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Proposed
Preferred Drug List
with
Clinical Criteria
Proposal for TennCare
November 10, 2009
Page 1 of 55
Novmber 10, 2009 Tennessee PAC
Responsibilities of the TennCare Pharmacy Advisory Committee
Source: Tennessee Code/Title 71 Welfare/Chapter 5 Programs and Services for Poor
Persons/Part 24 Tennessee TennCare Pharmacy Advisory Committee/71-5-2401 through 71-52404.
•
•
•
Make recommendations regarding a preferred drug list (PDL) to govern all state expenditures
for prescription drugs for the TennCare program.
o The TennCare Pharmacy Advisory Committee shall submit to the bureau of
TennCare both specific and general recommendations for drugs to be included on
any state PDL adopted by the bureau. In making its recommendations, the
committee shall consider factors including, but not limited to, efficacy, the use of
generic drugs and therapeutic equivalent drugs, and cost information related to each
drug. The committee shall also submit recommendations to the bureau regarding
computerized, voice, and written prior authorization, including prior authorization
criteria and step therapy.
o The state TennCare pharmacy advisory committee shall include evidence-based
research in making its recommendations for drugs to be included on the PDL.
o The TennCare bureau shall consider the recommendations of the state TennCare
pharmacy advisory committee in amending or revising any PDL adopted by the
bureau to apply to pharmacy expenditures within the TennCare program. The
recommendations of the committee are advisory only and the bureau may adopt or
amend a PDL regardless of whether it has received any recommendations from the
committee. It is the legislative intent that, insofar as practical, the TennCare bureau
shall have the benefit of the committee’s recommendations prior to implementing a
PDL or portions thereof.
Keep minutes of all meetings including votes on all recommendations regarding drugs to be
included on the state preferred drug list
The chair may request that other physicians, pharmacists, faculty members of institutions of
higher learning, or medical experts who participate in various subspecialties act as
consultants to the committee as needed.
Page 2 of 55
November 10, 2008 Tennessee PAC
PDL Decision Process
• The primary clinical decision that needs to be made is determining if the drugs within the
therapeutic class of interest can be considered therapeutic alternatives.
• A Therapeutic Alternative is defined by the AMA as: “drug products with different chemical
structures but which are of the same pharmacological and/or therapeutic class, and usually
can be expected to have similar therapeutic effects and adverse reaction profiles when
administered to patients in therapeutically equivalent doses” 1 .
• The Committee should not feel obligated to decide if every drug within the therapeutic class is
exactly equal to all other drugs within the class, nor should they feel obligated to decide if
every drug within the therapeutic class works equally well in every special patient population
or in every disease.
• In special situations (e.g., presence of comorbid conditions) and in special populations (e.g.,
pediatrics) use of a non-preferred drug might be the most appropriate therapy. These cases
can be handled through prior authorization (PA). PA serves as a “safety valve” in that it
facilitates use of the most appropriate agent regardless of PDL status.
Dependent upon diagnosis and length of therapy needed
LENGTH OF AUTHORIZATIONS:
to treat. (Most medications are used chronically, and thus would be approved for 1 year.)
1. Is there any reason the patient cannot be changed to a medication not requiring prior
approval within the same class?
Acceptable reasons include:
ƒ Allergy to medications not requiring prior approval
ƒ Contraindication to or drug-to-drug interaction with medications not requiring prior
approval
ƒ History of unacceptable/toxic side effects to medications not requiring prior approval
2. The requested medication may be approved if both of the following are true:
ƒ If there has been a therapeutic failure of at least two medications within the same
class not requiring prior approval (unless otherwise specified)
ƒ The requested medication’s corresponding generic (if a generic is available and
preferred by the State) has been attempted and failed or is contraindicated
3. The requested medication may be approved if the following is true:
ƒ An indication which is unique to a non-preferred agent and is supported by
peer-reviewed literature or an FDA approved indication exists.
-------------------------------------------------------------------------------------------------------------------------------The information provided for each drug class is organized into the following sections, when
applicable:
BACKGROUND:
• General overview
• Pharmacology
• Therapeutic effect(s)
• Adverse reactions
• Outcomes data
• Place in therapy according to current Treatment Guidelines
RECOMMENDATION:
• General recommendation regarding utility and therapeutic equivalence among the agents
in the class, as well as requirements for product availability (PDL placement)
1
AMA Policy H-125.991 Drug Formularies and Therapeutic Interchange
Page 3 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
REVIEW: NON-STERIODAL ANTI-INFLAMMATORY DRUGS (NSAIDS)
BACKGROUND
•
•
•
Pain is defined as an unpleasant sensory and emotional experience associated with
actual or potential tissue damage. An individual’s reaction to pain and response to pain
management can be highly variable. NSAIDs are commonly used to treat mild to
moderate pain as well as acute and chronic inflammatory conditions.
NSAIDs inhibit cyclooxygenase (COX), impairing the ultimate transformation of
arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. The COX enzyme
can be subdivided into: COX-1 and COX-2. The anti-inflammatory properties of NSAIDs
are associated with the inhibition of COX-2, which is expressed during states of
inflammation. COX-1 is expressed in most tissues and regulates normal cellular
processes including: gastric cytoprotection, vascular homeostasis, platelet aggregation
and kidney function. The inhibition of COX-1 is thought to be associated with the adverse
event profile of NSAIDs.
FDA indications:
Mild to
OA
RA
Moderate
Juvenile
Ankylosing
Dys-
Gouty
Bursitis/
Post
RA
Spondylitis
Menorrhea
Arthritis
Tendonitis
Surgical
Pain
Pain
Single Agents
Diclofenac
a
Epolamine
Diclofenac
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
Potassium
Diclofenac
Sodium
Etodolac
a
Fenoprofen
a
Calcium
Flurbiprofen
Ibuprofen
Indomethacin
Ketoprofen
a
a
a
a
a
Ketorolac
a
Meclofenamate
a
Mefenamic acid
a
a
a
Meloxicam
a
a
Nambutone
a
a
a
a
Oxaprozin
a
a
Piroxicam
a
a
a
a
a
a
Naproxen
a
a
a
a
a
a
a
a
a
a
a
Sodium
Sulindac
Tolmetin sodium
a
a
a
Combination Agent
Diclofenac Sodium/
a
misoprostol
Page 4 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
OA=Osteoarthritis; RA=Rheumatoid arthritis
•
The most common adverse effects seen with NSAIDs include: nausea, dyspepsia,
gastrointestinal (GI) pain, and heartburn. The more severe adverse effects seen with
NSAIDs include: GI ulceration, GI bleeding, worsening of congestive heart failure, and
acute renal failure.
o The NSAID class carries 2 black box warnings. The first is related to increased
cardiovascular (CV) risk (CV thrombotic events, myocardial infarction, and
stroke). The second is related to increased risk of serious GI events (bleeding,
ulceration, or perforation of stomach/intestines)
o Ketorolac carries an additional black box warning:
ƒ For only short term use (therapy should not exceed 5 days due to
increased risks of serious adverse events, including GI ulceration,
bleeding and perforation)
ƒ Review of specific contraindications
ƒ Dose should be adjusted for age and renal function
o All NSAIDs are contraindicated in the following situations:
ƒ Patients with increased GI and CV risk factors.
