over, deemed appropriate for oral therapy.
epidermal necrolysis in patients on other formulations of
azithromycin therapy. Rarely, fatalities have been reported.
Zmax and Zithromax are contraindicated in patients with
known hypersensitivity to azithromycin, erythromycin, or any
macrolide or ketolide antibiotic. If an allergic reaction occurs,
appropriate therapy should be instituted. Physicians should be
aware that reappearance of the allergic symptoms may occur
when symptomatic therapy is discontinued.
Clostridium difficile associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents, including
azithromycin, and may range in severity from mild diarrhea
to fatal colitis. CDAD must be considered in all patients who
present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to
occur over two months after the administration of
antibacterial agents. If CDAD is suspected or confirmed,
ongoing antibiotic use not directed against C. difficile may need
to be discontinued, and appropriate management and treatment
of C. difficile should be instituted as clinically indicated.
There have been rare reports of serious allergic reactions including
angioedema, anaphylaxis, Stevens Johnson syndrome, and toxic
As with all macrolides, including Zmax, exacerbations of
myasthenia gravis have been reported.
Zmax: 1 product — indicated for both
adult and pediatric patients2
Pediatric
patients
A higher incidence of gastrointestinal adverse events (8 of 19
subjects) was observed when Zmax was administered to a
limited number of subjects with GFR <10 mL/min.
Overall, the most common treatment-related adverse
reactions in:
-Adult patients receiving a single 2-g dose of Zmax were
diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%),
headache (1%), and vomiting (1%).
Adult
patients
-Pediatric patients receiving the recommended Zmax dose
of 1 mL/lb were vomiting (11.9%), diarrhea (8%), loose stools
(5.6%), abdominal pain (3%), rash (2.8%), nausea (1.7%), and
anorexia (1.2%).
References: 1. Zithromax (prescribing information). New York, NY:
Pfizer Inc; 2007. 2. Zmax (prescribing information). New York,
NY: Pfizer Inc; 2009.
Zmax® (azithromycin extended release) for oral suspension
Brief Summary of Prescribing Information
INDICATIONS AND USAGE
Zmax is indicated for the treatment with mild to moderate infections caused by susceptible isolates
of the designated microorganisms in the specific conditions listed below.
Acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis or
Streptococcus pneumoniae.
Community-acquired pneumonia in adults and pediatric patients six months of age or older due to
Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus
pneumoniae, in patients appropriate for oral therapy. Pediatric use in this indication is based on
extrapolation of adult efficacy.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax and other
antibacterial drugs, Zmax should be used only to treat infections that are proven or strongly suspected
to be caused by susceptible bacteria. When culture and susceptibility information are available, they
should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Appropriate culture and susceptibility tests should be performed before treatment to determine the causative
organism and its susceptibility to Zmax.Therapy with Zmax may be initiated before results of these tests are
known; once the results become available, antimicrobial therapy should be adjusted accordingly.
CONTRAINDICATIONS
Zmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any
macrolide or ketolide antibiotic.
WARNINGS AND PRECAUTIONS
Allergic and skin reactions
Serious allergic reactions, including angioedema, anaphylaxis, Stevens Johnson syndrome, and toxic
epidermal necrolysis have been reported rarely in patients on azithromycin therapy using other
formulations. Although rare, fatalities have been reported. Despite initially successful symptomatic
treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms
recurred soon thereafter in some patients without further azithromycin exposure.These patients
required prolonged periods of observation and symptomatic treatment. The relationship of these
episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has
not been determined.
If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware
that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Clostridium difficile-associated diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial
agents, including Zmax, and may range in severity from mild diarrhea to fatal colitis. Treatment with
antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing
strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to
antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present
with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been
reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need
to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Exacerbation of myasthenia gravis
Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been
reported in patients receiving azithromycin therapy.
Gastrointestinal Disturbances
A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmax
was administered to a limited number of subjects with GFR <10 mL/min.
Prolongation of the QT interval
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia
and torsades de pointes, have been seen in treatment with other macrolides. A similar effect
with azithromycin cannot be completely ruled out in patients at increased risk for prolonged
cardiac repolarization.
Development of drug resistant bacteria
Prescribing Zmax in the absence of a proven or strongly suspected bacterial infection is unlikely to
provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
ADVERSE REACTIONS
Clinical studies experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice.
Adults:
The data described below reflect exposure to Zmax in 728 adult patients. All patients received a single
2-g oral dose of Zmax. The population studied had community-acquired pneumonia and acute
bacterial sinusitis.
In controlled clinical trials with Zmax, the majority of the reported treatment-related adverse reactions
were gastrointestinal in nature and mild to moderate in severity.
Overall, the most common treatment-related adverse reactions in adult patients receiving a single
2-g dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache
(1%), and vomiting (1%). The incidence of treatment-related gastrointestinal adverse reactions was
17% for Zmax and 10% for pooled comparators. Treatment-related adverse reactions following Zmax
treatment that occurred with a frequency of <1% included the following:
Cardiovascular: palpitations, chest pain
Gastrointestinal: constipation, dyspepsia, flatulence, gastritis, oral moniliasis
Genitourinary: vaginitis
Nervous System: dizziness, vertigo
General: asthenia
Allergic: rash, pruritus, urticaria
Special Senses: taste perversion
Laboratory Abnormalities
In subjects with normal baseline values, the following clinically significant laboratory abnormalities
(irrespective of drug relationship) were reported in Zmax clinical trials:
- with an incidence of greater than or equal to 1%: reduced lymphocytes and increased eosinophils;
reduced bicarbonate;
- with an incidence of less than 1%: leukopenia, neutropenia, elevated bilirubin, AST, ALT, BUN,
creatinine, alterations in potassium.
Where follow-up was provided, changes in laboratory tests appeared to be reversible.
Pediatric Patients:
The data described below reflect exposure to Zmax in 907 pediatric patients. The population was 3
months to 12 years of age. All patients received a single 60 mg/kg oral dose of Zmax. As in adults, the
most common treatment-related adverse reactions in pediatric subjects were gastrointestinal in nature.
The pediatric subjects all received a single 60 mg/kg dose (equivalent to 27 mg/lb) of Zmax.
In a study with 450 pediatric subjects (ages 3 months to 48 months), vomiting (11%), diarrhea (10%)
loose stools (9%), and abdominal pain (2%) were the most frequently reported treatment-related
gastrointestinal adverse reactions. Many treatment related gastrointestinal adverse reactions with an
incidence greater than 1% began on the day of dosing in these subjects [43%(68/160)] and most
[53%(84/160)] resolved within 48 hours of onset. Treatment-related adverse events that were
not gastrointestinal, occurring with a frequency ≥ 1% were: rash (5%), anorexia (2%), fever (2%),
and dermatitis (2%).
In a second study of 337 pediatric subjects, ages 2 years to 12 years, the most frequently reported
treatment-related adverse reactions also included vomiting (14%), diarrhea (7%), loose stools (2%),
nausea (4%) and abdominal pain (4%).
A third study investigated the tolerability of two different concentrations of azithromycin oral suspension
in 120 pediatric subjects (ages 3 months to 48 months), all of whom were treated with azithromycin.The
study evaluated the hypothesis that a more dilute, less viscous formulation (the recommended
27 mg/mL concentration of Zmax) is less likely to induce vomiting in young children than a more
concentrated suspension used in other pediatric studies. The vomiting rate for subjects taking the dilute
concentration azithromycin was 3% (2/61). The rate was numerically lower but not statistically different
from the vomiting for the more concentrated suspension. Across both treatment arms, the only treatmentrelated adverse events with a frequency of ≥1% were vomiting (6%, 7/120) and diarrhea (2%, 2/120).
Treatment-related adverse reactions with a frequency of <1% following Zmax treatment in all 907
pediatric subjects in the Phase 3 studies were:
Body as a whole: chills, fever, flu syndrome, headache;
Digestive: abnormal stools, constipation, dyspepsia, flatulence, gastritis, gastrointestinal disorder,
hepatitis;
Hemic and Lymphatic: leukopenia;
Nervous System: agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability,
parasthesia, somnolence;
Respiratory: asthma, bronchitis, cough increased, dyspnea, pharyngitis, rhinitis;
Skin and Appendages: dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria;
Special Senses: otitis media, taste perversion;
Urogenital: dysuria.
Laboratory Abnormalities
In subjects with normal baseline values, the following clinically significant laboratory abnormalities
(irrespective of drug relationship) were reported in Zmax pediatric clinical trials:
- with an incidence of greater than or equal to 1%: elevated eosinophils, BUN, and potassium;
decreased lymphocytes; and alterations in neutrophils;
- with an incidence of less than 1%: elevated SGOT, SGPT and creatinine; decreased potassium; and
alterations in sodium and glucose.
Postmarketing experience with other azithromycin products
Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating
their frequency or establishing a causal relationship to drug exposure is not always possible.
Adverse events reported with azithromycin immediate release formulations during the post-marketing
period for which a causal relationship may not be established include:
Allergic: arthralgia, edema, urticaria and angioedema
Cardiovascular: palpitations and arrhythmias including ventricular tachycardia and hypotension
There have been rare reports of QT prolongation and torsades de pointes.
Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in
dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue
discoloration
General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal)
Genitourinary: interstitial nephritis, acute renal failure, moniliasis and vaginitis
Hematopoietic: thrombocytopenia, mild neutropenia
Liver/Biliary: abnormal liver function including hepatitis and cholestatic jaundice, as well as rare
cases of hepatic necrosis and hepatic failure, some of which have resulted in death
Nervous System: convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness,
agitation and syncope
Psychiatric: aggressive reaction and anxiety
Skin/Appendages: pruritus, rash, photosensitivity, rarely serious skin reactions including erythema
multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
Special Senses: hearing disturbances including hearing loss, deafness and/or tinnitus and rare
reports of taste/smell perversion and/or loss
DRUG INTERACTIONS
Warfarin
Although, in a study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin
time from a subsequently administered dose of warfarin, spontaneous post-marketing reports suggest
that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants.
Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral
anticoagulants concomitantly.
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats and
mice at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These daily
doses in rats and mice, based on mg/m2, are estimated to be approximately equivalent to one or onehalf of, respectively, the single adult oral dose of 2 g. In the animal studies, no evidence of harm to the
fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in
pregnant women. Because animal reproduction studies are not always predictive of human response,
azithromycin should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when azithromycin is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the treatment of pediatric patients under 6 months of age have not
been established.
Community-Acquired Pneumonia: The safety and effectiveness of Zmax have been established in
pediatric patients 6 months of age or older with community-acquired pneumonia due to Chlamydophila
pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae or Streptococcus pneumoniae. Use
of Zmax for these patients is supported by evidence from adequate and well-controlled studies of Zmax
in adults with additional safety and pharmacokinetic data in pediatric patients.
Acute bacterial sinusitis: Safety and effectiveness in the treatment of pediatric patients with acute
bacterial sinusitis have not been established.
Geriatric Use
Data collected from the azithromycin capsule and tablet formulations indicate that a dosage adjustment
does not appear to be necessary for older patients with normal renal function (for their age) and hepatic
function receiving treatment with Zmax.
In clinical trials of Zmax, 17% of subjects were at least 65 years of age (214/1292) and 5% of subjects
(59/1292) were at least 75 years of age. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects.
Renal Impairment
No dosage adjustment is recommended for patients with GFR >10 mL/min. Caution should be
exercised when Zmax is administered to patients with GFR <10 mL/min, due to a higher incidence
of gastrointestinal adverse events (8 of 19 subjects) observed in a limited number of subjects with
GFR <10 mL/min.
Gender
The impact of gender on the pharmacokinetics of azithromycin has not been evaluated for Zmax.
However, previous studies have demonstrated no significant differences in the disposition of
azithromycin between male and female subjects. No dosage adjustment of Zmax is recommended
based on gender.
OVERDOSAGE
Adverse events experienced in higher than recommended doses were similar to those seen at normal
doses. In the event of overdosage, general symptomatic and supportive measures are indicated
as required.
Please see full Prescribing Information for additional information about Zmax.
ZMU00173
©2009 Pfizer Inc.
All rights reserved.
