Download Volume 3, Issue 1 - Correct Rx Pharmacy Services

DOSE: a publication of Correct Rx Pharmacy Services, Inc.
Volume 3 July 2009
The Economy, The Environment...
DOSE
...Correct Rx Pharmacy Services
INSIDE:
H1N1 Influenza: Updated
Chronic Pain & Depression
NSAIDS: Pain Relief in Small Doses
This or DAT?: Dual Antiplatelet Therapy
...& More
C h a n g i n g
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w o r l d
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The work we’ve done in the past has led to some of today’s most effective treatments; the
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www.gsk.com
1
CONTENTS
Greetings
NSAIDS:
Greetings from
the President
4
Pain Relief
in Small Dosages
6
Jeffrey E. Keller, M.D.
Chronic Pain & Depression
Kesha O’Reilly, Pharm.D.
Value of a Clinical
Pharmacy Service
in a Correctional
Medical System
9
12
Hui Seo, Pharm.D.
(GERD)
17
Management of
gastroesophageal reflux disease
Sankung Sise, Pharm.D.
Lantus versus Levemir
®
Janet Mahoney, Pharm.D. candidate 2010
This or DAT?
®
A comparison of the longacting basal insulin analogs
Dual Antiplatelet therapy in Secondary
Prevention of Acute Coronary Syndrome
Akilah Streets, Pharm.D.
H1N1 Influenza
An Update on
Vaccine Production
Janet Mahoney and Andy Trinh, Pharm.D. candidates, Class of 2010
21
25
29
800.636.0501 * 803-A Barkwood Court * Linthicum, MD 21090
www.correctrxpharmacy.com * [email protected]
Editor: Helena H. Kim, Pharm.D. * Designer/Illustrator Matt Chapman
Correct Rx Pharmacy Services, Inc. is neither accountable for the content of paid advertisements nor does it endorse
same. No outside parties influenced the text of participated in the editing of this publication. Professional standards of care were taken to ensure accuracy; however, the authors and editors do not attest that the information
contained herein is free of errors or omissions. Sound clinical judgment is the responsibility of every professional in
addition to full consultation of all prescribing information prior to medication administration.
2
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3
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GREETINGS
FROM THE
PRESIDENT
***
DR. ELLEN H.
YANKELLOW
I hope you enjoy our “Green” issue of Dose. The “Green”
theme is a result of the key concerns of the day: The current
economic environment (green for money) and environmental
sustainability (green strategies). A successful Green
agenda will create synergies between sustainable business
efficiencies and environmental compliance.
By tackling the tough economic and environmental issues
we believe Correct Rx is enhancing client value which
creates real savings!! Correct Rx has taken the recession
as an opportunity to put out green goals in line with our
business goals and make targeted green investments that
will create short and long term value for our clients.
Included at No Charge is a list of value added services
and green projects designed to lower costs and preserve
“Your Green”:
Value Added Services - No Charge
•
•
•
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•
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•
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Access to Preferential Pricing - No Games
Strategic Location - Situated Next to the BWI Airport
Extended Cut Off Time to Accommodate Late Order
New and Refill Orders Have the Same Cut Off Time Continuity of Care
Skilled Program Management
Designated Facility Liaison
Collaborative Medication Therapy Management Improved Outcomes - Reduced Costs
Comprehensive Plan to Manage the Use and Cost of the
Emergency Back Up Pharmacies
On Site Clinical Consulting Services by Fully Licensed
Correct Rx Pharmacists
In-Service Training and Educational Programs
Web Based Drug Information Program “Ask a Correct
Rx Pharmacist”
Advanced Bar Code Technology
Computerized Order Entry Program
Automated Bar Code Refills
Full Time Regulatory Affairs Division - Licensed Attorney
to Ensure Compliance
• Customized Reports to Fit Your Needs
• Accreditation and Re-Accreditation Assistance - ACA,
NCCHC and JC
• CQI Performance Based Standards - Accuracy Rates
Far Above the National Average
• Proven Implementation Plan
• Financial Stability and Internal Audit Department
Green Projects - Staying Green While the
Global Economy Sees Red
• Commit Resources to Green Projects - Coordinated
Efforts Across Correct Rx Operations
• Install Recycling Containers Throughout the Company
• Recycle Empty Pharmaceutical Bottles - Number 2 Plastic
is the Most Easily Recycled
• Produce Electronic Reports - Including Electronic Billing
• Utilize Recycled Shipping Boxes
• Install Hand Dryers
• Recycle Printing Equipment, Cartridges and Toners
• Use Recycled Paper and Always Print on Both Sides
• Re-Use Office Supplies such as File Folders
• Donate Any Unused or Obsolete Office Supplies to
Local Non-profits
• Encourage Clients to Return Insulated Packages for
Refrigerated Items
• Use Biodegradable Cleaning Supplies
• Encourage All Associates to Conserve
Correct Rx Pharmacy is not Green with envy. Correct Rx is
turning Green by concentrating on helping patients, clients
and customers succeed. Economic, Environmental and
Social responsibility is essential to sustainable development
and to good business. Our commitment is to Customer
Value First!
As Warren Buffet once said, “Price is what you pay. Value
is what you get.” As the President and CEO of Correct
Rx Pharmacy I have come to realize that value goes way
beyond simply being cheaper. In today’s economy we have
an obligation to provide all of our clients with the value
added extras that Correct Rx has become known for in the
industry. Our goal is to pass along cost saving ideas so
our customers have a true partner that is committed to their
long term success. We believe this generosity will produce
healthier clients and will position all of us for a strong future.
This is our idea of Green! This is the “Correct Way.”
Sincerely,
Ellen H. Yankellow, Pharm.D. ~ President and CEO
4
5
Jeffrey E. Keller,
M.D.
Take the case of Non Steroidal Anti-inflammatory
Drugs (NSAIDS). The amount of harm that is
caused by the complications of NSAIDS is routinely
underappreciated. An estimated 16,500 patients die
from gastrointestinal (GI) bleeding caused by NSAIDS
each year. This is far more people than the 13,500
people who die of Acquired Immune Deficiency
Syndrome (AIDS) each year. In fact, the Centers for
Disease Control rank deaths due to NSAID-induced
GI bleeding as the 14th leading cause of death in
this country. Over 100,000 people are hospitalized
each year with GI complications caused by NSAID
use. Total spending in the United States to treat
NSAID complications is greater than 2 billion dollars
annually. The iatrogenic cost factor of NSAID use is
approximately two. In other words, for every dollar
spent on NSAIDS, approximately one more dollar is
spent treating NSAID-induced complications. Don’t
forget the renal failure and increased cardiovascular
events like myocardial infarctions and strokes that
can be caused by various NSAIDS.
..............
The question for today is how can we get the
benefits of NSAIDs while avoiding these serious
side effects? The answer lies in understanding the
mechanism of action of NSAIDS. NSAIDS inhibit
the enzyme cyclooxygenase (COX), which is involved
in prostaglandin production at various sites. Three
subtypes of this enzyme have been discovered so far:
COX-1, COX-2, and COX-3. The NSAID inhibition
of the COX-1 and COX-2 enzymes is responsible
for the anti-inflammatory effects; COX-1 and 2
inhibition is also responsible for the GI effects of
NSAIDS. Selective inhibition of the COX-2 enzymes
causes thrombotic cardiovascular complications. The
COX-3 subtype, found in the brain and spinal cord, is
thought to be responsible for the pain relieving effects
of the NSAIDS. Interestingly, acetaminophen also
inhibits COX-3 as its mechanism for pain reduction.
Acetaminophen is not an NSAID since it does not
act on the COX-1 or COX-2 enzyme and so does not
reduce inflammation.
NSAIDS:
Pain Relief
in Small
Dosages.
I have a confession to make.
Sometimes, I prescribe drugs
without enough consideration
for the harm they might cause.
Sometimes, I anticipate more
benefit to my patient than the drug
can possibly deliver. I think I am
not alone in this. I suspect that
all of us prescribers sometimes
get into similar bad habits and
need to critically examine our
prescribing practices.
Most NSAIDS are non-selective, meaning that they
inhibit all three of the COX enzymes. This group
6
includes ibuprofen and naproxen. Some of the
NSAIDS preferentially inhibit the COX-2 enzymes.
It had been hoped that this preference for COX-2
would result in fewer gastrointestinal complications.
Unfortunately, this reduction was much less than
hoped and the COX-2 selective inhibitors increased
thrombotic complications, resulting in Vioxx and
Bextra being pulled from the market. Aspirin is
a unique NSAID in that it is the only NSAID that
inhibits platelet aggregation in a way that is
cardio-protective.
There are several inferences we can draw from an
understanding of these effects, all of which have been
verified in clinical empirical trials. It is important to
emphasize that these points are not controversial.
Pain Relieving properties of NSAIDS
1. The pain reducing property of NSAIDS is separate
from their anti-inflammatory effects. NSAIDS
reduce pain through the COX-3 enzyme. They
inhibit inflammation through the COX-1 and 2
enzymes. It is a mistake to think of these properties
as being interconnected.