ƒ Treatment of peri-operative pain in setting of coronary artery bypass graft
(CABG) surgery.
ƒ Patients with known nasal polyps, angioedema or bronchospastic
reactivity to aspirin or other NSAIDs.
o Fenoprofen and mefenamic acid are contraindicated in patients with any preexisting renal disease.
o Ketorolac’s contraindications include: active peptic ulcer disease, recent GI bleed
or perforation, advanced renal disease or risk of renal failure due to volume
depletion, use in labor and delivery, use in nursing mothers, patients at high risk
of bleeding, use as prophylactic analgesic prior to surgery, patients currently
using aspirin, use in epidural or intrathecal injection, and concomitant use of
probenecid.
o There are numerous drug-drug interactions; significant interactions are included
below:
NSAIDs
(all)
NSAIDs
(all)
•
•
•
Interacting
Medication
Anti-platelet
agents, low
molecular weight
heparins, warfarin
Aspirin
Potential Result
NSAIDs used concurrently may result in an
increased risk of bleeding.
NSAIDs may reduce the cardioprotective effect of
low-dose uncoated aspirin and may cause a
higher risk of gastric irritation.
There have been numerous clinical trials conducted evaluating the efficacy and safety of
the NSAIDs. However the majority of literature supporting the use of these agents was
either published decades ago or are lacking in statistical significance and detail. Studies
have shown that no one NSAID has consistently been more efficacious when compared
to the other agents in the class.
One Cochrane meta-analysis of double blind, randomized trials (9 trials) compared 2 or
more NSAIDs in adults with osteoarthritis in the knee. The primary outcome was
withdrawal from therapy due to lack of efficacy. Results demonstrated no difference in
withdrawal rates between etodolac and diclofenac or between etodolac and naproxen.
Another double blind, randomized trial compared meloxicam (7.5mg and 15mg dosage)
to mefenamic acid in female patients with primary dysmenorrhea during their last 3
consecutive menstrual cycles. The primary outcome was reduction in lumbar and
Page 5 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
•
•
•
•
abdomino-pelvic pain from baseline measured by a visual acuity scale (VAS). Results
demonstrated there was a significant decrease in pain from baseline on VAS scale in all
three treatment groups (no P value reported). No statistical difference was shown
between the 2 doses of meloxicam.
Meloxicam is classified as an NSAID agent, however it has been demonstrated that
meloxicam has more COX-II inhibition when compared to other traditional NSAIDs. There
is no current literature demonstrating that meloxicam is more efficacious than traditional
NSAIDs in relief of pain and inflammatory conditions; however due to it’s more selective
COX-II inhibition, fewer GI adverse effects have been demonstrated when compared to
traditional NSAID therapy.
The combination of diclofenac and misoprostol is an additional combination formulation.
Misoprostol is a synthetic prostaglandin analog that acts to protect the gastrointestinal
lining to prevent ulcers from NSAID therapy.
One study evaluated the efficacy of diclofenac sodium/misoprostol in the treatment of
osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in comparison to diclofenac
alone or other NSAIDs (ibuprofen, indomethacin, naproxen and piroxicam). The results
demonstrated that diclofenac sodium/misoprostol is at least as efficacious as other
NSAIDs and is associated with fewer gastroduodenal ulcers than diclofenac alone. In
addition, Gomes et al and Agrawal et al observed that diclofenac sodium/misoprostol has
a lower rate of occurrence of gastric/duodenal ulcers when compared to traditional
NSAIDs.
NSAIDs are among the most commonly prescribed drugs to treat common pain and
inflammatory conditions. There are serious side effects associated with NSAID use
especially at larger doses and when administered chronically, their use should be
monitored closely for safety and efficacy. The American College of Rheumatology
Subcommittee on Osteoarthritis, the Treatment Guidelines for Pain from the Medical
Letter, the Joint Clinical Practice Guideline from the American College of Physician (ACP)
and the American Pain Society (APS) for the treatment of Lower Back Pain all
consistently recommend NSAIDS and APAP as first line therapy for mild to moderate
pain. All current guidelines recommend close monitoring of NSAIDS and other agents for
pain for safety and efficacy. Current guidelines do not give preference to one NSAID
agent over another. Additionally, there are no current head to head trials comparing
topical NSAID agents to oral NSAID agents.
RECOMMENDATION
NSAIDs are widely used to treat mild to moderate pain as well as acute and chronic inflammatory
conditions. The American College of Rheumatology, the ACP and APS all recommend NSAIDs as
first line therapy options for mild to moderate pain. Currently available treatment guidelines do not
give preference to one NSAID over another, but do recommend caution and close monitoring of
patients for efficacy and safety. Specifically, ketorolac is used only for short term management of
moderately severe post-surgical pain, and it has been associated with an increased risk of severe
adverse effects, specifically a black box warning for GI bleeding, renal failure, effects on platelets,
and use in labor, delivery, and nursing. Due to these safety concerns, it is recommended that
ketorolac therapy be reserved to no more than 5 days of therapy. With the exception of ketorolac,
all other NSAID agents have been demonstrated to be similar in efficacy and adverse effects, and
can be considered therapeutic alternatives. In order to ensure adequate prescriber choice, it is
recommended that at least 5 NSAID agents be available for use. There is no evidence to
demonstrate that topical NSAID agents are more effective than oral agents; however the topical
agents can be useful in patients with difficulty swallowing or with poor absorption. Therefore, it is
recommended that topical NSAID agents be available to those with swallowing or absorption
®
difficulties. Given its misoprostol component, Arthrotec is associated with fewer gastroduodenal
ulcers than diclofenac alone; therefore it is recommended that Arthrotec® be available for those at
high risk for GI ulcers.