Printed in USA/November 2009
PHARMACOLOGIC MANAGEMENT OF ALCOHOL DEPENDENCE
to be a logical option given the evidence of lasting
effects and improved drinking outcomes.20
Combination Treatment
It has been proposed that combination therapy may
result in improved efficacy compared with monotherapy. 17,21,22 Owing to their different mechanisms of
action, it may be theoretically appropriate to combine these agents for added benefit. Based on the literature, the combination of disulfiram and naltrexone appears to offer no additional benefits over treatment
with either medication alone. 23 Studies examining
the combination of disulfiram and acamprosate indicate that this combination may result in improved efficacy, but there is not much literature regarding concomitant use of these drugs.21
The bulk of the literature centers on the combination of naltrexone and acamprosate. The COMBINE
trial concluded that the concomitant use of these two
medications appeared to be safe and well tolerated, but
provided no additional therapeutic benefit versus naltrexone alone.17 In another trial, 160 patients were randomized to receive acamprosate, naltrexone, naltrexone plus acamprosate, or placebo.22 The combination
group had significantly lower relapse rates compared
with the placebo group and the acamprosate group,
but the combination was not more effective than naltrexone only.22
Overall, the combination of naltrexone and acamprosate appears to be safe and well tolerated, but
there may be an increase in certain adverse effects, such
as diarrhea and nausea.22 The combination seems to
provide some benefit compared with acamprosate alone.
Combination therapy may be a valid option for some
patients who are not responding to monotherapy. Further research is needed to clarify the utility of combination therapy in the treatment of alcohol dependence.
Off-Label and Investigational Treatments
Recently there has been a growing interest in exploring other potential treatments for alcohol dependence.
Most new research focuses on agents that are proposed
to target neurotransmitters that are affected by alcohol. These different classes of medications have been
used off-label in the hope that some new agents may
provide promising treatments in the future.
Topiramate, oxcarbazepine, lithium, carbamazepine,
gabapentin, and divalproex are some of the mood stabilizers and anticonvulsants that have been evaluated
for the treatment of alcohol dependence. 4,6,10 It is
believed that some anticonvulsants, such as topiramate,
are responsible for enhancing GABA activity and antagonizing glutamate activity, which may lead to decreased
alcohol consumption.4,10,24 Topiramate appears to be
the best studied of the anticonvulsants thus far. Several randomized, controlled trials of topiramate have
reported positive drinking outcomes (such as decreased
heavy drinking days and drinks per day) and increased
abstinent days compared with placebo.10,24,25 One trial
found that patients treated with topiramate achieved
26% more abstinent days than patients given placebo.24
Topiramate appears to hold promise as a treatment
for alcohol dependence.
Most of the other abovementioned drugs, such as
oxcarbazepine and divalproex, do not have conclusive
data concerning their utility in treating alcohol dependence, and further research is needed.10 Lithium currently does not have supportive evidence as a treatment
for alcohol dependence.7
Serotonergic agents constitute another medication
class that has been researched for its value in treating
alcohol dependence. It is theorized that serotonin plays
a role in alcohol consumption.4,26 Literature exists concerning the use of selective serotonin reuptake inhibitors
(SSRIs) for the treatment of alcohol dependence; however, results are inconsistent and do not support the
use of SSRIs to treat alcohol dependence as a primary
condition.4,6,7,26 It is thought that SSRIs may improve
psychiatric illness, which may have an effect on
drinking behavior.27 Ondansetron has been associated
with positive drinking outcomes such as fewer drinks
per day, fewer drinks per drinking day, more abstinent days, and more abstinent days per week.6
Dopamine antagonists may be involved in the treatment of alcohol dependence. Olanzapine has exhibited
some positive outcomes.10 Other agents, such as baclofen
and galantamine, also have been researched, but data
regarding their use are either mixed or negative.10
Currently, there are only a few options available
for the treatment of alcohol dependence. The agents
mentioned above may hold some promise for the future,
but more research is needed. Many of the current trials of these agents are methodologically weak or have
inconclusive findings. For those reasons, further investigation is needed before these agents can be recommended or used for the treatment of alcohol dependence. There is a great need for the discovery of new
potential options to treat alcohol dependence.
Conclusion
Alcohol dependence is a chronic disorder that has many
consequences. Optimal treatment with pharmacologic
agents may help achieve desired outcomes. The currently available treatments for alcohol dependence are
all valid options, and their use should be individualized. Pharmacists can optimize treatment by recommending agents based on the expected outcomes
associated with each medication. Pharmacists also can
provide care by educating patients regarding expected
outcomes, adverse effects, and precautions associated
with the pharmacologic agents.
References available online at www.uspharmacist.com.
65
U.S. Pharmacist • November 2009 • www.uspharmacist.com
Criminalization of
Medication Errors
A recent case
that equates a
pharmacist’s mistake
with manslaughter
also raises the
question of
pharmacy technician
responsibility.
H
ere is a sobering thought.
A pharmacist makes a mistake. The error results in
the death of a patient, and the pharmacist is charged with negligent
homicide. He is found guilty of
involuntary manslaughter and faces
up to 5 years in prison and a maximum fine of $10,000. Of course,
his pharmacist license is revoked
and chances are he will never work
in the profession again. His crime?
He did not check the accuracy of
calculations used by a pharmacy
technician under his charge to compound the concentration of sodium
chloride in a prescription for a cancer chemotherapy solution.
Negligent? Yes. Accountability
and responsibility? Yes and Yes. Malpractice? Yes. Loss of license? Yes.
Guilty? Yes. But a crime? Prison
term? For a mistake, albeit a mistake
with a worst-case outcome? That is
tough medicine to swallow. More
Jesse C. Vivian, BS Pharm, JD
Professor, Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Detroit, Michigan
important, how is justice served by
putting this pharmacist in jail? The
message to pharmacists and perhaps
all other health care practitioners—
watch out. There may be prosecutors out there just itching to put
you away.
Facts of the Case
On February 24, 2006, while working at the Rainbow Babies and
Children’s Hospital in Cleveland,
Ohio, licensed pharmacist Eric
Cropp received a prescription for a
chemotherapy solution of Eposin
(etoposide phosphate) that was supposed to be mixed in an IV bag of
normal saline containing 0.9%
sodium chloride.1 The patient,
Emily Jerry, was diagnosed with a
yolk sac tumor when she was about
a year and a half old. The tumor
was the size of a grapefruit and
stemmed from the base of her spine
into her abdomen. Her team of
doctors and nurses assured the parents that Emily’s cancer was not
only treatable but curable. Emily
endured months of surgeries, testing, and rigorous chemotherapy sessions, each of which lasted for 5 or
6 days. Emily’s treatment had been
so successful that her last MRI
clearly showed that the tumor had
shrunk dramatically, with minimal
residual scar tissue. However, her
physicians still felt one final treatment was necessary to prevent the
tumor from reappearing. She was
scheduled to begin her last
chemotherapy session on her second
birthday. This last treatment was
just to be sure that there were no
traces of cancer left.
The medication was to be the
fourth and final round of treatment.
Two days later, after the IV therapy
was started, the child collapsed in
her mother’s arms, crying in pain
and vomiting. She grabbed her head
and said, “Mommy, it hurts, it
hurts.” The IV was started at 4:30
PM. By 5:30 PM, she was on life support. She went into a coma and
died on March 1, 2006.2 The infusion caused intense cerebral edema.
For reasons that have never been
explained, the technician who made
the mixture, Katie Dudash, used a
saline base solution of 23.4%
sodium chloride instead of the commercially available standard bag of
normal saline. She told investigators
that she did not recall why she
decided to make a new solution of
saline from scratch instead of grabbing a premade bag of normal saline
that was available right there in the
pharmacy. She said she was distracted because she was talking on
her cell phone just before the incident happened, busy making plans
for her upcoming wedding.
An investigation into the incident disclosed that many circumstances contributed to the error’s
occurrence. The pharmacy computer system was not working and a
backlog of physician orders was piling up. The pharmacy was shortstaffed and everyone in the pharmacy was busy. The employee
shortage meant that normal work
and meal breaks were altered or not
available. The technician was distracted from her normal routine. A
floor nurse called the pharmacy and
asked the pharmacist to send the
66
U.S. Pharmacist • November 2009 • www.uspharmacist.com
CRIMINALIZATION OF MEDICATION ERRORS
solution early. As a result, he felt
rushed. Ironically, it was later determined that the IV bag was not
needed for several hours.
As can well be imagined, this
incident took a terrible toll on the
parents. They sued the hospital for
malpractice and obtained a $7 million settlement.3 Soon afterward,
the parents separated, and they
divorced a year later. The mother,
Kelly Jerry, had to obtain restraining
orders against Emily’s father, Chris
Jerry. He violated at least one of the
orders and lost custody of both of
his other children. In 2008, he was
arrested for possession of marijuana
and charged with resisting arrest.
His case was diverted to a mental
health court for sentencing. He
sought psychological counseling as
he looked for a way to work
through his problems.
Then, in 2009, Chris Jerry
found a way to make something out
of this tragedy. Mr. Jerry began
counseling families in local hospitals
whose children were on life-support
systems. He made himself present
simply as one who understands
what they were going through. “I
can speak to these people because I
have gone through something similar, I know what they need to hear,”
he said. “I can relate to them in
every way.”4 He also started Emily’s
Foundation, a charity he hopes to
use to push for a national law to
govern the work of pharmacy technicians and help prevent medical
errors like the one that killed his
daughter.5
Kelly Jerry attended all of the
civil and criminal proceedings and
made a compelling statement at the
board of pharmacy hearing on the
administrative complaint against the
pharmacist. Chris Jerry did not
attend any of the legal actions,
although now he no longer feels any
anger against the pharmacist. In fact
he has been quoted as saying, “I feel
very sorry for the pharmacist. This
guy is facing a prison sentence, and
I know it was an accident.”6
Unprofessional Conduct
The pharmacist and the technician
were dismissed by the hospital
about 1 month after the incident.
The tech went to back to work at
CVS/pharmacy where she had been
employed before working at the
hospital. The pharmacist found a
job at a local retail pharmacy just a
few weeks later. There, according to
records, he made an additional 13
more dispensing errors over a 10month period. One of those errors
caused harm to another child.7
The Ohio State Board of Pharmacy held a hearing on a formal
complaint against the pharmacist on
April 11, 2007, a little over a year
after the incident that caused the
death of Emily Jerry.8 For this error,
State
regulations vary
tremendously
with respect
to pharmacy
technicians.
the board found him responsible for
misbranding and mislabeling a drug
in violation of Ohio law.9 But this
incident was actually only the
beginning of Mr. Cropp’s problems.
On April 26, 2006, while working at a community pharmacy, Eric
Cropp misbranded a prescription
for Compazine (prochlorperazine)
10-mg tablets prescribed for “nausea and vomiting.”10 He typed the
label indicating the medication was
to be taken “as needed for pain.”
While at the same store, on July 18,
he dispensed tramadol with acetaminophen instead of the prescribed
Vicoprofen (hydrocodone and
ibuprofen). On July 25, he dispensed metformin ER 500-mg
tablets to a patient instead of the
Biaxin XL (clarithromycin) 500-mg
tablets that were prescribed. On
that same day, he gave the Biaxin to
the patient who should have been
given the metformin. On August
18, he received a prescription for
Phenergan (promethazine) 25-mg
suppositories with directions to be
used “rectally every 8 hours.”
Instead, he typed a label indicating
the medication was to be “taken by
mouth.” On September 19, he dispensed Adderall XR (amphetamine
and dextroamphetamine) 5-mg capsules to an 8-year-old child who
had been prescribed Focalin XR
(dexmethylphenidate) 5-mg capsules. The child suffered undisclosed injuries. On November 13,
he received a prescription for Disalcid (salsalate) 500 mg. He dispensed Azulfidine (sulfasalazine)
500 mg instead. On November 18,
he received a prescription for VoSol
HC (hydrocortisone and acetic
acid) from an ear, nose, and throat
physician with indications that the
medication was to be used “in the
ear.” He labeled the drug as for use
“in the eye.” On December 12, he
received a prescription for Zoloft
(sertraline) 100-mg tablets with
directions that the patient should
take “two tablets every evening.”
He labeled the medication to be
taken “twice daily.” On December
15, he received a prescription for
Avelox (moxifloxacin) 400 mg. He
labeled and dispensed the drug to
the wrong patient. On December
26, he received a prescription for
Zoloft (sertraline) 100-mg tablets.
Instead, he dispensed 50-mg
tablets. On February 3, 2007, he
received a prescription for E.E.S.