2. NSAIDS reduce pain through the same mechanism
as acetaminophen. Both act on the COX-3 enzyme
in the central nervous system. The difference is
that NSAIDS also affect the COX-1 and COX-2
enzymes whereas acetaminophen does not.
3. There is a ceiling effect on pain reducing dosage.
For acetaminophen, this is around 1000mg a dose.
You will get no increased pain relieving benefit from
giving 2000mg to a patient over 1000mg. And this
is never done. If a patient tells us that two extrastrength Tylenol have not relieved her headache,
we don’t say, “Well, take four Tylenol then.” But
this also holds true for the NSAIDS. For example,
the ceiling of ibuprofen is 400mg. You get no
increased pain relieving effect from giving 800mg a
dose than you get using 400mg. It makes no more
sense to give 800mg of ibuprofen to a patient for
headache than it is to give that patient 2000mg
of acetaminophen. So why do we do it? Probably
7
because we think that by using the larger dose, we
are reducing inflammation. In most cases, this is
wrong because in most clinical cases we deal with,
there is no significant inflammation. More about
that later.
4. There is no NSAID that is any better than any other
NSAID as far as pain relieving characteristics. And
since they act on the same receptors in the brain,
there is probably no NSAID that is any significantly
better at pain relief than is acetaminophen.
Inflammation Reducing Properties
of NSAIDS
1. Unlike the ceiling effect found for the pain
relieving effects of NSAIDS, there is no known
ceiling to the anti-inflammatory effects of
NSAIDS. The more NSAIDS you give the more
anti-inflammatory effect you get. Thus, 400mg of
ibuprofen is a pain relieving dose; 800mg is an antiinflammatory dose. However, it is also true that
the higher the dose of NSAID, the more likely they
are to cause side effects like ulcers, kidney failure
and thrombotic problems.
2. NSAIDS reduce inflammation by decreasing
prostaglandin production.
This means that
they reduce inflammation only in inflammatory
conditions where prostaglandins play an important
role.
Examples of prostaglandin mediated
inflammation are renal colic, dysmenorrhea,
rheumatoid arthritis, and gout. Examples of
disease processes in which prostaglandins are not
important are acute injuries, like a sprained ankle,
headaches and regular aches and pains like the ones
I get because I am getting older. If you are giving
anti-inflammatory doses of NSAIDS for a sprained
ankle, you are deluding yourself. Since there is
little prostaglandin synthesis to inhibit, you get
little, if any, anti-inflammatory effect. All you get
is increased side effects! If you use ibuprofen, the
first 400mg will give you all of the pain relief you
need. Everything else does nothing but increase the
likelihood of side effects.
3. Finally, NSAIDS are not equal in their propensity
to cause complications. For example, ketorolac
(Toradol) is over 10 times more likely to cause
complications than plain ibuprofen. Of all of the
NSAIDS, the least likely to cause complications
is good old ibuprofen. Naproxen is also a great
choice.
If we put this all together, the rules of appropriate
NSAID usage boil down to this:
1.
Acetaminophen is just as strong of a pain
reliever as NSAIDS. In fact, you can think of
acetaminophen as an NSAID without the side
effects! If acetaminophen were introduced as a
new drug today, that is how it would be marketed.
And it would be a blockbuster!
2. Some NSAIDS are more likely to cause side effects
than others. We should avoid them. Ibuprofen
and naproxen are great choices.
3. Most of the time, we should prescribe NSAIDS at
their pain relief dosage, not their anti-inflammatory
dosage. For ibuprofen, this is 400mg three times
daily. For naproxen, this is 250mg twice a day.
4.
Most people should not be getting NSAIDS
routinely on a set schedule. This is a recipe for a
disastrous complication, like a GI bleed! NSAIDS
should be taken as needed. By using these rules,
we can improve our practice habits with regards
to NSAIDS. Like all drugs, when we prescribe
NSAIDS, we should carefully consider the harm
they might cause. We should not over-estimate
their benefits.
References
. . .
1. Drug Class Review on Cyclo-Oxygenase (COX)2 Inhibitors and Nonsteroidal Antiinflammatory
Drugs (NSAIDS), Helfand and Peterson. Oregon
Evidence-Based Practice Center. http://www.
oregon.gov/DAS/OHPPR/ORRX/HRC/docs/
NSAIDUpdatedFinalReport2.pdf
2.
Evidence-based Use of NSAIDs in the
ED,
Raney.
Emedhome.com.
http://www.
emedhome.com/features_archive-detail.
cfm?SFID=100103&SFTID=news
3. Evidence Based Medicine: When It Comes to
NSAIDS—Less is More, Keller. CorrectCare, Fall
2004. http://www.ncchc.org/pubs/CC/nsaids.html
4. Is There A Limit to the Analgesic Effect of Pain
Medication? Motov and Ast. MedScape 6/17/2008.
http://www.medscape.com/viewarticle/574279?sr
c=mp&spon=30&uac=102525PG
5.
What is the Harm-Benefit Ratio of COX-2
Inhibitors? van Staa, T.P., et al, Internat J Epid
37(2):405, April 2008.
8
&
Chronic
Pain
Depression
Kesha O’Reilly, Pharm.D.
According to the National Commission on
Correctional Health Care (NCCHC), the prevalence
of chronic pain is higher in correctional facilities
than in the community. Several factors such as (1)
environmental conditions of confinement, (2) crowded
living conditions, (3) lack of exercise opportunities,
(4) increased social stress and (5) boredom may
contribute to the increased incidence of chronic pain
identified in corrections. Correctional health care
providers are tasked with assessing patient needs in a
very complex environment. Providers must evaluate
pain needs of patients while ensuring the abuse or
misuse of pain medications. To further complicate
this matter, depression, as a co-morbid factor in the
treatment of chronic pain, is a possibility.
Chronic pain and depression commonly occur
together. Both have a destructive effect on patients’
health, productivity, and quality of life. Approximately
30% of patients who experience chronic pain have
reported at least one depressive symptom and 40%
fulfilled the diagnosis of depression. In fact, the risk
of depression increases as pain intensifies in severity,
frequency, and duration. Individuals who experience
multiple pain symptoms are 3 to 5 times more likely
to be depressed than individuals without pain. Pain
symptoms are associated with a 2-fold increase for
9
coexisting depression. Patients with 2 or more pain
complaints are 6 times more likely to be depressed.
There are biological and psychological associations
with pain and depression. The link between pain and
depression lies in the central and peripheral nervous
systems. Both serotonin (5-HT) and norepinephrine
(NE) play a vital role in pain and depression. Through
ascending and descending neural pathways, 5-HT
and NE control pain transmissions. Pain originates
in the primary sensory neurons and terminates in
the dorsal horn of the spinal cord. In the spinal cord,
the descending fibers originating in the brainstem
act as homeostatic regulators and suppress pain
neurotransmission. 5-HT and NE are released by the
descending fibers. The dysregulation of 5-HT and NE
is associated with depression. A dysfunctional 5-HT or
NE system is likely to have a dysfunctional descending
5-HT or NE pathway, which explains comorbid pain
symptoms in patients with depression. Consequently,
individuals experiencing chronic pain are susceptible
to depression due to fear and guilt associated with the
constant, and possibly debilitative, discomfort.
Depression is under-diagnosed in patients with
chronic pain. When individuals with chronic pain visit
their medical provider, typical depression symptoms
are reported less. More than 50% of patients with
depression report somatic complaints only; 60% are
pain related.
Individuals tend to express physical
complaints (severity, duration, and frequency of
pain) rather than psychological indicators (irritability,
restlessness, appetite loss, persistent sadness, and
feelings of hopelessness). Patients’ presentation of
physical complaints interferes with the recognition
of depression. Chronic pain patients who experience
unresolved depressive symptoms are associated with
more physician visits, more pain medication refills,
and higher medical costs. Individuals with chronic
pain should routinely be evaluated for depression.
Furthermore, individuals with depression, particularly
with major depressive disorder (MDD) will describe
pain which tends to be vague and occurs frequently.
Since pain and depression share biological pathways,
there are medications which may improve both
conditions. In order to properly treat individuals with
chronic pain and depression, one must understand the
different types of pain. The 3 different types of pain are
(1) peripheral (nociceptive), (2) neuropathic, and (3)
central (non-nociceptive). Peripheral pain is caused
by inflammation or injury; examples are arthritis and
sports injury. Nonsteroidal anti-inflammatory drugs
(NSAIDS) are medications of choice in peripheral
pain. Psychotropic medications show little evidence
of resolving this type of pain. Neuropathic pain is
receptors--such as tricyclic antidepressants (TCAs),
selective serotonin reuptake inhibitors (SSRIs)
and serotonin-norepinephrine reuptake inhibitors
(SNRIs) have been examined in several randomized,
double-blind studies for the treatment of chronic pain
associated with depression. TCAs have been proven
to reduce chronic pain symptoms. Secondary-amine
TCAs (notriptyline, desipramine) are preferred
because of their tolerability over tertiary-amine TCAs
Figure 1. Treatment algorithm for
antidepressants used for chronic pain
Patient with chronic
pain and depression
Peripheral pain
(Sports injury)
with depression
Neuropathic pain
with or without
depression
Secondary-amine TCA
Duloxetine 60 mg/day venlafaxine, duloxetine
or more (alternative:
(alternatives:
venlafaxine)
other TCAs)
Central pain
(Fibromyalgia)
with or without
depression
TCA
(alternatives: SSRI,
SSRI + TCA, SNRI)
SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor;
TCA: tricyclic antidepressant
caused by peripheral nerve damage. Medications such
as opioids, anticonvulsants, and antidepressants that
work on 5-HT or NE receptors have demonstrated
efficacy in neuropathic pain management. Central pain
is due mostly to brain disturbances in pain processing;
examples are fibromyalgia, irritable bowel syndrome,
and chronic headache tension. Antidepressants may
be effective for central pain. Depression is frequently
associated with these illnesses.