Page 6 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: NON-STERIODAL ANTIINFLAMMATORY DRUGS (NSAIDS)
PREFERRED
NON-PREFERRED
Arthrotec® CC
Anaprox® (naproxen sodium)
Diclofenac potassium
Anaprox® DS (naproxen sodium)
Cataflam® (diclofenac potassium)
Diclofenac sodium
Clinoril® (sulindac)
Etodolac
Daypro® (oxaprozin)
Etodolac ER
EC-Naprosyn® (naproxen)
Fenoprofen
Feldene® (piroxicam)
Flurbiprofen
Flector® CC, QL (diclofenac epolamine)
Ibuprofen
Meclofen® (meclofenamate)
Indomethacin
QL
Mobic® ST, QL (meloxicam)
Ketorolac
Ketoprofen
Nalfon® (fenoprofen)
Ketoprofen ER
Naprelan® (naproxen sodium ER)
ST, QL
Naprosyn® (naproxen)
Meloxicam
Nabumetone
Ponstel® (mefenamic acid)
Naproxen
Mefenamic acid
Naproxen sodium
Voltaren® (diclofenac sodium)
Voltaren® GelCC (diclofenac sodium)
Oxaprozin
Voltaren® XR (diclofenac sodium)
Sulindac
Tolmetin
Clinical Criteria: Arthotec®
-PA approval not required for patients > 60 years old.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Clinical Criteria: Flector® patch & Voltaren® gel
• Approval will be granted for the following conditions:
-Patient has failed an adequate trial of ORAL generic diclofenac AND at least 1 other preferred
NSAID (to equal a total of at least 2 preferreds), OR
-Patient is unable to swallow/absorb PO medications.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Step Therapy for Mobic®
• Mobic® requires prior authorization for anyone < 60 years of age.
• For patients < 60 years: Prescriptions for Mobic® can be approved for those patients that have
had a therapeutic trial of one month of at least 2 traditional NSAID medications or are at risk
of a GI bleed as noted by one of the following contraindications:
Page 7 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
– History of PUD (peptic ulcer disease)/GI bleed
– GERD (gastroesophageal reflux disease) due to conventional NSAIDS
– Patient on anticoagulants (warfarin/heparin/LMWH)
– Patient on corticosteroids
– Hx of platelet dysfunction or coagulopathy
– Patient on methotrexate
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Quantity Limits
Flector® 2 patches/day
Ketorolac 4 tab/day (not to exceed 5 days duration)
Meloxicam (Mobic®) 7.5 mg tab/1 per day; 15mg tab/2 per day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed October, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed October, 2009.
3. MedMetrics. NSAIDs class review. February 10, 2009.
4. Watson M, Brookes ST, Faulkner A, Kirwan J. Non-aspirin, nonsteroidal antiinflammatory drugs for treating osteoarthritis of the knee. Cochrane Database Syst Rev.
2000;(2):CD000142.
5. De Mello NR, Baracat EC, Tomaz G, et al. Double-blind study to evaluate efficacy and
safety of meloxicam 7.5 mg and 15 mg versus mefenamic acid 1500 mg in the
treatment of primary dysmenorrhea. Acta Obstet Gynecol Scand. 2004 Jul;83(7):66773.
6. Noble S., Balfour JA. Meloxicam. Drugs. 1996;(3): 424-30.
7. Anon. Meloxicam and selective COX-II inhibition: the evidence for improved
gastrointestinal tolerability. Drugs Ther Perspectives. 1996;(8):1-4.
8. American College of Rheumatology Subcommittee on Osteoarthritis: Recommendations
for the Medical Management of Osteoarthritis of Hip and Knee. Arthritis Rheum. 2000
Sep;43(9):1905-15.
9. Medical Letter, Inc. Treatment guidelines from the Medical Letter: Drugs for Pain.
2007;5(56):23-32.
10. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint
clinical practice guideline from the American College of Physicians and the American
Pain Society. Ann Int Med. 2007 Oct 2;147(7):478-91.
11. McKenna F. Diclofenac/misoprostol: the European clinical experience. J Rheumatol
Suppl. 1998 May;51:21-30.
12. Melo Gomes JA, Roth SH, Zeeh J, Bruyn GA, Woods EM, Geis GS. Double-blind
comparison of efficacy and gastroduodenal safety of diclofenac/misoprostol, piroxicam,
and naproxen in the treatment of osteoarthritis. Ann Rheum Dis. 1993 Dec;52(12):8815.
13. Agrawal NM, Caldwell J, Kivitz AJ, et al. Comparison of the upper gastrointestinal safety
of Arthrotec 75 and nabumetone in osteoarthritis patients at high risk for developing
nonsteroidal anti-inflammatory drug-induced gastrointestinal ulcers. Clin Ther. 1999
Apr;21(4):659-74.
Page 8 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
RE-REVIEW: COX-II INHIBITORS
BACKGROUND
• Pain is defined as an unpleasant sensory and emotional experience associated with
actual or potential tissue damage. An individual’s reaction to pain and response to pain
management can be highly variable. NSAIDs are commonly used to treat mild to
moderate pain as well as acute and chronic inflammatory conditions. COX-2 inhibitors
are a newer class of NSAIDs developed to reduce the gastric complications associated
with traditional NSAIDs. Celecoxib is the only COX-II agent currently available.
• The COX-II enzyme is expressed during states of inflammation and pain, celecoxib acts
to selectively inhibit COX-II to provide anti-inflammatory relief.
• Celecoxib is FDA approved for the treatment of:
o Ankylosing spondylitis
o Osteoarthritis
o Rheumatoid and juvenile rheumatoid arthritis (RA)
o Management of acute pain
o Primary dysmenorrhea
o Oral adjunct to patients with familial adenomatous polyposis
• The most common adverse effects seen with COX-II inhibitors include: headache,
nausea, dyspepsia, and diarrhea.
o
The COX-II inhibitors carry two black box warnings: The first is related to
increased cardiovascular (CV) risk (CV thrombotic events, myocardial infarction,
and stroke). The second is related to increased risk of serious GI events
(bleeding, ulceration, or perforation of stomach/intestines)
o
COX-II inhibitors are contraindicated in:
ƒ
Patients with increased GI and CV risk factors.
ƒ
Treatment of peri-operative pain in setting of coronary artery bypass graft
(CABG) surgery.