(erythromycin ethylsuccinate) 200
mg/5 mL suspension. Instead, he
dispensed erythromycin with sulfisoxazole suspension. Finally, on
the following day, he received a prescription for two boxes of Imitrex
(sumatriptan) 6 mg/0.5 mL and
dispensed a quantity less than what
was called for by the prescription.
The Ohio Board of Pharmacy
found that all of the above conduct
constitutes “unprofessional conduct”
in violation of state law and then
permanently revoked the pharma-
67
U.S. Pharmacist • November 2009 • www.uspharmacist.com
CRIMINALIZATION OF MEDICATION ERRORS
cist’s license.11 The vote was six in
favor of this resolution with two
board members in opposition.
In May 2009, the pharmacist
pleaded no contest to a charge of
involuntary manslaughter for
improperly supervising the technician. On August 14, 2009, Mr.
Cropp was sentenced to 6 months
in prison, 6 months of home confinement with electronic monitoring, 400 hours of community service, a $5,000 fine, and payment of
court costs.12 Part of the community service sentence requires him
to seek out medical and legal
organizations where he can tell his
story and, hopefully, help prevent
others from making a similar mistake. Remember that his pharmacist license was permanently
revoked, so he will have a significant loss of future income. And
then, of course, there are the undisclosed attorney fees that the pharmacist incurred in his hearing in
front of the Board of Pharmacy and
his criminal prosecution.
Oh, and by the way, what happened to the pharmacy tech that
made the fatal error? Katie Dudash
was charged by the prosecutor with
negligent homicide, but the grand
jury gave her a “get out of jail free
card.” She gets off with no real
penalty and is now working in a
retail pharmacy. She was not
licensed, registered, or certified by
the state to work as a technician, so
REFERENCES
1. Emily’s Story. Emily Jerry Foundation.
http://emilyjerryfoundation.org/emilys-story/.
Accessed October 11, 2009.
2. Robins M. Fatal dose: Ohio girl is killed by medical
mistake. January 31, 2007. www.firstcoastnews.com/
news/usworld/news-article.aspx?storyid=75102.
Accessed October 4, 2009.
3. Whitley M. Chris Jerry, whose daughter Emily died
from a pharmacy technician’s mistake, starts foundation to
push for national law. June 13, 2009. http://blog.
cleveland.com/metro/2009/06/chris_jerry_whose_
daughter_emi.html. Accessed October 11, 2009.
4. News. Emily Jerry Foundation. October 7, 2009.
http://emilyjerryfoundation.org/chris-jerry-whosedaughter-emily-died-from-a-pharmacy-techniciansmistake-starts-foundation-to-push-for-national-law/.
Accessed October 11, 2009.
5. See note 4, supra. The Web site states, in part: “The
core of the Emily Jerry Foundation focuses on protecting
our nation’s babies and children from the all too redun-
there were no administrative sanctions available. She has no accountability or responsibility. She was just
an employee doing a job. She did
not do her job right, but there were
no consequences—other than losing
her job and maybe having to live
with the idea that her actions
directly caused the death of another
human being.
Emily’s Law
At the time, Ohio was one of many
states that had no minimum training, licensing, registration, or certification requirements for pharmacy
technicians. State regulations vary
tremendously with respect to pharmacy technicians. Currently, only
eight states license technicians, 31
states have registration, and five
states certify techs. Twenty states
have no educational requirements
(training, continuing education, or
certification exam) for technicians.13
On January 7, 2009, the governor
of Ohio signed SB 203, known as
“Emily’s Law,” which establishes
standards for qualified pharmacy
technicians and requires them to
undergo a criminal background
check.14 They must also pass a competency test. It also establishes
penalties for certain activities,
including compounding, packaging,
and preparing a drug by an individual who is not a pharmacist, pharmacy intern, or qualified pharmacy
technician.15
dant medical errors that keep occurring over and over
again in hospitals across the nation. These countless mistakes are killing our children and are most often avoidable.
We are increasing public awareness of these issues and
striving to get better legislation in place across the United
States. The Emily Jerry Foundation is helping to save
countless lives, as well as make our world-renowned medical facilities much safer.”
6. See note 4, supra.
7. Failure to track pharmacy mistakes may be
“prescription for trouble.” NewsNet5. March 23, 2009.
www.newsnet5.com/news/18917359/detail.html.
Accessed October 11, 2009.
8. Minutes of the April 9-11, 2007 meeting of the Ohio
State Board of Pharmacy. Docket Number D-061108-012.
http://pharmacy.ohio.gov/minutes/mins07040911.pdf.
Accessed October 11, 2009.
9. ORC § 3715.52(A)(2) and OHC Rule 4729-17-10.
10. See note 8, supra.
11. ORC § 4729.16.
12. Not a wonderful life: no George Bailey for pharmacist
The downside of making this
mistake, awful as it was, into a
criminal case with incarceration
for the offender is that it discourages others from ever wanting to
report errors with serious consequences. “We need to change the
system. I’m hopeful that we can
find something meaningful in
terms of safety from this child’s
death,” said Bona Benjamin, director of medication use quality
improvement at the American
Society of Health-System Pharmacists (ASHP).16 Some pharmacy
groups are beginning to push for
greater standardization of technician training. ASHP has developed
a model curriculum for pharmacy
technician training program
accreditation as the first effort to
develop a national standard. In
addition, the National Pharmacy
Technician Association, the Institute for the Certification of Pharmacy Technicians, and the Pharmacy Technician Certification
Board have all worked to develop
technician training standards.17
If nothing else, this case should
send a loud and serious message to
pharmacists. You can delegate
activities associated with the practice of pharmacy to technicians and
others. But you can never delegate
responsibility or accountability. It
is your name on the license, and
there are no excuses for mistakes of
this type.
Eric Cropp or his patient. September 5, 2009.
http://jparadisirn.com/2009/09/05/not-a-wonderful-lifeno-george-bailey-for-pharmacist-eric-cropp-or-his-patient/.
Accessed October 4, 2009.
13. Reid P. Former pharmacist indicted for manslaughter
after med error. Drug Topics. September 17, 2007.
http://drugtopics.modernmedicine.com/drugtopics/
Community+Pharmacy/Former-pharmacist-indicted-formanslaughter-after-/ArticleStandard/Article/detail/456584.
Accessed October 11, 2009.
14. Sangiacomo M. Ohio governor signs “Emily’s Law”
forcing standards for pharmacy technicians. Cleveland
Plain Dealer. January 7, 2009. www.cleveland.com/
medical/index.ssf/2009/01/emilys_law_enacted_by_gov_
stri.html. Accessed October 11, 2009.
15. Governor signs “Emily’s Law” legislation.
www.governor.ohio.gov/News/PressReleases/2009/
January2009/News1709/tabid/956/Default.aspx.
Accessed October 11, 2009.
16. See note 13, supra.
17. See note 13, supra.
68
U.S. Pharmacist • November 2009 • www.uspharmacist.com
&
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Join 160,000 pharmacists, techs, and students who are being invited to check out the new
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© JUPITERIMAGES
Emergency
Contraception
An Update of Clinical
and Regulatory Changes
E
mergency contraception (EC),
sometimes referred to as the
“morning-after pill,” is a safe
and effective method of preventing
pregnancy after intercourse. Levonorgestrel, a hormone found in many
birth control pills, is the active ingredient in most emergency contraceptive products used in the U.S. The
Food and Drug Administration (FDA)
approved the first levonorgestrel-only
emergency contraceptive, Plan B (levonorgestrel 0.75 mg oral tablets), in
1999 for prescription use. In 2006,
the FDA widened access to EC by
approving over-the-counter (OTC)
sale to consumers 18 years of age or
older.1,2 At the time, Plan B was the
first product to be approved in the
U.S. with dual status (a single product approved for OTC sale or prescription-only access to consumers
based on age). More recently, the FDA
further increased access to EC by
reducing the age for OTC access to
anyone 17 years and older, continuing access to girls under age 17 by
prescription only. Two new EC products recently became available in
the U.S. In July 2009, the FDA
approved a one-dose emergency contraceptive, Plan B One-Step (levonorgestrel 1.5 mg tablet) for OTC
Kathleen H. Besinque, PharmD, MSEd
Associate Professor of Clinical Pharmacy
School of Pharmacy
University of Southern California
Los Angeles, California
U.S. Pharmacist Continuing Education
GOAL: The goals of this educational program are to update pharmacists and other health
care professionals on the current clinical and regulatory information related to levonorgestrelbased emergency contraception and to provide effective strategies for educating consumers
about emergency contraception.
OBJECTIVES: After completing this activity, participants should be able to:
1. Discuss the clinical indications for emergency contraception.*
2. Compare available levonorgestrel-only emergency contraceptive regimens and the
requirements associated with the nonprescription sale of these products.*
3. Describe the evidence for the mechanism of action and safety profile of levonorgestrel-only
emergency contraceptive regimens.*
4. Discuss opportunities for pharmacists to provide improved access to emergency contraception,
including identification of and reduction of barriers in the pharmacy environment.*
5. Describe strategies to improve education and counseling of consumers regarding the
effective use of levonorgestrel emergency contraception regimens.*
* Also applies to pharmacy technicians.
sale to consumers age 17 and older
and by prescription to girls under age
17.3 Next Choice (levonorgestrel 0.75
mg tablets) was also approved in 2009
and is a generic formulation of the
original Plan B. Although three levonorgestrel EC products may be currently available—Plan B, Plan B OneStep, and Next Choice— the distribution
of Plan B will cease as Plan B OneStep launches into the marketplace.
All EC products are approved to prevent pregnancy when a contraceptive
method has failed or was not used
during intercourse.
Unintended pregnancies are associated with many personal and public health related consequences. In
the U.S., approximately half of all
pregnancies occurring each year are
unintended and as many as half of
the unintended pregnancies are terminated by elective abortion.4 When
taken within 72 hours of unprotected
intercourse, levonorgestrel-only EC
reduces the risk of pregnancy by as
much as 89%.2,3 Studies to date have
not been able to show that having
EC available without a prescription
has reduced the rates of unintended
pregnancy in the U.S. as was originally anticipated.5,6 The reason for
the lower-than-anticipated impact on
unintended pregnancy rates may be
related to the persistence of barriers
to EC access, including misunderstanding by consumers about when
to use EC.
Pharmacists and other health care
professionals can help to reduce bar-
70
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION: AN UPDATE
imen initiated within 72 hours of unprotected intercourse. Despite FDA approval, an increase in the utilization of EC by women was hampered by a number
of barriers (TABLE 1).
To improve access, a request was made to move Plan
• Lack of awareness by consumers that a method to
B to OTC status. Plan B appeared to satisfy FDA requireprevent pregnancy after intercourse was available
ments for conversion from prescription to OTC sta• Failure of doctors to discuss EC during medical
tus, which include a minimum of two years of prescripappointments
tion use with a high degree of safety and studies establishing
• Lack of information about EC among health care
that consumers can interpret labeled instructions corprofessionals
rectly. Although an FDA Advisory Committee voted in
• Misconceptions about how EC works
2003 in support of the request for nonprescription
• Confusion of EC and the “abortion pill”
status, the FDA approved a change for Plan B in 2006
• Difficulty obtaining EC by prescription within the
to “dual status” instead.11 Under dual status, Plan B was
narrow window of efficacy
made available without prescription to consumers at or
above a certain age (originally 18 years but now 17) and
riers that limit the use of EC by improving patient access remained available by prescription to younger women.
and being available to answer questions about the use Packaging for the product was approved to meet the
of EC. Pharmacists, as the “most accessible” health requirements for both prescription and nonprescription
care provider, are in a unique position and play a cru- products. Since then, Next Choice and Plan B Onecial role in providing timely access to and information Step have also been approved for dual status distribuabout EC to consumers. OTC availability in the phar- tion in pharmacies and clinics (TABLE 2).
Before the approval of dedicated products for EC,
macy to consumers age 17 and over improves access to
EC by reducing the delays that were associated with commercially available oral contraceptives containing
obtaining a prescription in the limited time frame needed ethinyl estradiol with either norgestrel or levonorgestrel
(often referred to as the “Yuzpe regimen”) were used for
for efficacy of the product.