Antidepressants that work upon 5-HT or NE
(amitriptyline, imipramine).
Current evidencebased guidelines recommend the use of secondary
amine TCAs and SNRIs as first-line options for the
treatment of neuropathic pain. Unlike SSRIs, SNRIs
(duloxetine and venlafaxine) have demonstrated
improvement in both pain and depression symptoms.
It has been concluded that the inhibition of both 5-HT
and NE is necessary to relieve pain occurring with
depression. In one randomized clinical study, a group
receiving duloxetine 80 mg/day exhibited significant
improvement in pain symptoms compared to other
10
groups receiving duloxetine 40 mg/day, paroxetine
20 mg/day, or placebo in individuals with chronic
pain and MDD. Venlafaxine (mean dose 225 mg/day)
significantly improved pain symptoms in depressed
patients compared with baseline. Table 1 summarizes
medication used to treat Neuropathic Pain.
health care providers discuss with patients the risks
and benefits of antidepressants, including the black
box warnings, and to provide appropriate counseling.
Table 1.
Antidepressants
Desipramine
Nortriptyline
Amitriptyline
Imipramine
Duloxetine
Venlafexine
Suggested Dose
Secondary-Amines TCAs
10-25 mg/d; titrate up to 300 mg/d
10-150 mg/d
Tertiary-Amine TCAs
10-25 mg/d; titrate up to 150 mg/d
10-150 mg/d
SNRIs
60-120 mg/d
Initially 37.5 – 75 mg/d; Max: 375 mg/d
In evaluating a patient with pain, a systematic approach
is recommended to cover the basic parameters. Pain
parameters include location, effect on function and
activities of daily living, levels at rest and during
activity, quality, radiation, timing, precipitating
factors, and medication history. Quality can be
evaluated by asking the patient to describe the pain
(e.g., aching, throbbing). Timing can be described as
occasional, intermittent, or constant. In addition,
prior to the initiation of antidepressant treatment for
chronic pain, the potential for adverse effects caused
by antidepressants should be carefully considered; the
benefits should outweigh the risks. All antidepressants
carry a black box warning detailing the increased risk
of suicidal ideation. The antidepressant dose should
be started low and slowly titrated up while monitoring
for adverse effects.
In conclusion, antidepressants have been proven
effective for various types of chronic pain associated
with depression such as neuropathy, and fibromyalgia.
Different antidepressant classes are effective for
different types of pain. When a patient presents with
chronic pain and depression, it is important to address
both conditions effectively. It is also critical that
11
References:
1. Blair MJ, Robinson RL, et al. Depression and
pain comorbidity: a literature review. Arch Inter
Med;163:2433-45
2. Burt VK. Plotting the Course of Remission: The
search for better outcomes in the treatment of
depression. J Clin Psychiatry. 2004;65 Suppl 12:20-5
3. Greist JH, Greden JF, et al. Depression and pain. J
Clin Psychiatry. 2008;69:1970-8
4. Jann MW, Slade JH. Antidepressant agents for
the treatment of chronic pain and depression.
Pharmacology 2007;27:1571-1587
Value of a Clinical
Pharmacy Service
in a Correctional
Medical System
Hui Seo, Pharm.D.
The value of clinical pharmacy
services is well documented
in the medical literature to
improve therapeutic outcomes
for patients; it demonstrates
that the implementation of a
clinical pharmacy service as
part of a comprehensive allied
health care team can have
dramatic
improvements
in
disease states while reducing
overall healthcare cost.
Surprisingly, this concept has not been fully realized
in correctional healthcare. Often pharmacy services
are evaluated on short-term indicators like the cost
of the medication and the number of prescriptions
dispensed. It misses the value a clinical pharmacy
service that promotes the safe and cost-effective use
of medications to achieve positive outcomes and
improve the well-being of our patients. Success in
avoiding unintended hospitalizations, preventing
a side effect, and optimizing medication therapy
are reflected in both the short and long term
healthcare expenditures.
Correctional healthcare systems are rich with
opportunities for clinical pharmacy services.
Consider that correctional healthcare systems are
disadvantaged in resources and inherently have
patients who require higher acuity of care. The
12
incarcerated population has had very little access
to healthcare or healthcare education prior to
incarceration. Lack of understanding of what and
why medications are prescribed often lead to poor
medication regimen adherence resulting in waste or
abuse. Drug seeking behavior in the incarcerated
population complicates care because the prescriber
becomes challenged to distinguish between real
medical need from manipulation.
Most correctional healthcare systems have limited
pharmacy budgets in a society where medication cost
increases every year by an average of 8% to 13%. Drug
selection is heavily influenced by advertisements
and direct marketing to both the patient and the
prescriber. This is a new phenomenon which began
in the mid 1990’s. With the current economic crisis,
the trend in correctional healthcare budgets runs in
the opposite direction to rising medication costs.
Along with increased availability and use of new
medications, adverse medication events and their
associated healthcare costs are a growing national
concern. Medication use in the correctional healthcare
setting is especially complex with significant use of
anti-retrovirals in for Acquired Immune Deficiency
Syndrome and psychotropic medications. These two
medication categories are associated with frequent
and clinically significant drug interactions.
In the community, pharmacists have been fully
integrated into the allied healthcare team to evaluate
13
medication therapy for cost-effectiveness and
appropriateness. It naturally follows that pharmacists,
the healthcare discipline with extensive experience
and knowledge of medication use, should be an
integral member of the healthcare team. In order to
improve healthcare delivery in the correctional setting,
a greater level of cooperation among the various
healthcare disciplines is required. What follows is a
description and results of a clinical pharmacy service
implemented by Correct Rx Pharmacy Services
in the Maryland Department of Public Safety and
Corrections.
Clinical Pharmacy Program Description
The goal of this clinical pharmacy program is to
improve patient outcomes and reduce unnecessary
healthcare costs through systematic and continual
evaluation of medication therapy involving the
patient, the prescriber, the nurse, and other health
professionals. This value added service assures
appropriate medication selection and use while
minimizing potential toxicities. The pharmacist
reviews medication regimens, meets with patients
to monitor their responses to therapies, identifies
and minimizes potential medication related
adverse effects, and provides education to patients
regarding their disease state(s), medications, lifestyle
interventions and medication adherence.
Acute Care
Clinical pharmacists were assigned to round with
medical teams in the infirmaries. The value of a
multidisciplinary team that includes a pharmacist
in acute care is well established in most primary,
secondary, and tertiary medical centers. The primary
role of the clinical pharmacist while rounding is
to provide medication regimen reviews, make
recommendations prospectively and provide drug
information to the team. Examples of the types of
reviews and assessments made by the pharmacist
include appropriate medication selection, dose,
indication, monitoring objective parameters (e.g.,
gentamicin levels and renal function), as well as
identifying and addressing adverse effects and
untoward reactions.
This service is especially
valuable for monitoring medications with a narrow
therapeutic range (e.g. phenytoin, gentamicin,
vancomycin, valproic acid, and lithium). The
pharmacist is able to provide additional attention to
recommending the appropriate time of laboratory
collection- which is critical in assessing therapy.
Furthermore, the pharmacist is able to provide real
time recommendations regarding medication dosing
and formulary management to positively impact
patient care and reduce healthcare costs.
Chronic Care Clinics
The addition of a clinical pharmacist to the chronic
care clinic setting was made in order to allow for
direct patient interaction for evaluation of medication
therapy and counseling. Pharmacists scheduled and
conducted patient interviews to assess and monitor
medication therapy. The encounters were recorded in
the electronic medical record documenting subjective
information, objective data, assessments, and plans
of care. Recommendations were provided to the
medical provider for review and implementation of
suggested regimen changes. Patient care assessments,
monitoring parameters and medication adjustment
recommendations were made based upon accepted
national clinical practice guidelines and best evidence
in the medical literature.
From the above clinical functions, the effect of using
clinical pharmacy services is measured by monitoring
the type and number of interventions generated by
the services rendered. The types of interventions are
grouped according to identified drug interactions,
therapeutic recommendations made to improve
outcomes, prevented medication errors, drug
information consultations, and facilitation of
operational delivery of care. All of the categories
were potential causes for unnecessary allocation of
custody and healthcare staff resources and ultimately
preventable hospitalizations.