ƒ
Patients with known nasal polyps, angioedema or bronchospastic
reactivity to aspirin or other NSAIDs.
o
COX-II inhibitors can cause elevations of alanine aminotransferase (ALT) or
aspartate aminotransferase (AST). Caution should be used in patients with liver
dysfunction or active liver disease.
o
Caution should be used with COX-II inhibitors in patients with aspirin sensitive
asthma. Cross-reactivity between celecoxib and aspirin has been reported.
o
There are numerous drug-drug interactions; significant interactions are included
below:
Celecoxib
Celecoxib
Celecoxib
•
Interacting
Medication
ACE inhibitors,
angiotensin II
receptor blockers
(ARBs)
Anti-platelet
agents, low
molecular weight
heparins, warfarin
Diuretics
Potential Result
Celecoxib may decrease the antihypertensive effect
of ACE inhibitors and ARBs and could precipitate
renal failure.
Celecoxib used concurrently may result in an
increased risk of bleeding.
Celecoxib may reduce the effectiveness of diuretics
and cause hyperkalemia or nephrotoxicity.
A double blind, multi-center trial compared celecoxib 100mg or 200mg twice daily with
diclofenac and naproxen twice daily. The trial evaluated 13, 274 patients with
Page 9 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
•
•
•
•
•
•
osteoarthritis of hip, knee or hand for a minimum of 6 months. Primary outcome was
measured as a visual acuity scale (VAS) of efficacy of management of signs/symptoms of
osteoarthritis (OA). Secondary outcomes were defined as gastrointestinal (GI) adverse
effects. Results demonstrated clinical efficacy of relief of signs and symptoms were
comparable among the two doses of celecoxib, diclofenac and naproxen (no P value
reported). Significantly more upper GI events were reported with the NSAID group
compared to the celecoxib groups (P=0.004).
Another double blind, randomized trial evaluated 8,059 patients with a diagnosis
rheumatoid arthritis (RA) or OA for a minimum of 3 months. The trial compared celecoxib
vs ibuprofen vs diclofenac, all patients were allowed to take aspirin for cardiovascular
protection. The primary outcome was defined as incidence of symptomatic GI ulcers and
ulcer complications (bleeding, perforation, obstruction). For all patients, the annualized
incidence rates of upper GI ulcer complications alone and combined with symptomatic
ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P=0.09) and 2.08% vs 3.54%
(P=0.02), respectively. For patients not taking aspirin, the annualized incidence rates of
upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib
vs NSAIDs were 0.44% vs 1.27% (P=0.04) and 1.40% vs 2.91% (P=0.02). Fewer
celecoxib treated patients than NSAID-treated patients experienced chronic GI blood
loss, GI intolerance, hepatotoxicity, or renal toxicity (no P value reported).
A double blinded, parallel group trial compared celecoxib to diclofenac in 655 patients
with adult onset RA. Primary endpoints were reported as number of swollen joints and
number of tender/painful joints per patient and physician assessment. Results
demonstrated the mean number of tender or painful or swollen joints decreased over time
in the two groups. The difference between treatment groups was not significant at any
time, apart from week 16, when the number of tender or painful joints was significantly
lower in the celecoxib treatment group (P<0.05). There were significantly more gastroduodenal ulcers in the group receiving diclofenac than in the celecoxib arm (34% vs 18%;
P<0.001). GI-related adverse events occurred in 48% of those taking diclofenac and 36%
of those taking celecoxib (P<0.05).The rate of withdrawal because of GI adverse effects
was 16% for diclofenac versus 6% for celecoxib (P<0.001).
Clinical trials have also been published evaluating the efficacy of celecoxib vs placebo for
the prevention of colorectal cancer in patients with familial adenomatous polyposis (FAP).
However, current clinical guidelines including the American Society of Colon and Rectal
Surgeons do not specifically address the use of COX-II inhibitors in their practice
parameters for colorectal cancer.
For the treatment of pain, OA and RA, current clinical guidelines include NSAID therapy
as a treatment option. The American College of Rheumatology Subcommittee on
Osteoarthritis, the Treatment Guidelines for Pain from the Medical Letter, the Joint
Clinical Practice Guideline for the treatment of Lower Back Pain from the American
College of Physician (ACP) and the American Pain Society (APS) all consistently
recommend NSAIDS and acetaminophen (APAP) as first line therapy for mild to
moderate pain. Additionally, the American College of Rheumatology Subcommittee on
Osteoarthritis recommends use of COX-II inhibitors in patients at increased risk of severe
GI adverse events. All current guidelines recommend close monitoring of NSAIDS and
other agents for pain for safety and efficacy. Current guidelines do not give preference to
one NSAID or COX-II agent over another. With the exception of the American College of
Rheumatology Subcommittee on Osteoarthritis the guidelines do not separate the NSAID
agents from the COX-II inhibitors.
In 2004 and 2005, rofecoxib and valdecoxib were voluntarily withdrawn from the market
due to safety concerns of an increased risk of cardiovascular events. Clinical studies
demonstrated increasing cardiovascular risk with COX-II therapy. Celecoxib data and
other meta analyses showed increased cardiovascular risk as well but at higher dosages
(400mg and greater). Subsequently the FDA issued a request for labeling updates to all
NSAIDS and COX-II agents addressing these cardiovascular risk concerns.
The American Heart Association (AHA) issued a statement to health care providers in
regards to use of all NSAID and COX-II agents. The AHA recommends a step approach
Page 10 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
•
therapy with NSAID or COX-II inhibitors in patients with cardiovascular disease or
patients who are at risk for cardiovascular events. AHA recommends nonpharmacological therapy (physical therapy, heat/cold therapy, etc.) first, then
acetaminophen, salicylates and narcotic analgesics. If it is determined that a patient
needs anti-inflammatory therapy, non-COX-II NSAIDs are recommended first, then
NSAIDs with some COX-II activity, and lastly COX-II selective NSAIDs. AHA
recommends health care providers utilize the lowest dose of COX-II agents that is
effective and not to exceed 200mg daily of celecoxib. Additionally, the AHA also
recommends stopping all NSAIDs and COX-II inhibitors at the onset of unstable angina
or myocardial infarction.
Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is more selective for
cyclooxygenase-2 (COX-2) and has demonstrated lower rates of gastrointestinal adverse
effects, as well as an absence of effects on platelet aggregation, compared to other nonselective NSAIDs. There is concern over the long-term safety of celecoxib on
gastrointestinal as well as cardiovascular events; these concerns are still being
addressed. The use of celecoxib should be limited to patients who are at high risk of
gastrointestinal side effects or to patients who cannot tolerate traditional NSAIDs.