EC. More recent studies have shown these combinaBackground and Clinical History of EC
tions to be less effective (ranging from 49% to 75%)
Levonorgestrel has been extensively studied as an than levonorgestrel-only regimens. 7,9 Furthermore,
emergency contraceptive worldwide since the 1970s. the Yuzpe regimen has more side effects, especially nauAfter almost 40 years of EC use, the high degree of sea and vomiting, which often require the addition of
efficacy in preventing pregnancy (up to 89% reduction) an antiemetic medication. Production of Preven, a comand the low rate of adverse effects have been well doc- mercially available equivalent to the Yuzpe regimen, was
umented.5,7-10 A 2009 update to a Cochrane review of stopped in 2004. Because of its lower efficacy and
EC interventions included more than 88 studies and increased frequency of side effects, use of the Yuzpe type
concluded that levonorgestrel is both safe and effective combination regimens has declined but remains an
in preventing pregnancy after intercourse.7
option when levonorgestrel is not available.
The first products approved by the FDA for EC were
Several other methods have been evaluated for EC,
Preven (ethinyl estradiol 0.25 mg/levonorgestrel 0.5 mg including combinations of estrogen with norethindrone,
tablets) in 1998 and Plan B (levonorgestrel 0.75 mg combining levonorgestrel with the COX-2 inhibitor
tablets) one year later. Both products were approved for meloxicam, Yuzpe or levonorgestrel regimens using difuse by prescription and to be taken in a two-dose reg- ferent time intervals or doses, insertion of a copper IUD,
an investigational progesterone
modulator ulipristal (availTable 2
able as ellaOne in Europe) and
Products Approved for Emergency Contraception
low doses of mifepristone.7,12
Combination regimens using
Levonorgestrel
norethindrone appear to be less
Brand
Manufacturer
Dose
per Dose (mg)
effective than levonorgestrel
One-Dose Regimen
regimens. 13 Regimens using
mifepristone in doses ranging
Plan B One-Step
Barr Pharmaceuticals
1 tablet per dose
1.5
from 10 mg to 50 mg appear
Two-Dose Regimens (administered immediately and 12 h later)
to be effective; however, these
Plan B
Barr Pharmaceuticals
doses are not available in the
Next Choice
Watson Pharmaceuticals 1 tablet per dose
0.75
U.S.7 Insertion of a copper IUD
up to 10 days after intercourse
Table 1
Early Barriers Preventing
Utilization of EC Methods
71
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION: AN UPDATE
appears to have a low failure rate (0.01% to 0.02%),
but IUD insertion requires a clinician visit and may not
be suitable for some women.8 The investigational progesterone receptor modulator recently approved in
Europe, ulipristal, may be as effective with similar side
effects as levonorgestrel.14 Studies evaluating the use
of levonorgestrel as a single dose (1.5 mg) did not find
a significant difference in efficacy compared with 0.75
mg two-dose regimens.7 The newly approved Plan B
One-Step (1.5 mg) is a single-dose regimen that may
be more convenient and easier to use.
Mechanism of Action
Levonorgestrel, the only active ingredient in Plan B,
Plan B One-Step, and Next Choice, is a synthetic
progestin also available in hormonal contraceptives.
The mechanisms by which levonorgestrel prevent pregnancy are likely similar to those of other hormonal contraceptives. All currently available hormonal methods
of contraception have been shown to act by one or
more of the following mechanisms: altering the endometrial lining, altering cervical mucus, interfering with
fertilization or transport of an egg, or preventing implantation. There is good evidence that levonorgestrel
prevents or delays ovulation as its primary mechanism of action; however, it is possible that additional
mechanisms may be involved.15-20 There are no data
supporting the view that levonorgestrel can impair the
development of the embryo or prevent implantation.20
A number of publications have shed light on the mechanisms of action for levonorgestrel-only EC.15-20 Levonorgestrel-only EC has been shown to inhibit the preovulatory surge of luteinizing hormone (LH), thereby
inhibiting follicular development and/or the release of
the egg. A properly timed and sufficient surge of LH is
required for the release of an ovum or ovulation. Ovulation must take place for fertilization to be possible.
Research has demonstrated that EC inhibits the midcycle surge of LH from the pituitary and, if taken at least
two days before ovulation, ovulation is delayed or pre-
Table 3
Indications for Use
of Emergency Contraception
•
•
•
•
•
•
•
Unprotected intercourse (including forgetting to use a
condom or diaphragm)
If a condom breaks or tears during intercourse
Missing one or more doses of an oral contraceptive
Being 2 or 3 days late to resume an ongoing
hormonal contraceptive regimen
While taking medication that may reduce the
effectiveness of a hormonal contraceptive
After exposure to a teratogen
After a sexual assault
vented. Ovulation may occur if the administration of
levonorgestrel is delayed until ovulation is imminent.20
If levonorgestrel is taken later in the cycle, the effect on
the LH surge may be equal to that of a placebo and pregnancy may occur. These time-sensitive events may explain
why taking EC as soon as possible after unprotected intercourse is critical for maximizing its effectiveness.
Studies of levonorgestrel and its potential effects on
endometrial function have not shown changes that would
prevent the implantation of a fertilized ovum.17 Women
who have used Plan B to prevent a pregnancy early in
their menstrual cycle remain at risk for pregnancy later
in the same cycle if contraception is not resumed or fails
again. This indicates that the endometrium is still intact
and capable of implanting a fertilized ovum.19
It has been speculated that levonorgestrel may alter
the movement of a fertilized egg, which would be expected
to increase the risk of an ectopic pregnancy. Studies
have not supported this assumption. The risk of an
ectopic pregnancy after levonorgestrel use may be slightly
lower than national ectopic pregnancy rates. 21 The
Cochrane review found only five cases of ectopic pregnancy reported in more than 45,000 uses of EC and
concluded that ectopic pregnancy was not associated
with any specific type of EC or a likely consequence
from using EC.7
The International Consortium for Emergency Contraception (ICEC), in a 2008 Policy Statement on mechanism of action, reported that levonorgestrel-only EC
pills inhibit, delay, or interfere with ovulation and may
possibly prevent the sperm and egg from meeting by
affecting cervical mucus or the ability of sperm to bind
to the egg.22 The ICEC also stated that there are no direct
clinical data to support mechanisms other than the
inhibition, delay, or alteration of ovulation.22 Levonorgestrelonly EC does not cause abortion or interfere with an
established pregnancy and, if inadvertently taken by a
woman who is pregnant, the pregnancy will not be harmed.
The ICEC noted that EC might actually prevent abortions by reducing unplanned pregnancies.22
Indications and Contraindications
EC is the use of a contraceptive method to prevent pregnancy after intercourse. Levonorgestrel products are
approved for use within 72 hours after intercourse.
There is evidence that taking EC as soon as possible
may maximize its effectiveness and that use up to 120
hours may be effective. Consumers who are unsure of
when to use EC or whether EC is needed may ask the
pharmacist about its appropriateness. Circumstances
where EC is indicated are listed in TABLE 3.
Pharmacists can reassure women that EC is safe
and effective and can be used when needed to prevent
pregnancy after unprotected intercourse. A myth that
may present a barrier to access to EC is belief that it
can only be used once in a lifetime, once per year, or
72
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION: AN UPDATE
only once during a menstrual cycle. Pharmacists should
not restrict the purchase of EC based on prior use or
out of concern that repeated use of EC is not safe.12
There is no evidence that repeat use of EC poses increased
risk to patients.23 Because EC is less effective as birth
control than ongoing methods of contraception (such
as condoms or birth control pills), it is recommended
only as a backup method and not as a substitute for
ongoing, more effective methods. EC can be purchased
in advance and kept at home in case the need arises, as
this avoids the delay of going to the pharmacy.
There are few contraindications to the use of EC.
The WHO Medical Criteria for Contraceptive Use 2005
stated that there are “no conditions where the risks of
EC outweigh the benefits.”23 Product labeling lists the
contraindications as an established pregnancy or known
allergy to the ingredients in EC. There are no studies
of EC use by women with migraine headaches, smokers over age 35, or other precautions applicable to the
regular use of combination oral contraceptives. However, these conditions should not limit the use of EC.
Timing of the EC Dose
Levonorgestrel is thought to be more effective the sooner
it is taken, therefore pharmacists should encourage
women take EC as soon as possible after unprotected
intercourse.24 The FDA-approved dosing recommends
initiating therapy within 72 hours of unprotected intercourse. For levonorgestrel 0.75 mg tablets, a second
dose is required 12 hours after the initial dose.5,8 Although
there is evidence of efficacy as late as 120 hours after
intercourse, women should be encouraged to seek treatment as soon as possible, preferably within the 72-hour
timeframe.21,25-28 Since the time required from intercourse or ovulation to implantation is approximately
6 to 7 days, use of hormonal EC beyond 120 hours is
not likely to be effective.13
Studies evaluating single-dose levonorgestrel (1.5
mg) have concluded that the single dose is not less effective than the two-dose regimen.21,28,29 Plan B One-Step
has been approved for use as a single 1.5 mg dose for
EC. The single dose formula may improve compliance
by simplifying the EC regimen and will replace the Plan
B 0.75 mg levonorgestrel preparation.
Concerns have been raised that providing EC to
women in advance of need to keep on hand “just in
case” of a contraceptive failure might lead to an increase
in unprotected intercourse or encourage women to discontinue the use of their usual method of contraception. However, studies evaluating the outcomes of
providing EC in advance of need have not found that
women engage in more unprotected intercourse or abandon their usual method. 6,7,30,31 These studies have
reported that women are more likely to use EC after
unprotected intercourse if it is provided in advance of
need. Based upon the findings of the studies, provid-
ing EC in advance of need can be recommended to
improve timely access to the product.
Dual Status: EC in the Pharmacy
The dual status of levonorgestrel-only EC necessitates
that products be kept within the pharmacy or behind
the counter. In the pharmacy a consumer has access to
the pharmacist, a knowledgeable health care provider,
to answer questions regarding the use of EC. EC
products must only be sold in pharmacies or licensed
clinics and are not available at other types of retail establishments. Keeping EC hidden behind the pharmacy
counter may pose a barrier to some consumers because
they may expect to find the products on pharmacy
shelves or within sight behind the pharmacy counter.
Pharmacists are encouraged to provide shelf tags or display EC products in a conspicuous location to facilitate access by consumers who may be reluctant to ask
if they do not easily see the product in the pharmacy.
“CARE” Program: Convenient
Access, Responsible Education
The terms of the FDA approval of Plan B for OTC
access by consumers age 17 and older included requirements restricting the distribution of EC, meeting labeling requirements for both OTC and prescription use,
and for the manufacturer to provide support and education about the use of the product to health care
providers and consumers and to continue ongoing monitoring. The dual-labeled, behind-the-counter labeling
launched with the approval of Plan B was the first
time the FDA had approved the same product package for both OTC and prescription-only use. The
approved packaging includes room for a prescription
label (to be used when the product is dispensed by
prescription), as well as the required Drug Facts box for
OTC sales.
The CARE program specifies that EC is to be sold
only from behind the counter in the pharmacy and
not be available through nonpharmacy retail outlets.
The FDA approval allows EC to be sold without a
prescription to women or men 17 or over as long as
they can show proof of age.2 Pharmacies must have a
pharmacist on duty and available for consumer consultation in order to sell EC. Although the pharmacist
must be available, it is not required that the pharmacist be the person who sells the product, or for the consumer to consult with the pharmacist. Any member of
the pharmacy staff working behind the pharmacy counter
may sell the products to eligible consumers as long as
a pharmacist is on duty and available for consultation
if requested by the purchaser.
Medical clinics may also sell EC if there is a
licensed health care provider on the premises for consumer consultation at the time of sale. Retail outlets
with pharmacies where the retail store has longer
73
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION: AN UPDATE
ask for EC (e.g., the “morning-after pill”),
and to respect the confidential nature of
and need for privacy that may accompany
the request. Pharmacy staff may offer but
should not require consultation with
Most Common
Plan B (levonorPlan B One-Step
the pharmacist to consumers asking about
Adverse Events in
gestrel 0.75 mg
(levonorgestrel 1.5
EC. Pharmacists may want to inform the
>4% of Women
oral tablets) (%)
mg oral tablet) (%)
entire staff that some consumers may preNausea
23.1
13.7
sent an “EC request card” (available online
Abdominal pain
17.6
13.3
at www.PlanBOne-Step.com/how-to-getFatigue
16.9
13.3
plan-b.asp or www.pharmacyaccess.org/
Headache
16.8
10.3
ECPromotionalOpps.htm) to avoid being
Heavier menstrual bleeding
13.8
30.9
overheard or because they are embarrassed
a
Lighter menstrual bleeding
12.5
to ask for EC at the pharmacy counter.
a
Dizziness
11.2
Keeping EC in an area where consumers
Breast tenderness
10.7
9.6
can easily see that the products are availa
Other complaints
9.7
a
able in the pharmacy may also be helpVomiting
5.6
a
ful to consumers.