In order to quantify the impact of the service,
pharmacists were required to provide documentation
on interventions made. The collected interventions
were then reviewed and categorized according to
type. A senior clinical pharmacist was responsible
for reviewing the interventions and assessing
clinical significance. Only interventions assessed
to be clinically significant were included in the cost
avoidance model. An intervention was determined
to be clinically significant if the recommendation
was accepted and positively impacted the patient’s
medical care. Examples of interventions that were
not included in the cost avoidance estimate were
when the pharmacists agreed with the medication
treatment plan and continued to follow their patients,
new recommendations for laboratory monitoring
according to accepted practice standards, or
assistance in medication handling and delivery.
During the twelve month period from July 2008 to June
2009, the on-site pharmacists produced significant
numbers of interventions.
Each intervention
was categorized into four categories:
Drug
Interactions Identified and Managed, Therapeutic
Recommendations, Medication Error Prevented,
and Drug Information Provided. There is a brief
description of each category on page 15.
There were a total of 1,920 interventions made during
the 12 months that translated into $2,782,298 in an
estimated cost avoidance to the medical system.
Short term outcomes were also monitored for specific
disease states. See Table 2.
14
Table 1.
Drug Interaction
Therapeutic Recommendation
Medication Error Prevention
Drug Information
1.
2.
1.
2.
3.
4.
5.
6.
7.
1.
2.
3.
4.
5.
1.
2.
Suspected adverse effect or side effect from medication(s)
Predictable Drug Interaction
Therapeutic duplication
Therapeutic contraindication
No therapeutic indication
Review of medication regimen
Sub-therapeutic medication regimen
Supra-therapeutic medication regimen
Inappropriate medication selection (better choice
available considering medication and patient characteristics)
Inappropriate dose
Inappropriate route
Inappropriate dosage form
Inappropriate duration of therapy
Inappropriate scheduled administration times
Drug Information to providers, nursing, and other allied
healthcare staff to ensure appropriate use of medications
Drug is not on the formulary
Table 2.
Type of Interventions
Cost Avoidance
Drug Interactions
Number of
Interventions
198
Therapeutic Recommendations
Medication Error Prevention
Drug Information Consults
Operational Delivery of Care
948
93
613
68
$1,126,224
$127,875
$1,202,093
Not Defined
In the statewide diabetes program, diabetics
uncontrolled with a HbA1C greater than 9 mg/dL were
enrolled in the clinical pharmacy service. The average
HbA1C was reduced from 10.5 mg/dL to 8.5 mg/dL.
There were approximately 300 diabetics enrolled in
the program. With improved glycemic control, it is
anticipated that the program will either prevent or
delay the onset of microvascular and macrovascular
complications associated with diabetes.
Warfarin is an anticoagulant commonly used for the
prophylaxis and/or treatment of thromboembolic
events; however, it is also one of the more dangerous
medications prescribed in the primary care setting
15
$326,106
in corrections. According to the United States
Department of Health and Human Services’ Food and
Drug Administration, warfarin is the second most
common drug, after insulin, implicated in emergency
room visits for adverse drug events. The clinical
pharmacist reviewed PT/INR laboratory data and the
patient’s medical record. Dosage recommendations
were made to ensure the anticoagulant effect is
within the narrow therapeutic range. Compliance
was assessed through review of the patient’s
medication administration record (MAR). Patient
interviews were performed to counsel on dietary and
lifestyle modifications to decrease the likely hood of
therapeutic failure.
Asthma is another disease state that Correct
Rx identified as contributing to increased
hospitalizations. According to the updated 2008
National Heart Lung and Blood Institute Report,
nationally, asthmatics are not well controlled. Correct
Rx developed and implemented a review of asthmatic
therapy to reduce unnecessary healthcare costs and
improve patient care. There were many patients
over-utilizing “as-needed” albuterol inhalers which
are indicators of poor asthma control. Conversely,
patients assessed with moderate to severe asthma
lacked the use of maintenance inhalers. The clinical
pharmacists have affected positive change in this
population by counseling patients on the purpose of
their medications (e.g. maintenance versus rescue
therapy), proper inhaler technique, trigger avoidance,
and recognizing the value of smoking cessation.
economic and humanistic value. Considering that
the correctional population is “sicker” and in need
of more attention than other patient groups, the
opportunities for clinical interventions are abundant.
The correctional population is in greater need of
clinical pharmacy services to provide a collaborative
approach to affect positive outcomes associated with
medication therapy.
The clinical pharmacy component demonstrated
significant results in optimizing medication therapy
for this correctional population. The cost avoidance
associated with a clinical pharmacy program is always
relative to the setting of healthcare services provided;
however, it does not diminish the actual number of
pharmacists interventions generated. Based upon
review of daily activities, the pharmacists on average
spent 68% of their time on patient care activities.
Their non-patient care activities included monthly
medication room inspections in 33 sites, mandatory
attendance at meetings, provision of in-services on
drug topics, and chairing the respective regional
Pharmacy and Therapeutics Committee meetings.
“Asthma is
another disease
state that
Correct Rx
identified as
contributing
to increased
hospitalizations.”
The clinical pharmacy program was initially designed
to target patients with diabetes, hypertension,
hyperlipidemia, and other cardiovascular disease
states but expanded its services to include patients
with asthma, anticoagulant therapy, mental health and
HIV treatment. The expansion of the patient groups
was a result of the demand for the service by patients
and providers who appreciated the value it provided.
Providers appreciate the pharmacists for being a
resource for information and for providing follow-up
care on a continuous basis. The benefits that patients
receive from pharmacists include education, continued
reinforcement of the importance of medication
adherence, and disease state counseling. Correct Rx
Pharmacy Services’ clinical programs have definitive
16
GERD
Management of
Gastroesophageal
Reflux Disease
Sankung Sise, Pharm.D.
Gastroesophageal reflux disease (GERD) is a common
chronic, relapsing condition that is associated with
a risk of significant morbidity and the possibility
of mortality from complications. An estimated 40
percent of the United States adult population has
heartburn, the hallmark of acid regurgitation, at
least once a month. Approximately 14 percent of
Americans have gastroesophageal symptoms weekly,
and 7 percent have symptoms daily.
Many patients self-diagnose and self-treat; they
do not seek medical attention for their symptoms.
Others can have a more severe presentation of the
disease, including erosive esophagitis. Patients who
have GERD generally report decreased quality of life,
reduced productivity, and decreased well-being. In
many of these patients, the reported quality of life
is lower than in patients who have untreated angina
pectoris or chronic heart failure.
17
Diagnosis
While there is no gold standard for diagnosing
GERD, a 24-hour pH monitoring (pH probe) is the
accepted standard for establishing or excluding
its presence. In patients with nonerosive reflux
disease or symptomatic reflux esophagitis, 24-hour
pH monitoring has a sensitivity and specificity of
more than 80 percent, but false-positive or falsenegative results are possible.
Endoscopy it is the
gold standard for assessing esophageal complications
of GERD, though it lacks sensitivity for identifying
pathologic reflux. Barium radiology is seldom useful
for diagnosing GERD. Diagnostic testing should be
reserved for patients who exhibit warning signs (e.g.
weight loss, dysphagia, gastrointestinal bleeding)
and patients who are at risk for complications of
esophagitis (i.e. esophageal stricture formation,
Barrett’s esophagus, and adenocarcinoma). Antireflux
surgery, including open and laparoscopic versions of
Nissen fundoplication, is an alternative treatment in
patients who have chronic reflux with recalcitrant
symptoms. Newer endoscopic modalities, including
the Stretta procedures are less invasive and have fewer
complications than antireflux surgery, but response
rates are lower.
Treatment
The primary treatment goals in patients with
gastroesophageal reflux disease are relief of symptoms,
prevention of symptoms relapse, healing of erosive
esophagitis, and the prevention of esophageal
complications. In patients with reflux esophagitis,
treatment is directed at acid suppression through the
use of lifestyle modification (e.g. elevating the head
of the bed, modifying the size and composition of
meals, avoiding acidic food- citric and tomato based
products, alcohol, caffeinated beverages, chocolate,
onions, garlic, and peppermint, decreasing dietary
fat intake). Smoking cessation is also strongly
encouraged. Other modalities include the avoidance
of medications that may potentiate GERD symptoms
when possible, including calcium channel blockers,
beta agonists, alpha adrenergic agonist, theophylline,
nitrates and some sedatives.