RECOMMENDATION
Celecoxib is an NSAID agent that is more selective for cyclooxygenase-2 (COX-2) and has
demonstrated a lower incidence of GI adverse effects as well as a lesser effect on platelet
aggregation than other non-selective NSAIDs. Current clinical guidelines, with the exception of
those from the American College of Rheumatology Subcommittee on Osteoarthritis, all
consistently recommend the NSAID class as a first line therapy option for mild to moderate pain
and do not give preference to one NSAID or COX-II agent over another. The American College of
Rheumatology Subcommittee on Osteoarthritis recommends use of COX-II inhibitors in patients at
increased risk of severe GI adverse events. Clinical studies have demonstrated that COX-II
inhibitors are as effective as traditional NSAID agents in regards to treatment of pain and
inflammatory conditions, but offer a more favorable gastrointestinal side effect profile. However,
due to ongoing safety concerns of increased risk of cardiovascular events the use of celecoxib
should be limited to patients who are at high risk of gastrointestinal side effects or to patients who
cannot tolerate traditional NSAIDs. Therefore, it is recommended that celecoxib be available for
use but be subject to step therapy criteria.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
PREFERRED
Celebrex ® ST, QL
APPROVED with MODIFICATION
RE-REVIEW: COX-II INHIBITORS
NON-PREFERRED
N/A
Step Therapy for Celebrex®
• All COX II inhibitors require prior authorization for anyone < 60 years of age.
• For patients < 60 years: Prescriptions for COX-II inhibitors can be approved for those patients
that have had an adequate trial therapeutic trial of one month of at least two traditional NSAID
medications or are at risk of a GI bleed as noted by ANY one of the following contraindications:
– History of PUD (peptic ulcer disease)/GI bleed
– GERD (gastroesophageal reflux disease) due to conventional NSAIDS
– Patient on anticoagulants (warfarin/heparin/LMWH)
– Patient on corticosteroids
– Hx of platelet dysfunction or coagulopathy
Page 11 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
– Patient on methotrexate
• Celebrex® for moderate to severe pain: Doses should be kept to ≤ 200mg per day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Quantity Limits: Celebrex®
Celebrex® 50 mg/2 per day
100mg/2 per day
200mg/2 per day
400mg/2 per day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed October, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed October, 2009.
3. Medmetrics. Cox-II inhibitors class review. February 1, 2009.
4. Singh G, Fort JG, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis
patients: success-I study. American Journal of Medicine. 2006;119:255-66.
5. Silverstein FE, Faich G, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal
anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis, the CLASS study.
JAMA. 2000;284(10):1247-55.
6. Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term
management of rheumatoid arthritis: randomized double-blind comparison. Lancet.
1999;354:2,106-11.
7. American College of Rheumatology Subcommittee on Osteoarthritis: Recommendations
for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000
Sep;43(9):1905-15.
8. Medical Letter, Inc. Treatment guidelines from the Medical Letter: Drugs for Pain.
2007;5(56):23-32.
9. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint
clinical practice guideline from the American College of Physicians and the American
Pain Society. Ann Int Med. 2007 Oct 2;147(7):478-91.
10. Solomon SD, Pfeffer MA, McMurray JJ, et al. Effect of celecoxib on cardiovascular
events and blood pressure in two trials for the prevention of colorectal adenomas.
Circulation. 2006;114: 1028-35.
11. Antman EM, Bennett JS, Daugherty A, Furberg C, Use of Nonsteroidal Antiinflammatory
Drugs: An Update for Clinicians: A Scientific Statement From the American Heart
Association. Circulation 2007;115;1634-1642; originally published online Feb 26, 2007;
available at: http://circ.ahajournals.org/cgi/content/full/115/12/1634.
12. 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. J Am
Coll Cardiol 2008;51:210-247.
13. 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. J
Am Coll Cardiol 2007;50:e1-e157.
Page 12 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
RE-REVIEW: NON-NARCOTIC ANALGESICS
BACKGROUND
•
•
•
•
•
Pain is defined as an unpleasant sensory and emotional experience associated with
actual or potential tissue damage. An individual’s reaction to pain and response to pain
management can be highly variable. Pain thresholds vary greatly between patients and
responses to therapy will vary between persons and may vary within the same patient.
Short acting opioids are a primary treatment option for moderate or severe pain
associated with a number of etiologies. Tramadol is a centrally acting synthetic opioid
analgesic used for the treatment of varying types of pain including moderate to
moderately severe pain as well as acute pain.
Tramadol’s primary mechanism of action is not completely understood but it is believed to
exhibit two complementary mechanisms of action: the binding to µ-opioid receptors and
weak inhibition of re-uptake of norepinephrine and serotonin.
FDA approved indications:
o Immediate release: management of moderate to moderately severe pain
o Extended release: management of moderate to moderately severe chronic pain
in adults who require around the clock treatment of pain for an extended period
of time
o Combination with acetaminophen: short term (less than 5 days) management of
acute pain.
The most common adverse effects reported with tramadol include: dizziness, headache,
somnolence, constipation, and nausea.
o Tramadol is contraindicated in patients with concomitant use of any other
significant CNS depressants (alcohol, hypnotics, narcotics, opioids, other
psychotropic agents); tramadol can worsen CNS depression and respiratory
depression.
o Caution should be used in patients with existing hepatic disease; tramadol can
cause increases in liver function tests.
o Tramadol should be used with caution in patients with pre-existing respiratory
impairments, tramadol can cause respiratory depression.
o Tramadol should be used with caution in patients with history of seizure disorder;
seizures have been reported with concomitant use of tramadol and SSRI’s,
tricyclic antidepressants, or MAOI’s.
o Tramadol usage should be monitored closely for possible abuse, addiction or
diversion, especially in patients requiring long term use.
o Significant Drug-Drug Interactions:
Tramadol Carbamazepine
Carbamazepine increases
tramadol metabolism possibly
resulting in significantly reduced
analgesic effect.
Tramadol CYP2D6 inhibitors
Concomitant administration may
lead the inhibition of the
metabolism of tramadol.
Tramadol Serotonin reuptake Additive serotonergic effects of
Inhibitors
tramadol when co-administered
with serotonin reuptake inhibitors
may result in serotonin syndrome.
Tramadol has been studied for the treatment of pain due to a number of underlying
conditions. Overall, tramadol and tramadol containing products appear more effective
than placebo. However the results are mixed when compared to other pain relief
therapies. There are currently no head to head comparisons of Ryzolt® versus Ultram
Page 13 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
•
•
•
•
ER®. The primary difference between the formulations is their pharmacokinetic profiles.