Diarrhea
5.0
a
Although consultation with the pharDelay of menses >7 days
4.5
macist is not required for the OTC pura
Reported in <4% of users.
chase of EC, many consumers will have
Source: Reference 3.
questions for the pharmacist. Common
questions about EC include its effechours of business than the pharmacy are not able to sell tiveness, possible side effects, and how to know if the
EC when the pharmacy is closed.
product was effective. When consumers ask the pharThere is no limit to the number of packages that macist about what to expect after taking EC, the pharmay be sold to an eligible consumer. A consumer may macist should include information about possible side
purchase one or more packages of the product in a effects, when to expect her next menstrual period,
single transaction. In addition, there is no require- how to resume routine birth control methods (e.g., oral
ment that this OTC product must be used by the pur- contraceptives), and when follow-up care is indicated
chaser, and men may purchase it as long as they are at (see FAQ).
least 17 years of age. There is no requirement for purMost women who take EC will not experience side
chasers of EC to sign a registry in the pharmacy or to effects. The most commonly experienced side effects
provide photo identification for purchases.
(nausea, dizziness, fatigue, headache, and breast tenderness) are mild (TABLE 4).3 The side effects resolve
Pharmacist Consultation
quickly after the regimen is completed and do not
Providing an environment where consumers can feel require treatment. Most women will have their next
comfortable asking questions can greatly improve access menses within one week of the originally expected
to EC. Because all members of the pharmacy staff can date. However, other menstrual changes can occur,
provide EC to consumers, they should be aware of where including spotting or changes to the menstrual flow
it is stocked in the pharmacy, how consumers might volume during the next cycle. Pharmacists may reas-
Table 4
Most Common Adverse Events Experienced by
Women Receiving Plan B and Plan B One-Step
Table 5
Combination Hormonal Contraceptives Used for Emergency Contraception
Number of
Tablets per Dosea
5
4
4
4
2
Dosage Regimen
2 doses 12 h apart
2 doses 12 h apart
2 doses 12 h apart
2 doses 12 h apart
2 doses 12 h apart
Estrogen Dose
100 mcg
120 mcg
120 mcg
120 mcg
100 mcg
Progestin Dose
b
0.50 mg LNG
0.60 mg LNGb
0.60 mgc
0.50 mg LNGb
0.50 mgc
a
Brand Names
Alesse, Aviane, Levlite,
Levlen, Levora, Nordette,
Lo/Ovral, Low-Ogestrel
Tri-Levlen, Triphasil, Trivora
Ovral, Ogestrel
Only active hormone-containing tablets can be used. Consult product information to verify the color/hormone content before making recommendations.
levonorgestrel.
cNorgestrel.
bLNG:
74
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION: AN UPDATE
sure women that changes in menses, while common,
are self-limiting. Women can be advised to obtain follow-up care if menses does not occur within seven
days of the expected onset date or, for women with
irregular menses, within three weeks after using EC.
Emergency contraceptives are less effective and are
more costly than routine methods of contraception
and thus should not be relied upon as an ongoing
method of contraception. Contraceptive use is needed
for future acts of intercourse if pregnancy is not desired.
Women may resume the use of barrier or oral con-
traceptives right away after taking EC.
The pharmacist should be aware that using EC reduces
the risk of pregnancy but does not provide protection
from sexually transmitted infections (STIs). When requested,
the pharmacist should be prepared to make referral to
clinics or health care providers that provide testing and
treatment for STIs. The use of condoms for protection
from STIs should be encouraged, when applicable.
Pharmacists may advise consumers to keep EC products at home and available in case of a contraceptive
failure. Keeping EC at home may be more convenient
Frequently Asked Questions (FAQ) About Emergency Contraception
A Reference for Pharmacists
Who can use levonorgestrel for
emergency contraception (EC)?
Levonorgestrel can be used by women after unprotected
intercourse to prevent pregnancy. Women who are
already pregnant or who have experienced an allergic
reaction to a levonorgestrel-containing product in the
past should not use this form of EC. Women with a
history of migraine headaches, smokers over age 35, or
other contraindications to the use of combination oral
contraceptives may use EC. EC should not be used by
women who are already pregnant because it is not
effective. If EC is taken by a woman who is already
pregnant or becomes pregnant after taking EC, it will not
harm the fetus or disrupt the pregnancy. Women who
are pregnant should consult a health care provider.
How effective is levonorgestrel for EC?
Plan B and Plan B One-Step have been shown to reduce the
risk of pregnancy by up to 89% when taken within 3 days
(72 hours) of a contraceptive failure or unprotected
intercourse. If taken within the first 24 hours after
unprotected sex, EC may be more effective. One way to
explain the effectiveness of EC is: if 100 women had
unprotected intercourse during week 2 or 3 of their
menstrual cycle and no contraception was used, eight
women would be expected to become pregnant. If all 100
women used EC, only one woman would be pregnant, thus
there is an 89% reduction in the pregnancy rate (one
instead of 8 women become pregnant). The effectiveness of
EC for an individual may vary depending on the timing of
intercourse, delay in taking EC, and the inherent fertility of
the couple.
How long should I wait to take EC?
For best results, EC should be taken as soon as possible
after unprotected intercourse or contraceptive failure. For
Plan B and Next Choice, the first tablet (0.75 mg
levonorgestrel) should be taken within 72 hours of
unprotected intercourse followed by a second tablet 12
hours later. For Plan B One-Step, a single tablet (1.5 mg
levonorgestrel) should be taken within 72 hours of
unprotected intercourse. Taking EC as soon as possible is
highly recommended.
What if it has been more than 72 hours
since intercourse?
Although EC has only been approved for use up to 72 hours
after unprotected intercourse, the available research indicates
that levonorgestrel retains significant activity in reducing the
risk of pregnancy for at least 120 hours after unprotected
intercourse.6 While EC is more effective when taken earlier,
using it up to 120 hours after intercourse may still prevent
pregnancy. (Please note that the use of levonorgestrel only EC
products after 72 hours for EC has not been approved by the
FDA.) Users of EC should be aware that the product may be
less effective when taken later than 72 hours after
unprotected intercourse.
What can I expect after using EC?
Most women do not experience side effects from taking EC.
Some mild side effects that may occur include: nausea,
headache, fatigue, mild abdominal discomfort, or a change in
the timing/bleeding of the next menstrual cycle. These are
self-limited and do not require treatment. Most women should
expect to have their period within about 1 week of when it
would be expected. If a woman does not menstruate within 3
weeks of using EC, she should consult her health care
provider and/or use a home pregnancy test.
Is EC also known as the “abortion pill”?
No, the “abortion pill,” Mifeprex (mifepristone) or RU486, is
completely different from EC. Levonorgestrel (the hormone in
EC) does not cause an abortion and will not be effective if
taken by a woman who is already pregnant. Similar to oral
contraceptives, EC has been shown to work by preventing
ovulation. Once implantation of an embryo begins, EC is not
effective.
What if I have taken EC more than once?
Women may use EC once or more than once depending on
their regular birth control method and their personal
circumstances. Levonorgestrel for EC is safe and may be
used when needed to prevent pregnancy. EC is not as
effective as other methods of contraception (such as
condoms, oral contraceptives) and therefore the routine use
of EC is not recommended. EC is intended to be a backup
method of contraception.
75
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION: AN UPDATE
and better facilitate timely administration. Although EC
is indicated for use after unprotected intercourse, consumers do not need to wait to purchase it until after they
have experienced a contraceptive emergency.
Pharmacists who are available to consumers with
questions about EC will have an opportunity to make
referrals to community resources. Pharmacists are in
an excellent position to serve as a resource for consumers and provide information about other methods
of contraception that, when used before or during intercourse, are more effective than EC in preventing unintended pregnancies. Pharmacists should have available
the name, address, and phone number for local referral services when the consumer’s contraceptive needs
cannot be met in the pharmacy. This may include consumers lacking proof of age needed to purchase EC
without a prescription, girls under the age of 17, consumers unable to pay for EC, or those who want to
be examined for STIs. In the event that the pharmacy
does not have EC in stock, the pharmacy staff should
be prepared to provide consumers with contact information for a nearby pharmacy, after verifying the product is in stock, to avoid delays in starting therapy.
Pharmacists should be aware that some women seeking EC may be victims of sexual assault. If a woman
discloses violence to the pharmacist, whether in the
context of purchasing EC or first aid supplies such as
bandages, offering access to a private phone and
referral information for support services is indicated.
Every pharmacist should also have national and local
domestic and sexual violence service agency contact
information readily available for consumers.
Pharmacy Access Programs
In states with pharmacy access programs, women seeking EC who are unable to show proof of age or who
need a prescription for insurance purposes may be
able to have a prescription for EC initiated by a pharmacist. Direct access from a pharmacist is currently
permitted in nine states: Alaska, California, Hawaii,
Maine, Massachusetts, New Mexico, New Hampshire,
REFERENCES
1. FDA. Plan B (levonorgestrel 0.75 mg) [Letter FDA to Sponsor]. August
26, 2005. www.fda.gov/bbs/topics/news/2005/duramed_ ltr.html. Accessed
September 2009.
2. FDA. Plan B (levonorgestrel 0.75 mg) [Approval letter]. August 24,
2006. www.fda.gov/cder/foi/nda/2006/021045s011_Plan_B_APPROV.pdf.
Accessed September 2009.
3. FDA. Plan B One-Step (levonorgestrel 1.5 mg) [Approval letter]. July
10, 2009. www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/
021998s000ltr.pdf. Accessed September 2009.
4. Finer LB, Henshaw SK. Disparities in the rates of unintended pregnancy
in the United States 1994-2001. Perspect Sex Reprod Health. 2006;38:90-96.
5. Plan B One-Step (levonorgestrel 1.5 mg tablets) package insert. Pomona,
New York: Duramed Pharmaceuticals, Inc. July 2009.
6. Trussell J, Schwarz EB, Guthrie K, Raymond E. No such thing as an
easy (or EC) fix. Contraception. 2008;78:351-354.
7. Cheng L, Gulmezoglu AM, Piaggio G, et al. Interventions for emergency
contraception. Cochrane Database Syst Rev. 2008;(2):CD001324.
Vermont, and Washington. 3 1 States permitting
pharmacists to initiate prescriptions have specific
requirements for pharmacist participation that may
include training and/or collaborative protocol arrangements. In some states with pharmacy access it may
be permitted to provide other prescription oral contraceptive products for use as EC under certain circumstances, such as when levonorgestrel-only products are unavailable (TABLE 5).
Pharmacy access programs are not available to males
under age 17 seeking EC because only the person taking the medication can receive a prescription from
the pharmacist. If EC products are out of stock or
otherwise unavailable, there are alternative regimens
such as oral contraceptive combinations that can be
provided by the pharmacist under some access programs. These regimens have more side effects and may
be less effective; however, if there are no other options
(such as referral to a nearby pharmacy or clinic) they
may serve as a backup option.8,25,32
Summary and Conclusions
Levonorgestrel-only EC is safe and effective for preventing unintended pregnancy after intercourse.
The OTC sale to consumers at least 17 years of age
is a major step toward improving access and removing barriers to the use of EC in the U.S. The timesensitive nature of EC means that ready access to
women is an essential component of successful use.
Pharmacists serve a critical role in expanding access
to EC and are relied upon for up-to-date information
regarding the safety and efficacy of EC. The role of
the pharmacist includes: providing information and
counseling to consumers seeking EC, maintaining an
adequate supply of EC at all times, and in states where
collaborative practice allows pharmacists to provide
EC directly to those under age 17, becoming an ECdirect provider. By understanding the appropriate use
and distribution of EC products, pharmacists can significantly reduce barriers preventing consumers from
using these products.
8. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists, Number 69, December 2005. Emergency oral contraception. Obstet Gynecol. 2005;106:1443-1452.
9. Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet.
1998;352:428-433.
10. Turner A, Ellertson C. How safe is emergency contraception? Drug
Safety. 2002;25;695-706.
11. Minutes of the FDA Joint Advisory Committee Meeting December 16,
2003. www.fda.gov/ohrms/dockets/ac/03/transcripts/4015T1.htm. Accessed
September 2009.