Generic Names
Brand Names
Dosage Form
Alginic acid
Alumnium Hydroxide
Calcium carbonate
Magnesium carbonate
Sodium bicarbonate
Gaviscon
Suspension
Tablet
Aluminum hydroxide
Alu-Cap
Capsule
Alu-Tab
Tablet
Amphojel
Suspension
Aluminum hydroxide
Magnesium hydroxide
Mylanta Ultimate Strength
Suspension
Aluminum hydroxide
Magnesium hydroxide
Simethicone
Maalox Advanced
Suspension
Bismuth subsalicylate
Kaopectate
Suspension
Maalox Total Relief
Suspension
Pepto-Bismol
Suspension
Tablet
TUMS
Tablet
Antacids
Calcium carbonate
Mylanta
Mylanta Max Strength
Rolaids
Maalox Regular Strength
Calcium carbonate
Magnesium hydroxide
Mylanta Ultimate Strength
Tablet
Mylanta Supreme
Suspension
Calcium carbonate
Simethicone
Maalox Advanced
Tablet
Magnesium hydroxide
Phillips Milk of Magnesia
Suspension
Sodium bicarbonate
Alka-Seltzer
Tablet
Cimetidine
Tagamet
Injection
Solution
Tablet
Famotidine
Pepcid
Gelcap
Injection
Power for suspension
Tablet
Nizatidine
Axid
Capsule
Solution
Tablet
Ranitidine
Zantac
Capsule
Injection
Syrup
Tablet
Esomeprazole
Nexium
Capsules
Granules for suspension
Injection
Tablet
Lansoprazole
Prevacid
Capsule
Granules for suspension
Tablet
Omeprazole
Prilosec
Capsule
Tablet
Pantoprazole
Protonix
Granules for suspension
Injection
Tablet
Rabeprazole
Aciphex
Tablet
Histamine-2 Receptor Antagonist
Proton Pump Inhibitors
18
Drug selection should be based on the frequency or
severity of symptoms at presentation. The preferred
empiric approach is step up therapy or step down
therapy. For the purposes of this article we will be
discussing the step up therapy in GERD where erosive
esophagitis is not present.
The most common and effective treatment of GERD
is to reduce gastric acid secretion with Over the
Counter (OTC) acid suppressants and antacids, a
histamine 2 receptor antagonist (H2RA) or a proton
pump inhibitor (PPI). H2RA agents inhibit the
action histamine at the H2 receptor of the parietal
cell, decreasing both basal and food stimulated acid
secretion. The PPIs bind to the activated proton pump
of the parietal cell, inhibiting secretion of hydrogen
ions into the gastric lumen. Regardless of the drug
choice, the medication dose should be titrated to the
severity of disease for each patient, the goal being
to raise the intragastric pH above 4 during periods
of the day that reflux is likely to occur. The greater
the degree of pathologic esophageal acid exposure,
the greater the degree of acid suppression required.
These therapies do not prevent reflux; they remove
the acidity from the refluxate.
OTC acid suppressants and antacids are considered
appropriate initial therapies for GERD. Antacids (e.g.
Tums®, Rolaids®, Maalox®) and combination antacid
and alginic acid preparations (Gaviscon) have been
shown to be effective in relieving GERD symptoms.
Almost one third of patients with heartburn related
symptoms use one of these agents at least twice
weekly, for an annual expenditure of more than
$1 billion.
If a patient does not find relief of the GERD symptom
with the OTC antacids, the patient should step up to
taking a H2RA: cimetidine (Tagamet®), famotidine
(Pepcid®), nizatidine (Axid®) and ranitidine (Zantac®).
All four agents in the H2RA class have similar clinical
efficacy. The H2RAs are believed to be more effective
than antacids and alginic acid. Dosage of H2RAs
may need to be decreased in patients with renal
insufficiency. Severe adverse effects are uncommon
with H2RAs, but headache, lethargy, confusion,
19
depression and hallucinations can occur. Cimetidine
inhibits the activity of hepatic enzymes 1A2, 2C19
and 2D6. Clinically significant effects have occurred
when cimetidine is taken in combination with drugs
that are metabolized by the same enzymes and have
narrow therapeutic to toxic ratio (e.g. theophylline,
warfarin and phenytoin). Patients should be treated
initially with H2Ra for eight weeks; if symptoms do
not improve, change to PPI. At this time the United
States Food and Drug Administration has approved
the use of all four H2RA as OTC preparations, with
dosage for each medication uniformly one half of the
standard lowest prescription dosage. Patients who
self treat elect to take the medications one of two
ways. Some patients with GERD, who may be able
to predict when they will have reflux symptoms, may
benefit from premedication with an OTC H2RA.
Alternatively, patients may elect to take the medication
when symptoms occur (on demand therapy).
If a patient who was initially started on twice daily
H2RA therapy does not respond after two weeks,
appropriate step up therapy is to switch to once daily
PPI therapy. Also, in patients with erosive esophagitis
identified on endoscopy, PPI is the initial treatment
of choice. They are most effective when taken 30-60
minutes before the first meal of the day. PPIs include
lansoprazole (Prevacid®), omeprazole (Prilosec®),
pantoprazole (Protonix®), rabeprazole (Aciphex®)
and esomeprazole (Nexium®). For these agents, no
significant differences have been demonstrated in
the symptomatic treatment of GERD or the healing
of erosive esophagitis. There are differences in
pharmacokinetics. Theoretically, PPIs, with the
exception of pantoprazole, may affect the metabolism
of cytochrome P450 CYP2C19 and CYP3A4
substrates like, theophyline, diazepam, warfarin, and
phenytoin. Pantoprazole is metabolized by cytosolic
sulfotransferase and less likely to interfere with drug
metabolism. Omeprazole drug interactions may
warrant closer monitoring in slow metabolizers.
Otherwise drug interactions in this category do not
affect drug selection.
PPIs usually cause few adverse effects; however,
headache, nausea, abdominal pain, constipation,
flatulence and diarrhea have been known to occur.
A potential concern, with any form of gastric acid
inhibition, is an increased risk of enteric infections.
Gastric acidity normally protects against these
infections; studies have shown that PPI have greater
“The primary treatment
goals in patients with
gastroesophageal reflux
disease are relief of
symptoms, prevention
of symptoms relapse,
healing of erosive
esophagitis, and the
prevention of esophageal
complications.”
risk of causing C. difficile diarrhea in patients exposed
to antibiotics. Long-term use of PPIs may also
influence bone metabolism. Hypochlorhydria could
theoretically reduce calcium absorption and inhibit
osteoclastic activity thereby decreasing bone density.
Although clinically important drug interactions with
PPIs are rare, some relevant interactions have been
proposed such as decreased efficacy of clopidogrel.
and should not replace acid suppression therapy.
The addition of an H2RA to PPIs may be useful in
controlling nocturnal symptoms; however, the
effectiveness of this strategy will decrease over time.
The use of sucralfate in combination with PPIs or
H2RAs shows little or no value unless significant
neuromuscular dysfunction is involved.
The benefits of long-term treatment are difficult
to assess. Once patients are treated with PPIs, it is
reasonable to implement a step-down approach to
H2RAs. In patients with moderate to severe GERD,
maintenance therapy is usually required. In at least
one study, the cost of pharmacologic acid suppression
therapy was lower compared to surgical intervention;
however, the costs were calculated to be equal after
10 years. Patients with persistent symptoms should
be evaluated for strictures and other complications.
The importance of life-style modifications should be
routinely reinforced with patients to maximize the
effect of pharmacologic treatment.
References
1. Kahrilas, PJ, Shaheen, NJ, Vaezi, M. American
Gastroenterological Association Institute Technical
Review on the Management of Gastroesophageal
Reflux Disease. Gastroenterology 2008; 135:1392
2. KR DeVault and DO Castell. Updated guidelines for
the diagnosis and treatment of gastroesophageal
reflux disease. Am J Gastroenterology 2005:
100:190
3. GR Heudebert, R Marks, CM Wilcox, et al. Choice
of long-term strategy for the management of
patients with severe esophagitis: A cost-utility
analysis. Gastroenterology 1997; 112: 1078-1086
There is limited data to support combination therapy
in GERD. Promotiliy agents, such as metoclopramide,
are used as adjuncts to acid suppression therapy.
Unfortunately, metoclopramide is associated with
side effects such as sedation, extrapyramidal effects,
and changes in mental status that limit its use. Other
promotility agents include bethanecol and baclofen.
These agents are not recommended for monotherapy
20
Lantus versus Levemir :
®
®
A comparison of the long-acting
basal insulin analogs
By: Janet Mahoney, Pharm.D. candidate 2010
Diabetes Mellitus is a group of metabolic diseases
resulting from defects in insulin secretion, insulin
action, or both. Hyperglycemia is a characteristic
of Diabetes Mellitus and, if not treated, can lead
to long-term microvascular and macrovascular
complications. Evidence from the Diabetes Control
and Complications Trial (DCCT), the United
Kingdom Prospective Diabetes Trial (UKPDS), and
the Action to Control Cardiovascular Risk in Diabetes
Trial (ACCORD) suggests that tight glycemic control
is crucial for reducing the risk of diabetes-related
complications. Insulin therapy, an option for patients
with Type 1 or Type 2 diabetes, is one way in which
hyperglycemia can be reduced and tight glycemic
control may be achieved.
Recent advances in insulin therapy have brought
two long-acting basal insulin analogs to the market,
Lantus® (insulin glargine) and Levemir® (insulin
detemir). Basal insulin, also referred to as background
insulin, suppresses glucose production overnight
and between meals. In patients without Diabetes
Mellitus, basal insulin is secreted at near constant
levels and provides up to 50% of the body’s daily
insulin requirement. In patients with Type 1 diabetes
exogenous basal-bolus insulin is required. In Type
2 diabetes exogenous basal insulin may be used in
addition to oral anti-hyperglycemic medications, or
basal-bolus insulin therapy may be employed.