Ryzolt® achieves peak concentration and steady state more quickly than Ultram ER®.
One prospective trial compared tramadol versus diclofenac in patients with posttonsillectomy pain. Primary endpoint was defined as analgesic efficacy measured by
visual acuity score (VAS) pain scores. Average VAS pain scores for the 14 days did not
differ significantly. (Diclofenac group: mean 38.4, tramadol group mean 37.8, P=0.66)
Another randomized trial compared tramadol/APAP versus codeine/APAP in adults with
chronic nonmalignant low back pain, osteoarthritis pain or both (N=462). Primary
endpoint was efficacy (measured by patient reported pain relief and pain intensity using
Likert scales, and overall efficacy as reported by investigators). Secondary endpoint was
safety. Mean total pain relief (TOTPAR) scores and mean pain intensity difference from
baseline (SPID) scores were similar for tramadol/APAP and codeine/APAP at each visit.
(no P values reported) The percentage of patients requiring supplemental ibuprofen at
any point was comparable between the 2 groups and ranged from 21% to 30% for each
week of the study. The mean duration of therapy was 25.5 days for tramadol/APAP and
25.0 days for codeine/APAP (no P values reported). The overall rates of treatmentemergent adverse events were comparable for the 2 groups, 71% of the tramadol/APAP
and 76% of the codeine/APAP treated patients reported adverse events. Somnolence
(24%) and constipation (21%) were significantly more common in the codeine/APAP
group than in the tramadol group (17% and 11%; P=0.05 and P<0.01, respectively).
A randomized multicenter trial compared tramadol/APAP to hydrocodone/APAP to
placebo in patients with ankle sprain diagnosed by ligament tear, N=709. The primary
endpoint was total pain relief (defined by visual analog scale [VAS]). The tramadol/APAP
and hydrocodone/APAP groups provided greater total pain relief than placebo
(tramadol/APAP mean score 6.6, hydrocodone/APAP score 6.8, placebo score 5.4,
P=<0.001). There were no statistically significant differences in total pain relief when
comparing tramadol/APAP to hydrocodone/APAP.
Tramadol is a unique analgesic in that it possesses both opiate and noradrenergic
qualities. In clinical trials it appears to be as effective as non-steroidal anti-inflammatory
drugs (NSAIDS) and mild opiates in the relief of pain due to various causes. The
American College of Rheumatology (ACR) Subcommittee on Osteoarthritis, recommends
pharmacologic therapy to begin with acetaminophen (APAP) or non-steroidal antiinflammatory (NSAID) agents as first line. If no adequate response to first line therapy,
the guidelines recommend tramadol as an alternative agent if patients cannot tolerate
NSAIDs or more selective NSAIDs, such as cyclooxygenase (COX)-II inhibitors. The
American College of Physicians (ACP) guidelines for Diagnosis and Treatment of Lower
Back Pain also include tramadol and opioid analgesics as treatment options when
patients have failed APAP or NSAID therapy. Additionally, the World Health Organization
(WHO) has developed a “pain ladder” for treatment of cancer pain; however the ladder
characteristics have been applied to all types of pain scenarios. The ladder recommends
three steps: step one includes treatment with nonopioids (APAP and NSAIDs), step two
includes treatment with mild opioids (codeine and tramadol) and step three includes
treatment with strong opioids (morphine, oxycodone, etc). Compared to opiate agents,
tramadol and tramadol containing products may be better tolerated and have less side
effects. Additionally, these agents may have less dependence and abuse potential than
opiate agents.
RECOMMENDATION
Tramadol is a centrally acting synthetic opioid analgesic. Tramadol is a unique analgesic in that it
possesses both opiate and noradrenergic qualities. Tramadol plays a role in the treatment of both
acute and chronic pain. When compared to opiate agents, tramadol may be better tolerated, have
lesser side effects and may have a lower potential for abuse and psychological/physical
dependence when used short term. However, cases of abuse and dependence have occurred and
patients should be monitored closely for efficacy and misuse, especially in the setting of long term
use. Current clinical guidelines consistently recommend use of tramadol when treatment with
APAP and NSAIDs are not adequate or contraindicated. Clinical trials have demonstrated efficacy
Page 14 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
in treating pain due to a number of etiologies Therefore, it is recommended that at least one
tramadol-containing analgesic be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: NON-NARCOTIC ANALGESICS
PREFERRED
NON-PREFERRED
tramadolQL (compares to Ultram®)
RyzoltTM QL (tramadol extended release)
Tramadol/APAPQL
Ultracet® QL (Tramadol/APAP)
Ultram® QL (tramadol)
Ultram ER® QL (tramadol extended release)
Quantity Limits
RyzoltTM 1 tab/day
Tramadol 8 tabs/day
Tramadol/APAP 8 tabs/day
Ultracet® 8 tabs/day
Ultram® 8 tabs/day
Ultram ER® 1 tab/day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed October, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed October, 2009.
3. MedMetrics. Non-Narcotic Analgesics class review. 02/04/2009.
4. Courtney MJ, Cabraal D. Tamadol vs. diclofenac for post tonsillectomy analgesia. Arch
Otolaryngol Head Neck Surg. 2001;127:385-8.
5. Mullican WS, Lacy JR. Tramadol/acetaminophen combination tablets and
codeine/acetaminophen combination capsules for the management of chronic pain: A
comparative trial. Clin Ther. 2001;23:1429-45.
6. Hewitt DJ, Todd KH, Xiang J. et al. Tramadol/Acetaminophen or
Hydrocodone/Acetaminophen for the Treatment of Ankle Sprain: a randomized,
placebo-controlled trial. Ann Emerg Med. 2007;49:468-80.
7. American College of Rheumatology Subcommittee on Osteoarthritis: Recommendations
for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000
Sep;43(9):1905-15.
8. American College of Physicians (ACP): Guidelines for the diagnosis and treatment of
low back pain. [Guideline on the internet]. [Cited 2009 Jan 28]. Available from:
www/annals.org/cgi/content/full/147/7/478. 2007.
9. WHO’s pain ladder. The World Health Organization. Available from:
http://www.who.int/cancer/palliative/painladder/en/ (Accessed October 2009).
Page 15 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
RE-REVIEW: SHORT ACTING NARCOTICS
BACKGROUND
•
•
•
•
•
•
•
•
Pain is defined as an unpleasant sensory and emotional experience associated with
actual or potential tissue damage. An individual’s reaction to pain and response to pain
management can be highly variable. Pain thresholds vary greatly between patients and
responses to therapy will vary between persons and may vary within the same patient.