12. Abuabara K, Becker D, Ellertson C, Blanchard K, et al. As often as
needed: appropriate use of emergency contraceptive pills. Contraception.
2004:69:339-342.
13. Ellertson C, Webb A, Blanchard K, et al. Modifying the Yuzpe regimen
of emergency contraception: a multicenter randomized controlled trail.
Obstet Gynecol. 2003;101:1160-1167.
76
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION: AN UPDATE
14. Creinin MD, Schlaff W, Archer DF, et al. Progesterone receptor modulator for emergency contraception. A randomized controlled trial. Obstet
Gynecol. 2006;108:1089-1097.
15. Croxatto HB. Emergency contraception pills: how do they work? IPPF
Med Bull. 2002;36:1-2.
16. Gemzell-Danielsson K, Marions L. Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception. Hum
Reprod Update. 2004;10:341-348.
17. Croxatto HB, Brache V, Pavez M, et al. Pituitary-ovarian function following the standard levonorgestrel emergency-contraception dose or a single
0.75 mg dose given on the days preceding ovulation. Contraception.
2004;70:442-450.
18. Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency
contraception. Contraception. 2001;64:227-234.
19. Davidoff F, Trussell J. Plan B and the politics of doubt. JAMA.
2006;296:1775-1778.
20. Baird DT. Emergency contraception: how does it work? Reprod Biomed
Online. 2009;18(suppl 1):32-36.
21. Trussell J, Hedley A, Raymond E. Ectopic pregnancy following use of
progestin-only ECPs. J Fam Plann Reprod Health Care. 2003;29:249.
22. International Consortium for Emergency Contraception and the International Federation of Gynecology & Obstetrics. How do levonorgestrelonly emergency contraceptive pills work to prevent pregnancy? October
2008. www.cecinfo.org. Accessed September 2009.
23. WHO Fact Sheet 244. Emergency contraception. Revised October
2005. www.who.int/mediacentre/factsheets/fs244/en/ index.html. Accessed
October 2009.
24. Piaggio G, Von Hertzen H, Grimes DA, Van Look PF. Timing of emergency contraception with levonorgestrel or the Yuzpe regimen. Lancet.
1999;353:721.
25. Ellertson C, Evans M, Ferden S, et al. Extending the time limit for starting the Yuzpe regimen of emergency contraception to 120 hours. Obstet
Gynecol. 2003;101:1168-1171.
26. Rodrigues I, Grou F, Joly J. Effectiveness of emergency contraceptive pills
between 72 and 120 hours after unprotected sexual intercourse. Am J Obstet
Gynecol. 2001;184:531-537.
27. Von Hertzen H, Piaggio G, Ding J, et al. Low dose mifepristone and two
regimens of levonorgestrel for emergency contraception: a WHO multicentre
randomized trial. Lancet. 2002;360:1803-1810.
28. Arowojulu AO, Okewolw IA, Adekunle AO. Comparative evaluation of
the effectiveness and safety of two regimens of levonorgestrel for emergency
contraception in Nigerians. Contraception. 2002;66:269-273.
29. Hamoda H, Ashok PW, Stalder C, et al. A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception. Obstet Gynecol.
2004;104:1307-1313.
30. Raine TR, Harper CC, Rocca CH, et al. Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs:
a randomized controlled trial. JAMA. 2005;293:54-62.
31. GO2EC. Comparison of EC pharmacy access states. Models for EC pharmacies. www.go2ec.org/ModelsForECPharmacies.htm. Accessed September
2009.
32. International Consortium for Emergency Contraception. Emergency Contraceptive Pills: Medical and Service Delivery Guidelines. 2nd ed. Washington,
DC; 2004. www.cecinfo.org/publications/PDFs/resources/MedicalServiceD
liveryGuidelines_Eng.pdf. Accessed September 2009.
Disclosure Statements:
Kathleen H. Besinque, PharmD, MSEd, has no real or apparent conflicts of
interest in relation to this program.
U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the
activity was planned to be balanced, objective, and scientifically rigorous.
Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective
analysis of scientific data.
Disclaimer:
EXAMINATION
Select one correct answer for each question and record
your responses on the examination answer sheet. Mail it
to U.S. Pharmacist, address shown on the answer sheet
(photocopies are acceptable). Please allow four weeks for
processing. Alternatively, this exam can be taken online at
www.uspharmacist.com. Please contact CE Customer Service at (800) 825-4696 or [email protected]
with any questions.
2 CE Credits
Emergency Contraception:
An Update of Clinical and
Regulatory Changes
1. Which of the following statements accurately
describes emergency contraception (EC) with
levonorgestrel?
A. A hormonal method of contraception after
intercourse
B. A method of contraception that has
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product
information, and comparison with recommendations of other authorities.
been studied since the 1970s
C. A safe and effective method for preventing
unintended pregnancy
D.All of the above
2. Which of the following describes when
EC is indicated?
A. After a condom fails (dislodges/breaks) during
intercourse
B. After a sexual encounter when a woman has
missed one or more doses of her oral
contraceptive
C. When a contraceptive method was not used
during intercourse
D.All of the above
3. Clinical studies have demonstrated that
levonorgestrel-based emergency contraceptives
prevent pregnancy by which of the following
mechanisms?
A. Inhibition or delay of ovulation
B. Disruption of an implanted embryo
C. Changes to endometrial lining of the uterus
D.All of the above
77
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION: AN UPDATE
4. Which of the following statements best
describes the effectiveness of levonorgestrel
EC regimens?
A. Efficacy is increased by initiating EC as soon
as possible after unprotected intercourse
B. Studies have shown a 30% reduction in the risk
of pregnancy when EC is taken within 72 hours
of unprotected intercourse
C. The products have demonstrated efficacy when
taken up to 7 days after unprotected intercourse
D.The products are as effective as barrier methods
of contraception
5. The FDA approved regimen for
Plan B One-Step is:
A. One tablet to be taken within 120 hours after
unprotected intercourse
B. Two doses of one tablet taken 12 hours apart,
started within 72 hours of unprotected
intercourse
C. One tablet to be taken within 72 hours of
unprotected intercourse
D.Two doses of one tablet taken 12 hours apart,
started within 120 hours of unprotected
intercourse
6. The most common side effects resulting from
the use of levonorgestrel for EC include:
A. Severe headache or eye pain
B. Mild nausea and fatigue
C. Increased risk of blood clots
D.All of the above
7. The use of levonorgestrel for EC between 72
and 120 hours after unprotected intercourse:
A. Has been shown to be ineffective
B. Is less effective than when used within 72 hours
and has not been approved by the FDA
C. Has been shown to cause more side effects than
use within 72 hours
D.Is not permitted in the U.S.
8. Medical contraindications to the use of
levonorgestrel-based emergency contraception
include:
A. A history of migraine headaches
B. An established pregnancy
C. Age over 35 years
D.All of the above
9. Outcomes reported in studies evaluating
advanced provision of EC include:
A. A reduction in the use of other contraceptive
methods
B. An increase in the frequency of unprotected
intercourse
C. An increase in the use EC after unprotected
intercourse
D.An increased rate of sexually transmitted
infections
10. Which statement best describes requirements
for nonprescription sales of EC in a pharmacy?
A. Only one package can be sold at a time to
consumers without a prescription
B. Plan B but not Plan B One-Step can be
sold to men
C. EC can be provided to a 17-year-old without
a prescription
D.EC products can be kept on shelves with other
OTC products for women
11. Pharmacy staff members able to sell
nonprescription EC to eligible consumers
include:
A. A licensed pharmacist
B. A pharmacy technician
C. A pharmacy clerk working behind the
pharmacy counter
D.All of the above
12. When selling EC without a prescription
to a man, pharmacists:
A. Need to check for proof that he is at least 17
years of age
B. Must limit sales to one package
C. Must ask for the name and age of the woman
who will be taking the product
D.Keep a log with his name and signature at the
point of purchase
13. Which of the following is appropriate
for a pharmacist to say to a woman asking
to purchase nonprescription EC?
A. Have you had unprotected intercourse?
EC can only be sold after a contraceptive
emergency
B. It is important to take a pregnancy test before
using EC
C. You may not purchase more than one package
at a time
D.Do you have any questions about the use
of this product?
14. Nonprescription sale of EC requires:
A. The purchaser to present proof that he/she is at
least 17 years of age
B. The person who will be taking the medication
to come to the pharmacy
C. The purchaser’s signature on a registry kept
in the pharmacy
D.Consultation by the pharmacist
78
U.S. Pharmacist • November 2009 • www.uspharmacist.com
EMERGENCY CONTRACEPTION
Examination Answer Sheet
Credits: 2.0 hours (0.20 ceu)
Expires: November 30, 2011
This exam can be taken online at www.uspharmacist.com. Upon passing, you can print
out your statement immediately and view your test history. Alternatively, you can mail
this answer sheet to the address below. Please contact CE Customer Service at (800)
825-4696 or [email protected] with any questions.
Emergency Contraception:
An Update of Clinical and Regulatory Changes
Directions: Select one answer for each question in the exam and completely darken
the appropriate circle. A minimum score of 70% is required to earn credit. An identifier
is required to process your exam. This is used for internal processing purposes only.
Mail to: U.S. Pharmacist–CE, PO Box 487,
Canal Street Station, New York, NY 10013
Supported by an educational grant from
Teva Women’s Health.
1.
2.
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5.
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1 = Excellent
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Rate the effectiveness of how well the activity:
2 = Very Good
3 = Good
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B
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D
A
B
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A
B
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4 = Fair
5 = Poor
21. Met objective 1:*
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25. Met objective 5:*
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26. Related to your educational needs:
1
2
3
4
5
A
B
C
D
A
B
C
D
27. The active learning strategies
(questions, cases, discussions) were
appropriate and effective learning tools:
1
2
3
4
5
A
B
C
D
28. Avoided commercial bias:
1
2
3
4
5
29. How would you rate the overall
usefulness of the material presented?
A
B
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D
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D
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D
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30. How would you rate the quality of the faculty? 1
2
3
4
5
D
31. How would you rate the appropriateness
of the examination for this activity?
2
3
4
5
C
D
32. Comments on this activity:
B
C
D
B
C
D
1
* Also applies to pharmacy technicians.
Please retain a copy for your records. Please print clearly.
You must choose and complete ONE of the following three identifier types:
1 SS #
-
-
2 Last 4 digits of your SS # and date of birth
-
3 State Code and License #
(Example: FL12345678)
First Name
Last Name
E-Mail
The following is your:
Home Address
Business Address
Business
Name
Address
City
State
15. Which of the following may be barriers
for consumers to access EC?
A. The requirement to keep EC behind the
pharmacy counter
B. Embarrassment about asking the pharmacy staff
for the product
C. Misinformation about when to use EC
D.All of the above
16. Which of the following actions should
be taken when a woman requests EC, but the
pharmacy is out of stock?
A. Tell her you will order the medication and she
should come back in a couple of days
B. Direct her to a nearby pharmacy where the
medication is available
C. Tell her you are out of stock
D.A and C only
17. Which of the following emergency
contraceptive products contains a single dose
of 1.5 mg levonorgestrel?
A. Plan B
B. Plan B One-Step
C. Next Choice
D.All of the above
18. Pharmacists can improve access to EC by:
A. Placing emergency contraceptive products in an
easy to see location in the pharmacy
B. Educating the pharmacy staff about EC
C. Being available to answer consumer questions
D.All of the above
19. In states with Pharmacist Access
programs for EC, the participating
pharmacist is able to:
A. Provide Plan B or Plan B One-Step to men
of all ages
B. Initiate a prescription for Plan B to those without
proof of age or who need a prescription for
insurance purposes
C. Provide women of any age with routine hormonal
contraception
D.Test women for STIs in the pharmacy
ZIP
Telephone #
-
-
Fax #
-
-
Profession:
Pharmacist
Pharmacy Technician
Other
By submitting this answer sheet, I certify that I have read the lesson in its entirety and
completed the self-assessment exam personally based on the material presented.
I have not obtained the answers to this exam by any fraudulent or improper means.
Signature
®
Date
Postgraduate Healthcare Education, LLC is accredited by the
Accreditation Council for Pharmacy Education as a provider
of continuing pharmacy education.
Lesson 106417
Type of Activity: Knowledge
0430-0000-09-027-H01-P
0430-0000-09-027-H01-T
20. Which of the following statement(s) are
important for consumer education regarding
the use of EC?