Table 1. Characteristics of Lantus® and Levemir®
Lantus®
Levemir®
Mechanism of action
Regulation of glucose metabolism via binding to insulin receptors
Differences compared to human Asparagine at A21 is replaced
Threonine at position B30 is
insulin
by glycine and two arginines are omitted and a C14 fatty acid
added to the C-terminus of the chain is attached to the lysine
B-chain
at B29
Product characteristics
Clear, acidic, sterile solution
Clear, neutral, sterile solution
Possibility of mixing with other May not be diluted or mixed with other insulin products
insulin
Typical starting dose (Type 2
10U once daily
10U once or twice daily
diabetes, insulin-naive)
Administration
Indicated for subcutaneous injection only
Product availability
10mL vial
10mL vial
3mL cartridge system
3mL FlexPen®
3mL SoloStar® device
21
Pharmacokinetics and Pharmacodynamics
insulin analog over the other in Type 1 diabetes.
Both Lantus® and Levemir® have a prolonged duration
of action allowing them to be used as bolus insulin with
the possibility of once daily dosing. Lantus® is injected
as an acidic solution and is neutralized once it enters
the subcutaneous tissue. The neutralized solution
forms micro precipitates from which small amounts
of insulin glargine are slowly released. This provides
a constant concentration versus time profile with no
peak. Levemir® has a prolonged duration of action
due to self-association and albumin binding. Selfassociation occurs between the hexameric Levemir®
molecules such that the fatty acid chains at each pole
of the hexamer complex interact to form dihexamers.
The dihexamers then bind to plasma albumin. These
interactions slow the absorption of insulin detemir
leading to a relatively constant, although not peakless,
concentration versus time profile.
The 2009 guidelines from the American Diabetes
Association (ADA) and the European Association
for the Study of Diabetes (EASD) recommend basal
insulin therapy as the most effective option for patients
with Type 2 diabetes whose disease is not controlled
by metformin monotherapy. In a randomized,
double-blind, crossover study, once-daily Levemir®
was comparable to once-daily Lantus® in providing
glycemic control over 24 hours in patients with Type
2 diabetes.4 In a 52 week, randomized, treat-totarget trial comparing Levemir® with Lantus® when
administered as add-on therapy to antihyperglycemic
medications in insulin-naïve subjects with Type 2
diabetes, higher doses of Levemir® were required to
demonstrate non-inferiority and achieve glycemic
goals.5 This is likely due to the fact that Lantus® was
given once daily at bedtime regardless of glycemic
Table 2. Pharmacokinetics
Brand
Lantus®
Levemir®
Generic
Insulin glargine
Insulin detemir
Onset
2-4 hours
2-4 hours
Use in Type 1 and Type 2 Diabetes Mellitus
At this time neither Lantus® nor Levemir® is clearly the
superior long-acting insulin analog. Both are associated
with less hypoglycemia and equal A1C lowering in
Type 1 diabetes compared to intermediate acting
insulin.1 In a randomized, open-label trial comparing
twice-daily Levemir® and once-daily Lantus® in
subjects with Type 1 diabetes using intensive insulin
therapy, similar glycemic control was achieved.2 The
incidence of both severe and nocturnal hypoglycemia,
however, was significantly reduced with Levemir®.
In a separate trial comparing Levemir®, Lantus®, and
NPH insulin, Levemir® proved advantageous in that
it had a more predictable glucose-lowering effect
with significantly lower within-subject variability in
patients with Type 1 diabetes.3 It is apparent that at
this time clinical trial data is lacking and evidence
does not clearly support the use of one long-acting
Peak
None
6-14 hours
Duration
20-24 hours
16-20 hours
profile, while for Levemir® an option was provided for
adding a second dose based on the pre-dinner blood
glucose value. Interestingly, in this and in other such
comparison trials, Levemir® was associated with less
weight gain compared to Lantus® in type 2 diabetics
treated with oral hypoglycemic agents. However,
as is the case for Type 1 diabetes, evidence does not
strongly support the use of one versus the other in
Type 2 diabetes.
Cost Effectiveness
With no clear front-runner in terms of efficacy
between the long-acting insulin analogs, it is
important for health care providers to consider
cost effectiveness. In Table 3, AWP cost is lower
for Levemir compared to Lantus. The actual cost is
variable and the difference in cost between Levemir
and Lantus maybe more significant. With respect to
22
total healthcare cost, a recent study comparing health
care costs with Levemir® and Lantus® in insulin-naïve
patients with Type 2 diabetes in a managed care
population found that patients receiving Levemir®
incurred lower diabetes-related medical and total
health care costs.6 In this population daily insulin
dose and glycemic control did not differ significantly,
nor did all-cause health care costs. Though there were
several limitations to this study including its short
length of duration and exclusion of patients who had
previously used NPH insulin, it does employ data
from a usual community-practice population that
may be informative as health care providers decide
which long-acting insulin analog is right for their
patients.
In summary, Levemir may provide an economic
advantage over Lantus. Levemir has demonstrated
similar efficacy in controlling hyperglycemia in
both Type 1 and Type 2 diabetics despite significant
differences in formulation and pharmacokinetics. In
addition, Levemir may have an added advantage of
limiting weight gain as compared to Lantus.
Table 3. Cost Effectiveness
Drug
Lantus®
Levemir®
Generic
10mL vial
10mL vial
AWP Cost
$107.46
$95.74
References
1. Nathan DM, et al. Medical management of
hyperglycemia in Type 2 diabetes: a consensus
algorithm for the initiation and adjustment of
therapy. Diabetes Care 32:193-203, 2009.
2. Pieber TR, et al. Comparison of insulin detemir and
insulin glargine in subjects with Type 1 diabetes
using intensive insulin therapy. Diabetic Medicine
24:635-642, 2007.
3. Heise T, et al. Lower within-subject variability of
insulin detemir in comparison to NPH insulin and
insulin glargine in people with Type 1 diabetes.
Diabetes 53:1614-1620, 2004.
4. King AB. Once-daily insulin detemir is comparable
to once-daily insulin glargine in providing
23
glycaemic control over 24 h in patients with type
2 diabetes: a double-blind, randomized, crossover
study. Diabetes, Obesity and Metabolism. 11:69-71,
2009.
5. Rosenstock J. A randomised, 52-week, treat-totarget trial comparing insulin detemir with insulin
glargine when administered as add-on to glucoselowering drugs in insulin-naive people with type 2
diabetes. Diabetologia. 51:408–416, 2008.
6. Borah BB, et al. A comparison of insulin use, glycemic
control, and health care costs with insulin detemir
and insulin glargine in insulin-naive patients with
type 2 diabetes. Clinical Therapeutics. 31:623-631,
2009.
Rodney Williams
Recently released from prison
Models for illustrative
purposes only; not an
actual patient profile
©2009 Abbott Laboratories Abbott Park, IL 60064 045-230005 March 2009 Printed in U.S.A.
24
Dual Antiplatelet therapy in Secondary
Prevention of Acute Coronary Syndrome
THIS or DAT?
25
Akilah Streets,
Pharm.D.
Coronary heart disease (CHD) is a very prevalent
medical condition, with estimated direct and indirect
costs of $165.4 billion for 2009. It is projected that
785,000 Americans will have a new coronary attack
and over 470,000 will have a recurrent attack this year.
Acute coronary syndrome (ACS), a manifestation
of CHD, is a compilation of ailments that involves
unstable angina (UA) and acute myocardial infarction
(MI), with or without ST-segment elevation (STEMI
or NSTEMI). ACS is the end result of atherosclerosis,
a diffuse disease of medium- and large-sized arteries
characterized by plaque formation.
There are two approaches to the initial management
of patients with ACS depending on the presentation:
1) a conservative medical management approach or 2)
an early invasive strategy. Medical management may
include therapy with anticoagulation (e.g., heparin,
enoxaparin), glycoprotein IIb/IIIa inhibitors (e.g.,
eptifibatide, tirofiban, abciximab), or fibrinolytics
(e.g. alteplase, tenecteplace). Invasive management
of ACS includes percutaneous coronary intervention
(PCI) in which an intracoronary stent, whether bare
metal or drug eluting, is placed to restore blood flow
to the compromised myocardium.
Several studies have demonstrated that roughly 20%
of patients with a prior MI, treated conservatively,
will be re-hospitalized within one year, with estimated
direct and indirect cost of $360 million. Roughly
14% of patients treated invasively will develop stent
thrombosis with the gradual return of narrowing
of blood vessels presenting with recurrent angina.
Clinical restenosis adds roughly $4,000 to the first
year cost of each PCI patient. Based on this data,
there have been a number of guidelines published by
the American Heart Association, American College of
Cardiology, Society for Cardiovascular Angiography
and Interventions, American College of Surgeons, and
American Dental Association that address the need
for strict and efficient secondary prevention of ACS
with emphasis on dual antiplatelet therapy (DAT).
Secondary prevention of ACS includes optimal control
of comorbid conditions (i.e. diabetes, hypertension,
hyperlipidemia), as well as lifestyle modifications
(e.g. smoking cessation, increased physical activity,
and weight loss). Another measure for secondary
prevention includes maximizing medical therapy
with angiotensin-converting enzyme inhibitors,
beta-adrenergic antagonists, HMG-CoA reductase
inhibitors, and antiplatelet agents. DAT has taken a
prominent role in secondary prevention based on its
documented benefit over monotherapy.