Short acting opioids are a primary treatment option for moderate or severe pain
associated with a number of etiologies.
Opioid agonists exert their mechanism of action through opioid receptors: mu, kappa, and
delta.
The mu receptor is considered the classic opioid receptor. Stimulation of the mu receptor
produces analgesia, euphoria, decreased gastrointestinal (GI) motility, respiratory
depression, sedation, nausea, tolerance and physical dependence.
Stimulation of the kappa receptor produces analgesia, dysphoria, psychotomimetic
effects, and respiratory depression.
Stimulation of the delta receptor produces analgesia without respiratory depression.
Tapentadol inhibits reuptake of norepinephrine in addition to its effects on the mu
receptor.
Opioids are available as single agents and as combination products along with aspirin,
acetaminophen, ibuprofen, caffeine, and butalbital.
FDA-Approved indications include:
Mild to
Moderate
Pain
Single Agents
Codeine
Hydromorphone
Meperidine
Morphine immediate release (IR)
Oxycodone
Oxymorphone
Propoxyphene
Propoxyphen napsylate
Tapentadol
Combination Agents
Codeine/acetaminophen (APAP)
Codeine/APAP/caffeine/butalbital
Codeine/aspirin (ASA)
Codeine/ASA/caffeine/butalbital
Dihydrocodone/ASA/caffeine
Dihydrocodone/APAP/caffeine
Hydrocodone/APAP
Hydrocodone/ibuprofen
a
a
a
•
Other
a
a
a
a
a
Post-operative pain
a
a
a
a
a
a
a
a
Oxycodone/APAP
Oxycodone/ASA
Oxycodone/ibuprofen
Propoxyphene/APAP
Propoxyphene/ASA/caffeine
Propoxyphene napsylate/APAP
Moderate
to Severe
Pain
a
a
Tension Headache
Tension Headache
Short term management
of acute pain
Short term management
of acute pain
a
a
a
The most common adverse effects seen with opioid agonists include: nausea, vomiting,
sedation, constipation, dizziness, and lightheadedness. More severe adverse effects
Page 16 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
include: bradycardia, palpitations, syncope, disorientation, hallucinations, weakness, and
bronchospasm.
o Black Box warnings:
ƒ Propoxyphene: related to fatal reactions when used in combination with
other CNS depressant drugs, alcohol, or tranquilizers; caution in patients
who are suicidal or addiction prone.
ƒ NSAID-containing products: related to increased risk of serious
cardiovascular thrombotic events, myocardial infarction and stroke.
o Short acting opioid agonists are contraindicated in patients with significant
respiratory depression.
o Short acting opioids should be used with caution in patients with pre-existing
respiratory impairments: asthma, chronic obstructive pulmonary disease (COPD).
o Short acting opioids can affect cerebrospinal fluid and should be used with
caution in patients with head injuries, intracranial lesions or elevated intracranial
pressure.
o Short acting opioids can affect a patient’s hemodynamic status. Caution should
be used in patients with depleted blood volume or concurrent use of drugs that
affect vasomotor tone.
o All short acting opiate usage should be monitored closely for possible abuse,
addiction or diversion.
o Use of all short acting opiates and concomitant CNS depressants should be
avoided and/or used with extreme caution.
o Specifically, propoxyphene and its active metabolite can cause significant CNS
effects such as: lightheadedness, dizziness, sedation, and dysphoria (these
effects are more pronounced in elderly patients and use of propoxyphene should
be avoided in this population.)
o Tapentadol should be used with caution when administered with other
serotonergic agents because of increased risk of serotonin syndrome
o There are numerous potential drug interactions with short acting opioids.
Significant drug-drug interactions include:
Drug
All agents
Hydrocodone,
Meperidine,
Morphine,
Oxycodone,
Tapentadol
All agents
•
•
Interacting
Medication
CNS
depressants
Monoamine
oxidase
inhibitors
(MAOIs)
Anti-cholinergics
Potential Result
May produce additive depressant effects.
Respiratory depression, hypotension and
profound sedation or coma may occur.
MAOIs may intensify the effects of opioid
drugs causing increased anxiety, confusion,
and significant depression of respiration or
coma.
Concurrent use may produce increased
urinary retention and/or constipation.
Short acting narcotics have been studied in a number of clinical trials to evaluate and
compare analgesic effects in the treatment of pain. Clinical trials have shown their
efficacy in treating pain due to a number of etiologies. However, no one short acting
narcotic has continuously proven to be more effective than another when given at
equipotent doses.
One double blind, randomized trial evaluated pain relief of 300 patients who were status
post total hip or knee replacement surgery. Patients received oxymorphone IR (10, 20, or
30mg) or oxycodone IR (10mg) or placebo. Primary outcomes were measured as total
pain relief (TOTPAR), sum of pain intensity differences (SPID), and sum of combined
pain relief and pain intensity differences (SPRID) at 4, 6, and 8 hours. Fifty percent pain
relief was achieved by 90% of patients in the oxymorphone IR 20 mg group (P<0.001),
Page 17 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
•
•
•
•
82% of patients in the oxymorphone IR 10 mg group (P=0.022), 77% in the oxymorphone
IR 30 mg group (P value not significant), and 69% in the oxycodone IR 10 mg group (P
value not significant). The incidence of adverse events was more frequent among the
oxymorphone IR groups than in the oxycodone IR 10 mg group (39% to 50% versus
27%).
A parallel group, double blinded, randomized clinical trial compared use of
codeine/acetaminophen (CA) and hydrocodone/acetaminophen (HA) in 121 patients with
chronic and moderate cancer pain. Primary outcome was measured as proportion of
patients who achieved pain relief. Overall, 39/59 (66%) patients who received CA therapy
and 44/62 (71%) patients who used HA therapy experienced pain relief (P=0.69). The
most common adverse events in the CA and HA groups were constipation, dizziness,
vomiting, and dry mouth. None of the differences between adverse events in the 2
groups were statistically significant.
A double blind, randomized trial compared tapentadol 50mg and 75 mg to oxycodone
10mg and placebo in patients who were candidates for primary joint replacement surgery
as the result of end-stage degenerative joint disease (N=674). Primary endpoint was 5
day sum of pain intensity differences (SPID). Secondary endpoints included reductions in
pain intensity, reductions in pain relief (PR), safety, and tolerability. Both tapentadol
treatment groups had a significant reduction in pain intensity compared with placebo
(both P<0.0001). Both tapentadol treatment groups had significant reductions in pain
intensity, with increasing 2- and 10-day SPID values (all P<0.001). Both tapentadol 50
mg and 75 mg provided analgesic efficacy that was noninferior to that of oxycodone.