A. Taking EC as soon as possible may increase its
effectiveness
B. EC is not intended to replace your other methods
of birth control
C. Taking EC reduces the risk of pregnancy but not
the risk of sexually transmitted infections
D.All of the above
79
U.S. Pharmacist • November 2009 • www.uspharmacist.com
U.S. Pharmacist Classifieds
CAREER OPPORTUNITIES
We are currently hiring for the following positions:
G
Director of Pharmacy
DE – Smyrna
KY – Prestonburg
LA – Shreveport (2)
MD – Baltimore
MD – Rockville
MT – Libby
RI – Westerly
TN – Springfield
G
Assistant Director of Pharmacy
NC – Wilmington
G
Clinical Manager
NY – Valhalla
G
System Clinical Manager
LA – Shreveport
G
Clinical Staff Pharmacist
AZ – Phoenix; Tempe
G
Staff Pharmacist
DE – Smyrna
FL– Tampa (PRN)
NV – North Las Vegas
(4) PRN
PA – Waynesburg
G
G
G
TX – Odessa;
Port Arthur
WV – Princeton
WY – Jackson Hole
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and technologies for the health care industry
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TX – Bryan
TX - Odessa; San Antonio
TX – Sulphur Springs (PRN);
San Antonio (1) F/T,
(1) PRN;
TX – The Woodlands
UT – Layton (PRN)
Salt Lake City (PRN)
WV – Bluefield (P/T)
(PRN)
Pharmacy Technicians
AZ – Mesa; Phoenix
DE – Smyrna
FL – Port St. Lucie
TX – The Woodlands
UT – Layton
Rxe-sourceSM (Staff Pharmacists at Remote Centers, 7on/7 off Overnight)
CA – Glendale
NC – Cary
MA – Marlborough
Pharmacy Intern
AZ – Phoenix (2)
CAREER OPPORTUNITIES
Nome, Alaska
Where else might you see musk oxen and sled dogs
on your way to work and still pan for gold on the beach?
Serve the people of northwest Alaska in a unique, comprehensive health system
in a vast, stark and fiercely beautiful yet surprisingly livable Seward Peninsula.
Director of Pharmacy: $140,000+ DOE, benefits, relocation allowance
and potential for student loan repayment from the Indian Health Service.
Norton Sound Health Corporation
Steve Brock
[email protected] | 877-538-3142
(NO Recruitment firms or agency reps)
PRODUCTS AND SERVICES
FILL RXS FASTER- TIME IS LIFE
phone or fax NOW:
1-800-487-5024
Improved...Shake & Roll speedy tab/cap counter.
Durable, maintenance-free, over 20,000 sold.
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Chem-Pharm Corp
Who
is Cardinal Health?
Box 6246, West Palm Beach, FL 33405.
Who is Pharmacy Services?
• We bring 40 years of expertise in helping hospitals and healthcare
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and the quality of patient care.
• 1,000 pharmacists employed, including 110 clinical specialists
• Participate in more than 140 accreditation survey reviews each year
• We process four million order lines remotely each year and identified
20,000 patient safety events through our Rxe-sourceSM centers
in 2008
• Rxe-viewTM solution is an automated medication order management
and clinical intervention tracking tool
• We also offer a customized portfolio of drug contracts
For information or to apply,
call 800-231-9807 ext. 1315
or fax 281-749-2026
CAREER OPPORTUNITIES
U.S. Pharmacist Classifieds
CAREER OPPORTUNITIES
To place a classified ad, call:
Toll Free: (800) 983-7737
Phone: (610) 854-3770
Fax: (610) 854-3780
AD INDEX
National
Health Systems
New Products - National
AstraZeneca . . . . . . . . . . . . . . . CV4
Coca-Cola Co. . . . . . . . . . . . . . . . . 23
Daiichi-Sankyo. . . . . . . . . . . . . . . . 37
Dr. Reddy's . . . . . . . . . . . . . . . . . . 55
Fougera . . . . . . . . . . . . . . . . . . . . . . 9
Greenstone LLC . . . . . . . . . . . . . . 57
King Pharmaceuticals, Inc. . . . . . . 31
Mylan Pharmaceuticals Inc. . . . . . . 7
Novartis Pharmaceuticals . . . . . . . 27
Paddock Laboratories . . . . . . . . . . 59
Pfizer Inc. . . . . . . . . . . . . . . . . . . . 62
QS/1 Data System. . . . . . . . . . . . . 25
Schering-Plough . . . . . . . . . . . . . . 16
ScriptPro . . . . . . . . . . . . . . . . . . . . 19
Takeda Pharmaceuticals North
America . . . . . . . . . . . . . . . . CV2, 42
Teva Pharmaceuticals . . . . . . . . . . 11
Baxter Healthcare . . . . . . . . . . HS31
Cubist Pharmaceuticals. . . . . . HS03
Dr. Reddy's . . . . . . . . . . . . . . . HS29
Eli Lilly and Company . . . . . . . HS23
Medi-Dose Group . . . . . . . . . . HS25
Mylan Pharmaceuticals Inc. . . .HS11
Ortho-McNeil . . . . . . . . . . . . . . HS17
Pfizer Injectables . . . . . . . . . . . HS01
Sagent Pharmaceuticals . . . . . HS27
Teva Pharmaceuticals . . . . . . . HS21
Waste Management - Segments . . HS07
Embeda /
King Pharmaceuticals, Inc. . . . . . . . .31
Kapidex / Takeda Pharmaceuticals
North America. . . . . . . . . . . . . . . . . . .42
Onglyza / AstraZeneca . . . . . . . . . CV4
Uloric / Takeda Pharmaceuticals
North America. . . . . . . . . . . . . . . . . CV2
Welchol / Daiichi-Sankyo . . . . . . . . . .37
New Products - Health Systems
New Products - National
Distinctive Labeling /
Baxter Healthcare . . . . . . . . . . HS31
Authorized Generics /
Greenstone LLC . . . . . . . . . . . . . . . . .57
Product Labeling /
Teva Pharmaceuticals . . . . . . . HS21
Afinitor / Novartis Pharmaceuticals . .27
Injectables / Pfizer Injectables . . . HS01
Product News
Valstar Reintroduction Fills
Bladder Cancer Treatment Gap
Endo Pharmaceuticals announced
the reintroduction and availability
of a reformulated version of Valstar. Widely used to treat an
aggressive type of recurrent bladder cancer before it became
unavailable in 2002, the drug was
reapproved by the FDA in February 2009 for bacille CalmetteGuérin (BCG) vaccine–refractory
carcinoma in situ of the urinary
bladder. Valstar represents a new
treatment option for patients who
may otherwise have exhausted all
other FDA-approved treatment
alternatives, including BCG.
Medi-Dose/EPS Announces
Three New Products
To complement their popular
Butterfly labels for syringes,
ampules, and small containers,
Medi-Dose, Inc., has introduced
Butterfly labels in five new colors
to call attention to medication
requiring special handling. MediDose labels can be printed with a
regular laser printer, and their
unique hourglass design provides
practitioners with ample area for
medication identification.
To reduce the number of
errors in operating rooms due to
mishandling of look-alike medications, EPS, Inc., has released two
new ShrinkSafe ID Bands for
chemotherapy and high-alert
drugs. ShrinkSafe was designed to
easily wrap around various-sized
able by prescription only, hyoscyamine tablets come in bottles of
100 in 0.375-mg strength.
vials and is available in bright
colors to indicate medications
requiring special handling.
In addition to its English
Pharmacy Warning and Instruction Labels, Medi-Dose/EPS has
introduced a line of Spanish
Pharmacy and Nursing Auxiliary
Labels. These labels call attention
to the same special information
and indications for medications
as the company’s English versions.
CBI Announces
TruTag Technology
Cellular Bioengineering, Inc.,
announced the development of a
novel technology that can help
prevent counterfeiting of medicine
and pharmaceutical products. TruTag is an edible, microscopic,
nanoporous silica microtag that
can be used to safely and directly
mark medicine.
Bioniche and
Synerx Launch
Fomepizole
Injection
Bioniche Pharma
and Synerx Pharma,
LLC, announced the
launch of fomepizole
injection, the
generic equivalent of
Antizol (Paladin
Labs, Inc.). Fomepizole is available in
1.5-g/1.5-mL vials.
Par Receives Approval
to Market Starlix
Par Pharmaceutical Companies,
Inc., has received FDA approval
for nateglinide tablets. Nateglinide
is a generic version of Starlix
(Novartis) and is indicated as an
adjunct to diet and exercise to
improve glycemic control in
adults with type 2 diabetes
mellitus.
Perrigo Announces Approval
for Polyethylene Glycol 3350
Perrigo Company announced
FDA approval for OTC Polyethylene Glycol 3350, Powder for
Solution. The product is indicated for the treatment of occasional constipation and is comparable to MiraLax Products
(Schering-Plough).
Paddock Labs
Releases New Product
Paddock Laboratories, Inc.,
announced the addition of hyoscyamine sulfate extended-release
tablets to its product line. Avail-
82
U.S. Pharmacist • November 2009 • www.uspharmacist.com
ONGLYZA™ (saxagliptin) tablets
Brief Summary of Prescribing Information. For complete prescribing
information consult official package insert.
INDICATIONS AND USAGE
Monotherapy and Combination Therapy
ONGLYZA (saxagliptin) is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus. [See Clinical Studies
(14).]
Important Limitations of Use
ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or
diabetic ketoacidosis, as it would not be effective in these settings.
ONGLYZA has not been studied in combination with insulin.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Use with Medications Known to Cause Hypoglycemia
Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore,
a lower dose of the insulin secretagogue may be required to reduce the risk
of hypoglycemia when used in combination with ONGLYZA. [See Adverse
Reactions (6.1).]
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of
macrovascular risk reduction with ONGLYZA or any other antidiabetic drug.
ADVERSE REACTIONS
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect the
rates observed in practice.
Monotherapy and Add-On Combination Therapy
In two placebo-controlled monotherapy trials of 24-weeks duration, patients
were treated with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg daily, and placebo.
Three 24-week, placebo-controlled, add-on combination therapy trials were
also conducted: one with metformin, one with a thiazolidinedione (pioglitazone
or rosiglitazone), and one with glyburide. In these three trials, patients were
randomized to add-on therapy with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg
daily, or placebo. A saxagliptin 10 mg treatment arm was included in one of
the monotherapy trials and in the add-on combination trial with metformin.
In a prespecified pooled analysis of the 24-week data (regardless of glycemic
rescue) from the two monotherapy trials, the add-on to metformin trial, the
add-on to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the
overall incidence of adverse events in patients treated with ONGLYZA 2.5 mg
and ONGLYZA 5 mg was similar to placebo (72.0% and 72.2% versus 70.6%,
respectively). Discontinuation of therapy due to adverse events occurred in
2.2%, 3.3%, and 1.8% of patients receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg,
and placebo, respectively. The most common adverse events (reported in at
least 2 patients treated with ONGLYZA 2.5 mg or at least 2 patients treated
with ONGLYZA 5 mg) associated with premature discontinuation of therapy
included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2%
and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%),
and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). The
adverse reactions in this pooled analysis reported (regardless of investigator
assessment of causality) in ≥5% of patients treated with ONGLYZA 5 mg, and
more commonly than in patients treated with placebo are shown in Table 1.
Table 1: Adverse Reactions (Regardless of Investigator Assessment
of Causality) in Placebo-Controlled Trials* Reported in 5%
of Patients Treated with ONGLYZA 5 mg and More
Commonly than in Patients Treated with Placebo
Number (%) of Patients
ONGLYZA 5 mg
Placebo
N=882
N=799
Upper respiratory tract infection
68 (7.7)
61 (7.6)
Urinary tract infection
60 (6.8)
49 (6.1)
Headache
57 (6.5)
47 (5.9)
* The 5 placebo-controlled trials include two monotherapy trials and one
add-on combination therapy trial with each of the following: metformin,
thiazolidinedione, or glyburide. Table shows 24-week data regardless of
glycemic rescue.
In patients treated with ONGLYZA 2.5 mg, headache (6.5%) was the only
adverse reaction reported at a rate ≥5% and more commonly than in patients
treated with placebo.
In this pooled analysis, adverse reactions that were reported in ≥2% of patients
treated with ONGLYZA 2.5 mg or ONGLYZA 5 mg and ≥1% more frequently
compared to placebo included: sinusitis (2.9% and 2.6% versus 1.6%,
respectively), abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis
(1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%).