DAT is accomplished by using medications that affect
platelet functions through different mechanisms. The
medications most commonly used are aspirin and
the thienopyridines (i.e. clopidogrel, ticlopidine). The
remainder of this article will review the guidelines for
(Figure 1) and evidence supporting the use of DAT for
the secondary prevention of ACS, whether managed
invasively or conservatively.
The data from Figure 1 is supported by several large,
randomized controlled studies that demonstrate
the effectiveness of DAT in patients with ACS. Key
clinical trials and supportive data that prove DAT to
significantly reduce the risk of death and recurrent
myocardial infarction are discussed below.
Clopidogrel in Unstable angina to prevent
Recurrent Events (CURE)
The CURE trial included 12,562 patients who
presented with NSTEMI who were mostly managed
medically (>75% did not receive a PCI). Patients
were randomized to receive clopidogrel 75 mg
daily in addition to aspirin 75mg to 325 mg daily,
or aspirin 75mg to 325 mg daily with placebo for
up to 12 months. The primary end point of death
from cardiovascular causes, nonfatal MI, or stroke
was significantly reduced with the use of clopidogrel
versus placebo (relative risk RR 0.80; 95% CI, P <.001).
This result was primarily driven by a reduction in
nonfatal MI (RR 0.77; 95% CI, P <.05).
Clopidogrel for the Reduction of Events
During Observation (CREDO)
To further investigate the use of DAT for secondary
prevention, the CREDO trial examined 2,116 patients
undergoing elective coronary catheterization with
planned PCI or high likelihood of PCI. The study did
not specify what type of stent was used (i.e. BMS or
DES). Patients were randomized to receive a 300mg
loading dose of clopidogrel or placebo; both groups
then continued clopidogrel 75 mg daily and aspirin
325 mg daily until day 28. Both groups continued to
receive standard aspirin therapy (81mg to 325 mg
daily) for one year. On day 29, the group that did not
receive the loading dose of clopidogrel was changed
to placebo, while the other continued clopidogrel
75 mg daily. The continuation of DAT for one year
resulted in a 26.9% RRR in the composite end point of
death, MI, or stroke (8.5% vs. 11.5%; 95% CI; P =.02).
Clopidogrel and Metoprolol in Myocardial
Infarction Trial (COMMIT)
COMMIT included 45,852 patients with suspected
MI (93% met criteria for STEMI and 54% were treated
with fibrinolytics). Patients were randomized to
receive either 1) placebo plus aspirin 162 mg daily or
2) clopidogrel 75 mg daily plus aspirin 162 mg daily.
Clopidogrel was continued for a mean duration of
14.9 days after randomization. The primary end point
26
of death, reinfarction, or stroke was significantly
reduced in the group receiving clopidogrel versus
those receiving placebo at 28 days after randomization
(9.2% vs. 10.1%; RRR 9%; P =.002). Although DAT
is highly efficacious in reducing morbidity and
mortality for the secondary prevention of ACS,
there is an associated risk of bleeding. DAT should
be used with caution in patients who are already at
an increased risk for bleeds (e.g. patients with peptic
ulcer disease and those on NSAIDS). Healthcare
providers should be cautious when considering
concomitant anticoagulation with warfarin. Use with
warfarin significantly increases the risk of bleeding;
it is recommended to reduce the target international
normalized ratio (INR) to 2.0 to 2.5. In the event of
a procedure or surgery and patients must discontinue
thienopyridine, aspirin should be continued if at all
possible and the thienopyridine restarted as soon
as possible.
In conclusion DAT is a crucial component in the
medical therapy for the secondary prevention of
ACS. It has been shown to be effective in patients
with UA, NSTEMI, or STEMI and in those following
PCI. Although there is a moderate increased
risk of bleeding, this therapy is lifesaving and has
overwhelming benefits.
Figure 1. Antiplatelet Therapy after Acute Coronary Syndrome
UA/NSTEMI
STEMI
UA/NSTEMI or STEMI
UA/NSTEMI or
STEMI
Medical Therapy Without Stent
ASA 75 -162 mg/day indefinitely
PLUS
Clopidogrel 75 mg/day for at least one month and ideally up to 1 year
ASA 75 -162 mg/day indefinitely
PLUS
Clopidogrel 75 mg/day for at least 14 days and ideally up to 1 year
Bare Metal Stent
ASA 162-325 mg/day for 1 month,
then 75-162 mg/day indefinitely
PLUS
Clopidogrel 75 mg/day for at least 1 month and ideally up to 1 year
Drug Eluting Stents
ASA 162-325 mg/day for 3-6 months,
then 75-162 mg/day indefinitely
PLUS
Clopidogrel 75 mg/day for at least 1 year
References:
27
Dental Association. Circulation. 2007;115:813-818.
1. King SB III, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused
update of the ACC/AHA/SCAI 2005 guideline update for
percutaneous coronary intervention: a report of the ACC/
AHA Task Force on Practice Guidelines. J Am Coll Cardiol.
2008;51:172-209.
3. Antman EM, Hand M, Armstrong PW, et al. 2007 focused
update of the ACC/AHA 2004 guidelines for the management
of patients with ST-elevation myocardial infarction: a
report of the ACC/AHA Task Force on Practice Guidelines.
Circulation. 2008;117:296-329.
2. Grines CL, Bonow RO, Casey DE Jr, et al. Prevention of
premature discontinuation of dual antiplatelet therapy in
patients with coronary artery stents: a science advisory from
the AHA, ACC, Society for Cardiovascular Angiography and
Interventions, American College of Surgeons, and American
4. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007
guidelines for the management of patients with unstable
angina/non ST-elevation myocardial infarction: a report of the
ACC/AHA Task Force on Practice Guidelines. Circulation.
2007;116:803-877.
Roche
From Research to Real Life
Roche is a leader in hepatitis C management, and we are proud to be in the
forefront of designing innovative clinical approaches to fight this chronic disease.
In addition to discovering and developing a current market-leading therapy,
Roche is conducting research into novel compounds and has several ongoing
collaborations with biotechnology companies. We are committed to the discovery
of innovative new medicines that may enable us to deliver a new standard of care
for patients with HCV.
For additional information about Roche and hepatitis C, please visit our website at
http://www.roche.us
28
2009-H1N1 Influenza:
An Update on Vaccine Production
Janet Mahoney and Andy Trinh, Pharm.D. candidates, Class of 2010
The 2009-H1N1 virus, commonly known as swine
flu, is a novel influenza A virus first detected in April
of 2009. According to a situational update published
by the World Health Organization on June 8, 2009,
a total of 25,288 cases of the 2009-H1N1 virus have
been reported in 73 countries and 139 deaths have
occurred.1 The 2009-H1N1 virus is thought to be
transmitted from person-to-person in a similar
manner as seasonal influenza; mainly via the coughs
and sneezes of persons infected with the virus;
however, since 2009-H1N1 is a new viral strain,
most people will not have immunity to it and the
illness may have the potential to be more severe and
widespread as a result. Thus, prevention measures
such as respiratory hygiene/cough etiquette, hand
29
washing, and vaccination are crucial to preventing
the spread of the virus.
While the 2009-H1N1 is a novel virus strain, the
H1N1 virus itself is not an unknown virus. In 1976,
an outbreak of “swine flu” occurred in the wintertime
among troops stationed at Fort Dix army base in New
Jersey. The virus, at the time thought to be related
to the 1918 flu pandemic that killed millions, never
spread beyond the confines of the army base. The
1976 virus and the 2009 virus are often commonly
called “swine flu” because a swine flu influenza virus
is any strain of the influenza family of viruses that is
usually endemic in pigs. The current 2009-H1N1 virus
is different from the 1976 virus in that the current
virus is a hybrid of swine flu, human flu, and avian
flu, whereas the 1976 virus did not have any avian flu
in it.2 Consequently, the 2009-H1N1 virus should not
be referred to as “swine flu” as this is not an accurate
representation of the hybrid influenza virus.
Differences Between 2009-H1N1 and
Seasonal Influenza Vaccine
At this time an effective vaccine against the 2009H1N1 virus is not readily available. Current scientific
evidence suggests that the seasonal influenza vaccine
will offer little or no protection against the 2009H1N1 virus, thus work is underway to develop a new
vaccine. Currently there are two types of vaccines
licensed for the prevention of seasonal influenza in
the United States, inactivated vaccines that are based
on chemically killed influenza viruses and injected
intramuscularly; and live, attenuated vaccines that are
based on a weakened influenza virus and are given
as a nasal spray. The seasonal influenza vaccines
contain three antigenic components: type A/H1N1,
type A/H3N2, and type B antigens. This year they
contain the following strains: A/Brisbane/59/2007
(H1N1)-like virus, A/Brisbane/10/2007 (H3N2)like virus, and B/Brisbane/60/2008-like virus for the
inactivated vaccine; for the live attenuated vaccine
the A/Brisbane/59/2007 is replaced with A/South
Dakota/6/2007.3
A potentially unique aspect of the 2009-H1N1
vaccine compared to the seasonal influenza vaccine
may be the use of an adjuvant. An adjuvant is an
additive to a vaccine that helps to generate a stronger
immune response to the vaccine, potentially reducing
the vaccine dose and the number of doses needed.
Examples of adjuvants include MF59, a squalene oil in
water emulsion used in Europe, and ASO3, a squalene/
monophosphoryl lipid A/QS-21 emulsion in clinical
trials in the US and Europe. The current seasonal
influenza vaccine does not use an adjuvant. Vaccine
researchers will review safety and immunogenicity
data from the 2009-H1N1 vaccine, once it is available,
to determine if an adjuvant is necessary in order
to employ the safest and most effective dosage for
generation of a strong immune response. Aside
from potential adjuvant use, the novel 2009-H1N1
vaccine will be made using the same procedures as
the seasonal influenza vaccine and will be available as
both an inactivated and a live vaccine. It is estimated
that vaccine development will take 5-6 months.
The Vaccine Development Process
Figure 1 provides an illustration of the vaccine
development process. The first step in the process
is isolation and characterization of the virus. Virus
reference strains, also known as seed viruses, are
then prepared. In this process a sample of the new
influenza virus is combined with another influenza
virus that grows in eggs, thus enabling the new virus
to be grown in eggs; a technique used in commercial
production. Once a final virus reference strain/master
seed virus is ready it will be distributed to vaccine
manufactures for use in production.
Once the seed virus is given to the vaccine
manufacturers, production of pilot lots of the
vaccine will take place. The pilot lots must be
clinically evaluated for in order to gain approval by
the FDA. The evaluation will take place via clinical
trials conducted on humans at National Institute of
Allergy and Infectious Diseases (NIAID) Vaccine and
Treatment Evaluation Units (VTEU). These trials will
be used to test pilot lots to determine whether the
vaccine is safe, induces protective immune responses,
and to determine the appropriate dose and number of
dosages needed.
At the same time pilot lots are being tested, commercial
production of vaccine for bulk storage will take place.
The vaccine will then be formulated, orders will be
filled, and the vaccine will be delivered.
How the Current H1N1 Vaccine
30
Figure 1. Vaccine Development Process4
Isolation
and
Characterization
Clinical
Evaluation
Scale-up for (e.g. in Formulation,
Filling and
commercial
VTEUs)
Delivery
production
Commercial
production
Pilot Lots
Seed
Virus
Influenza
Virus
New
Vaccine
Differs from the 1976 Vaccine
The current 2009-H1N1 virus outbreak and discussion
of vaccine production conjures memories and
perhaps fears related to the 1976 “swine flu” outbreak.
In 1976, President Ford ordered the mass vaccination
of Americans fearing an epidemic would break out
like that of the 1918 flu. The “swine flu” of 1976 did
not reach epidemic portions; however, reports of
Guillain-Barré syndrome began to appear weeks after
the start of the mass vaccination campaign. GuillainBarré syndrome is a rare neurological condition that
causes muscles to weaken and paralysis to ensue. It
may be observed following a variety of infections,
including influenza. Studies suggest that regular
seasonal influenza vaccines could be associated with
an increased risk of Guillain-Barré syndrome such
that the incidence is 1-2 cases per million vaccinated
persons; however, approximately 10 cases of
Guillain-Barré syndrome were reported per 1 million
vaccinations in 1976 leading to discontinuation of the
vaccination effort.5
The cause of the Guillain-Barré syndrome brought
to light during the 1976 vaccination campaign
still remains unclear and there is some question
as to whether the same risk exists with the 2009H1N1 vaccine. The 2009-H1N1 vaccines will be
Figure 2. NIAID-approved VTEU locations4
Group Health
Cooperative
Seattle
Childrens Hospital
Medical Center
Cincinnati
University of
Maryland
Baltimore
Established in 1962
>160 Phase I, II, and III
clinical trials since 1995
Emory
University
Atlanta
University of
Iowa
Iowa City
31
Saint Louis
University
St. Louis
Vanderbilt
Baylor College of
University
Medicine
Nashville
Houston
Trials of
- Seasonal vaccines
- Pre-pandemic vaccines
- Antivirals
manufactured according to established standards;
however, they are new products so there is an
inherent risk that they will cause adverse reactions
in humans. Close monitoring and investigation of all
serious adverse events following administration of
the vaccine is essential. Safety monitoring systems,
such as the Vaccine Adverse Event Reporting System
(VARES), are an integral part of the strategies for
the implementation of the new pandemic influenza
vaccines. Quality control for the production of
influenza vaccines has improved substantially since
the 1970s, thus researchers are confident that the
problems of the past will not repeat with this future
2009-H1N1 vaccine.
current timeline of 2009-H1N1 vaccine development
is found in Figure 3.
Currently, there are no plans to move forward with
a full-scale production of the 2009-H1N1 vaccine
until production of the seasonal influenza vaccine
is complete. This is due to the fact that seasonal
influenza can cause severe illness and death. The mass
production of the 2009-H1N1 vaccine would have to
be based on several factors which include severity
and spread of the virus, and the vaccine’s safety and
efficacy. A decision to mass-produce the 2009-H1N1
vaccine will occur in the late summer or early fall. If
the vaccine undergoes full production, it will be an
adjunct to the seasonal flu vaccine.
An Update on 2009-H1N1 Vaccine
Production
Our experience with the 2009-H1N1 virus since
its initial presentation in April 2009 has shown us
that overall the virus tends to be mild and people
recover from it quickly. So far the virus has behaved
like the seasonal influenza strain which typically
affects younger people. What makes this novel strain
different is that it is presenting after the seasonal flu
season is ending. Consequently, scientists will be
watching to see if the novel 2009-H1N1 virus will
mutate to a more virulent form, if it will become
As of June 4, 2009, samples of the 2009-H1N1 virus
taken from around the world have been found to be
genetically the same as the virus in the United States.6
Since the viral genetics are the same worldwide, it
makes it easier for researchers to develop a vaccine
for the novel 2009-H1N1 virus. The US government
has allocated $1 billion to develop a vaccine. The
Figure 3. 2009-H1N1 Vaccine Strategy7
U.S. 2009 - H1N1 Vaccine Strategy
Epidemiology of the Virus
VACCINE DEVELOPMENT
Virus
Reference
Strain Prep.
Clinical
Sample
Isolation
Determination of virus severity and transmissibility in populations
U.S.
Congressional
Summer Recess
Master Virus
Seed Prep.
Clinical Investigational
Lot Mfg.
Clinical Studies Antigen and Adjuvant
VACCINE MANUFACTURING
Potency Assay Reagent Prep. and Calibration
Commercial Scale Bulk Antigen Manufacturing Without Adjuvant
Commercial Scale Bulk Antigen Manufacturing With Adjuvant
Bulk Adjuvant Manufacturing
H1N1 2nd Wave
?
Vaccine Formulation Fill Finish
Commercial Scale Syringe/Needles
H1N1 1st Wave
?
Vaccine Distribution & Administration
Immunization Planning
Monitoring Effectiveness & Safety
Seasonal Flu Vaccine
Manufacturing - SH
Seasonal Flu Vaccine
Formulation/Fill Finish Manufacturing - NH
Seasonal Flu Vaccine
Bulk Antigen Mfg. - NH
Seasonal Flu
Northern Hemisphere
2009-10 Season
Seasonal Flu
Southern Hemisphere
2009
Mar 09
Apr 09
May 09
Jun 09
Jul 09
Aug 09
Sept 09
Oct 09
Nov 09
Dec 09
Jan 10
Feb 10
32
33
resistant to antiviral drugs, or if it will be more
contagious than seasonal influenza. Until a 2009H1N1 vaccine becomes available, the best prevention
methods remain respiratory hygiene/cough etiquette
and hand washing.
4 National Institute of Allergy and Infectious
Diseases. NIAID 2009 H1N1 Influenza Research
Program.
http://www3.niaid.nih.gov/topics/Flu/
understandingFlu/2009h1n1.htm. Accessed June
4 2009.
References:
1 Influenza A(H1N1) - update 45. http://www.who.
int/csr/don/2009_06_08/en/index.html. Accessed
June 9 2009.
5 World Health Organization. Vaccines for the new
influenza A (H1N1). http://www.who.int/csr/
disease/swineflu/frequently_asked_questions/
vaccine_preparedness/en/index.html.
Accessed
June 4 2009.
2 Health Day News. 1976 Swine Flu Outbreak Offers
Echoes, Lessons Today. http://www.nlm.nih.gov/
medlineplus/news/fullstory_83760.html. Accessed
June 9 2009.
6 Health Day News. Global Testing Shows No
Variation in Swine Flu Virus. http://www.nlm.
nih.gov/medlineplus/news/fullstory_85223.html.
Accessed June 5 2009.
3 Influenza Virus Vaccine for the 2009-2010 Season.
http://www.fda.gov/BiologicsBloodVaccines/
idanceComplianceRegulatoryInformation/PostMarketActivities/LotReleases/ucm162050.htm.
Accessed June 5 2009.
7 US 2009-H1N1 Vaccine Strategy. https://www.
medicalcountermeasures.gov/BARDA/
documents/h1n1vacstrat508.pdf. Accessed June
4 2009.
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