In the add-on to TZD trial, the incidence of peripheral edema was higher for
ONGLYZA 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence
of peripheral edema for ONGLYZA 2.5 mg was 3.1%. None of the reported
adverse reactions of peripheral edema resulted in study drug discontinuation.
Rates of peripheral edema for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus
placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1%
versus 2.2% given as add-on therapy to metformin, and 2.4% and 1.2% versus
2.2% given as add-on therapy to glyburide.
The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years,
respectively, for ONGLYZA (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and
placebo. The incidence rate of fracture events in patients who received
ONGLYZA did not increase over time. Causality has not been established and
nonclinical studies have not demonstrated adverse effects of saxagliptin on
bone.
An event of thrombocytopenia, consistent with a diagnosis of idiopathic
thrombocytopenic purpura, was observed in the clinical program. The
relationship of this event to ONGLYZA is not known.
Adverse Reactions Associated with ONGLYZA (saxagliptin)
Coadministered with Metformin in Treatment-Naive Patients with
Type 2 Diabetes
Table 2 shows the adverse reactions reported (regardless of investigator
assessment of causality) in ≥5% of patients participating in an additional
24-week, active-controlled trial of coadministered ONGLYZA and metformin
in treatment-naive patients.
Table 2: Initial Therapy with Combination of ONGLYZA and Metformin
in Treatment-Naive Patients: Adverse Reactions Reported
(Regardless of Investigator Assessment of Causality) in 5%
of Patients Treated with Combination Therapy of ONGLYZA
5 mg Plus Metformin (and More Commonly than in Patients
Treated with Metformin Alone)
Number (%) of Patients
ONGLYZA 5 mg + Metformin*
Metformin*
N=320
N=328
Headache
24 (7.5)
17 (5.2)
Nasopharyngitis
22 (6.9)
13 (4.0)
* Metformin was initiated at a starting dose of 500 mg daily and titrated up
to a maximum of 2000 mg daily.
Hypoglycemia
Adverse reactions of hypoglycemia were based on all reports of hypoglycemia;
a concurrent glucose measurement was not required. In the add-on to
glyburide study, the overall incidence of reported hypoglycemia was higher for
ONGLYZA 2.5 mg and ONGLYZA 5 mg (13.3% and 14.6%) versus placebo
(10.1%). The incidence of confirmed hypoglycemia in this study, defined as
symptoms of hypoglycemia accompanied by a fingerstick glucose value of
≤50 mg/dL, was 2.4% and 0.8% for ONGLYZA 2.5 mg and ONGLYZA 5 mg and
0.7% for placebo. The incidence of reported hypoglycemia for ONGLYZA
2.5 mg and ONGLYZA 5 mg versus placebo given as monotherapy was 4.0%
and 5.6% versus 4.1%, respectively, 7.8% and 5.8% versus 5% given as
add-on therapy to metformin, and 4.1% and 2.7% versus 3.8% given as
add-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in
treatment-naive patients given ONGLYZA 5 mg plus metformin and 4.0% in
patients given metformin alone.
Hypersensitivity Reactions
Hypersensitivity-related events, such as urticaria and facial edema in the
5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4%
of patients who received ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo,
respectively. None of these events in patients who received ONGLYZA required
hospitalization or were reported as life-threatening by the investigators. One
saxagliptin-treated patient in this pooled analysis discontinued due to
generalized urticaria and facial edema.
Vital Signs
No clinically meaningful changes in vital signs have been observed in patients
treated with ONGLYZA.
Laboratory Tests
Absolute Lymphocyte Counts
There was a dose-related mean decrease in absolute lymphocyte count
observed with ONGLYZA. From a baseline mean absolute lymphocyte count of
approximately 2200 cells/microL, mean decreases of approximately 100 and
120 cells/microL with ONGLYZA 5 mg and 10 mg, respectively, relative to
placebo were observed at 24 weeks in a pooled analysis of five
placebo-controlled clinical studies. Similar effects were observed when
ONGLYZA 5 mg was given in initial combination with metformin compared to
metformin alone. There was no difference observed for ONGLYZA 2.5 mg
relative to placebo. The proportion of patients who were reported to have a
lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the
saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most
patients, recurrence was not observed with repeated exposure to ONGLYZA
although some patients had recurrent decreases upon rechallenge that led to
discontinuation of ONGLYZA. The decreases in lymphocyte count were not
associated with clinically relevant adverse reactions.
The clinical significance of this decrease in lymphocyte count relative to
placebo is not known. When clinically indicated, such as in settings of unusual
or prolonged infection, lymphocyte count should be measured. The effect of
ONGLYZA on lymphocyte counts in patients with lymphocyte abnormalities
(e.g., human immunodeficiency virus) is unknown.
Platelets
ONGLYZA did not demonstrate a clinically meaningful or consistent effect on
platelet count in the six, double-blind, controlled clinical safety and efficacy
trials.
DRUG INTERACTIONS
Inducers of CYP3A4/5 Enzymes
Rifampin significantly decreased saxagliptin exposure with no change in the
area under the time-concentration curve (AUC) of its active metabolite,
5-hydroxy saxagliptin. The plasma dipeptidyl peptidase-4 (DPP4) activity
inhibition over a 24-hour dose interval was not affected by rifampin. Therefore,
dosage adjustment of ONGLYZA is not recommended. [See Clinical
Pharmacology (12.3).]
Inhibitors of CYP3A4/5 Enzymes
Moderate Inhibitors of CYP3A4/5
Diltiazem increased the exposure of saxagliptin. Similar increases in plasma
concentrations of saxagliptin are anticipated in the presence of other moderate
CYP3A4/5 inhibitors (e.g., amprenavir, aprepitant, erythromycin, fluconazole,
fosamprenavir, grapefruit juice, and verapamil); however, dosage adjustment
of ONGLYZA is not recommended. [See Clinical Pharmacology (12.3).]
Strong Inhibitors of CYP3A4/5
Ketoconazole significantly increased saxagliptin exposure. Similar significant
increases in plasma concentrations of saxagliptin are anticipated with other
strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir,
itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).
The dose of ONGLYZA should be limited to 2.5 mg when coadministered with
a strong CYP3A4/5 inhibitor. [See Dosage and Administration (2.3) and Clinical
Pharmacology (12.3).]
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human
response, ONGLYZA (saxagliptin), like other antidiabetic medications, should
be used during pregnancy only if clearly needed.
Saxagliptin was not teratogenic at any dose tested when administered to
pregnant rats and rabbits during periods of organogenesis. Incomplete
ossification of the pelvis, a form of developmental delay, occurred in rats at a
dose of 240 mg/kg, or approximately 1503 and 66 times human exposure to
saxagliptin and the active metabolite, respectively, at the maximum
recommended human dose (MRHD) of 5 mg. Maternal toxicity and reduced
fetal body weights were observed at 7986 and 328 times the human exposure
at the MRHD for saxagliptin and the active metabolite, respectively. Minor
skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg,
or approximately 1432 and 992 times the MRHD. When administered to rats
in combination with metformin, saxagliptin was not teratogenic nor
embryolethal at exposures 21 times the saxagliptin MRHD. Combination
administration of metformin with a higher dose of saxagliptin (109 times the
saxagliptin MRHD) was associated with craniorachischisis (a rare neural tube
defect characterized by incomplete closure of the skull and spinal column) in
two fetuses from a single dam. Metformin exposures in each combination were
4 times the human exposure of 2000 mg daily.
Saxagliptin administered to female rats from gestation day 6 to lactation day
20 resulted in decreased body weights in male and female offspring only at
maternally toxic doses (exposures ≥1629 and 53 times saxagliptin and its
active metabolite at the MRHD). No functional or behavioral toxicity was
observed in offspring of rats administered saxagliptin at any dose.
Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.
Nursing Mothers
Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio
with plasma drug concentrations. It is not known whether saxagliptin is
secreted in human milk. Because many drugs are secreted in human milk,
caution should be exercised when ONGLYZA is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of ONGLYZA in pediatric patients have not been
established.
Geriatric Use
In the six, double-blind, controlled clinical safety and efficacy trials of ONGLYZA,
634 (15.3%) of the 4148 randomized patients were 65 years and over, and
59 (1.4%) patients were 75 years and over. No overall differences in safety or
effectiveness were observed between patients ≥65 years old and the younger
patients. While this clinical experience has not identified differences in
responses between the elderly and younger patients, greater sensitivity of
some older individuals cannot be ruled out.
Saxagliptin and its active metabolite are eliminated in part by the kidney.
Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection in the elderly based on renal function. [See
Dosage and Administration (2.2) and Clinical Pharmacology (12.3).]
OVERDOSAGE
In a controlled clinical trial, once-daily, orally-administered ONGLYZA in healthy
subjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no
dose-related clinical adverse reactions and no clinically meaningful effect on
QTc interval or heart rate.
In the event of an overdose, appropriate supportive treatment should be
initiated as dictated by the patient’s clinical status. Saxagliptin and its active
metabolite are removed by hemodialysis (23% of dose over 4 hours).
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
Instructions
Patients should be informed of the potential risks and benefits of ONGLYZA
and of alternative modes of therapy. Patients should also be informed about
the importance of adherence to dietary instructions, regular physical activity,
periodic blood glucose monitoring and A1C testing, recognition and
management of hypoglycemia and hyperglycemia, and assessment of diabetes
complications. During periods of stress such as fever, trauma, infection, or
surgery, medication requirements may change and patients should be advised
to seek medical advice promptly.
Physicians should instruct their patients to read the Patient Package Insert
before starting ONGLYZA therapy and to reread it each time the prescription
is renewed. Patients should be instructed to inform their doctor or pharmacist
if they develop any unusual symptom or if any existing symptom persists
or worsens.
Laboratory Tests
Patients should be informed that response to all diabetic therapies should
be monitored by periodic measurements of blood glucose and A1C, with a
goal of decreasing these levels toward the normal range. A1C is especially
useful for evaluating long-term glycemic control. Patients should be informed
of the potential need to adjust their dose based on changes in renal function
tests over time.
Manufactured by:
Princeton, NJ 08543 USA
Marketed by:
Bristol-Myers Squibb Company
Princeton, NJ 08543
and
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
1256316
1256317
SA-B0001A-07-09
Iss July 2009
For your adult patients with type 2 diabetes struggling
to gain glycemic control
Significant reductions in A1C when
partnered with key oral antidiabetic agents*
• Onglyza is weight neutral
• Discontinuation of therapy due to adverse events
occurred in 3.3% and 1.8% of patients receiving
Onglyza and placebo, respectively
• Convenient, once-daily dosing
• Rapidly growing formulary access1
Indication and Important Limitations of Use
ONGLYZA is indicated as an adjunct to diet and
exercise to improve glycemic control in adults with
type 2 diabetes mellitus.
ONGLYZA should not be used for the treatment of
type 1 diabetes mellitus or diabetic ketoacidosis.
ONGLYZA has not been studied in combination
with insulin.
Important Safety Information
• Use with Medications Known to Cause
Hypoglycemia: Insulin secretagogues, such
as sulfonylureas, cause hypoglycemia. Therefore,
a lower dose of the insulin secretagogue may be
required to reduce the risk of hypoglycemia when
used in combination with ONGLYZA
• Macrovascular Outcomes: There have been
no clinical studies establishing conclusive evidence
of macrovascular risk reduction with ONGLYZA
or any other antidiabetic drug
Most common adverse reactions (regardless of
investigator assessment of causality) reported in
≥5% of patients treated with ONGLYZA and more
commonly than in patients treated with control
were upper respiratory tract infection (7.7%, 7.6%),
headache (7.5%, 5.2%), nasopharyngitis (6.9%,
4.0%) and urinary tract infection (6.8%, 6.1%).
When used as add-on combination therapy with
a thiazolidinedione, the incidence of peripheral
edema for ONGLYZA 2.5 mg, 5 mg, and placebo
was 3.1%, 8.1% and 4.3%, respectively.
*metformin, glyburide, or thiazolidinedione (pioglitazone or rosiglitazone)
Onglyza – A Welcome Partner
Please read the adjacent Brief Summary of the Product Information.
For more information about Onglyza, a DPP-4 inhibitor, visit www.onglyza.com.
Reference:
1. Fingertip Formulary® data as of October 2, 2009. Data on File, October 2009.
©2009 Bristol-Myers Squibb 422US09AB12901 10/09
Onglyza™ is a trademark of Bristol-Myers Squibb
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