Overall PR status was rated as “very much improved” or “much improved” by 49% and
42% of tapentadol 50 mg and 75 mg groups (both P<0.001 vs placebo). The incidence of
selected gastrointestinal adverse events was significantly lower for both doses of
tapentadol compared with oxycodone (P<0.001 for all events). The incidence of
nausea/vomiting and constipation were significantly less when compared to oxycodone,
For tapentadol 50 mg vs oxycodone the odds ratio (OR) was 0.21 (95% CI, 0.128 to
0.339) for the composite nausea/vomiting, and the OR for the incidence of constipation
was 0.13 (95% CI, 0.057 to 0.302). For tapentadol 75 mg, the OR vs oxycodone was
0.32 for the composite of nausea/vomiting (95% CI, 0.204 to 0.501) and 0.20 for
constipation (95% CI, 0.098 to 0.398). A post hoc analysis found a significant difference
in the percentage of patients who discontinued treatment between the tapentadol 50 mg
group and the oxycodone group (P<0.001); rates of discontinuation did not differ
significantly between the tapentadol 75 mg and oxycodone groups (P value not reported).
Gastrointestinal and central nervous adverse events were the primary reason for study
discontinuation.
Another multicenter trial compared tapentadol with oxycodone in patients with a minimum
3 month history of lower back pain, or osteoarthritis of knee or hip (n=849). Primary
endpoints were adverse events, tolerability, and withdrawal symptoms. Secondary
endpoint was efficacy. A smaller proportion of patients treated with tapentadol
experienced treatment-emergent adverse events compared to those receiving oxycodone
(76.3% vs 82.9%; P value not reported). Gastrointestinal, nervous system, and skin
adverse events were the most common treatment-emergent adverse events. Patients in
the tapentadol group experienced less nausea (10.3% vs 21.8%) and vomiting (3.5% vs
12.9%) compared to oxycodone on day 2 (P values not reported). After more than three
weeks, the incidences of vomiting diminished to similar, low levels in both treatment
groups, however there was a consistently higher frequency of nausea over the entire
study with oxycodone. There were no relevant changes in laboratory, urinalysis, vital
signs, or ECG findings among patients in the two treatment groups. Withdrawal
symptoms, measured by the clinical opioid withdrawal score (COWS), which were only of
mild to moderate intensity, were detected in a significantly lower percentage of patients in
the tapentadol group compared to the oxycodone group (17.0% vs 29.0%; P<0.05).
Tapentadol has been shown to be superior to placebo and demonstrated noninferiority to
immediate release oxycodone in the management of moderate to severe pain. Therapy
with tapentadol may have a more favorable side effect profile, specifically in terms of the
Page 18 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
•
•
•
•
incidence of gastrointestinal adverse events, compared to placebo or immediate release
oxycodone. With the exception of tapentadol, the short acting opioids are similar in their
adverse effects and many of the adverse effects subside with continued dosing as
tolerance builds.
The American Pain Society (APS) Guidelines for Use of Chronic Opioid Therapy in NonCancer Pain state that opioid therapy is a treatment option for non-cancer pain but should
be used with caution. The APS specifically recommends practitioners monitor patients
closely for efficacy, aberrant behavior, and medication side effects. The APS guidelines
do not recommend one agent over another. A Joint Clinical Practice Guideline for
Treatment of Lower Back Pain from the APS and the American College of Physicians
(ACP) recommends opioids as second line therapy after acetaminophen and nonsteroidal anti-inflammatory drugs. The APS/ACP Practice Guideline does not recommend
one agent over another. Additionally, the World Health Organization (WHO) has
developed a “pain ladder” for treatment of cancer pain; however the ladder characteristics
have been applied to all types of pain scenarios. The ladder recommends three steps:
step one includes treatment with nonopioids (APAP and NSAIDs), step two includes
treatment with mild opioids (codeine and tramadol) and step three includes treatment with
strong opioids (morphine, oxycodone, etc).
In January 2009, in a joint advisory meeting, the Anesthetic and Life Support Drugs
Committee and the Drug Safety and Risk Management committees, voted on a
recommendation to advise the FDA to consider withdrawal of propoxyphene from the
market due to lack of efficacy and significant safety issues.
o Two meta analyses included in the FDA’s advisory review, concluded that
propoxyphene is a weak analgesic, information related to propoxyphene’s
efficacy is limited, and when compared to acetaminophen there are varying
reports of efficacy.
o No current head to head comparisons of propoxyphene and other oral analgesics
or current efficacy data are available. The available information is dated and
lacks the desired statistical significance needed to demonstrate propoxyphene’s
efficacy when compared to other analgesics. Several older studies concluded
that propoxyphene napsylate/APAP was only slightly better than acetaminophen
in the setting of post-surgical dental pain, and in the setting of postpartum
episiotomy pain acetaminophen was statistically better than propoxyphene alone
(no P values available).
Subsequently in July 2009, the FDA decided not to withdraw propoxyphene from the
market. The FDA ruled to require strengthening of the labeling requirements of
propoxyphene products to emphasize the risks associated with over dosage. Additionally,
manufacturers were also required to provide patients with medication guides stressing
the importance of appropriate use.
Opioid agents are a primary class of drugs used in pain management with short acting
opioid agents playing a key role in the treatment of acute pain and breakthrough pain in
patients with chronic pain. Clinical trials have demonstrated efficacy in treating pain due
to a number of etiologies. However, no one agent has continuously proven to be more
effective than another when given at equipotent doses.
RECOMMENDATION
Opioid agents are a primary class of drugs used in pain management with short acting opioid
agents playing an important role in the treatment of acute pain and breakthrough pain in patients
with chronic pain. With the exception of trials involving propoxyphene, clinical trials have
consistently demonstrated the efficacy of short acting opioid agents, and studies comparing the
various short acting opioids have demonstrated that no one single agent is definitively superior
over the other agents in the class. The short acting opioids are similar in their adverse effects and
many of the adverse effects subside with continued dosing as tolerance builds. Currently
available clinical guidelines recommend use of the short acting opioid agents for acute pain and
chronic breakthrough pain. The guidelines recommend monitoring patients closely for efficacy,
misuse and adverse effects, but do not recommend one agent over another. Therefore, it is
Page 19 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
recommended that at least 2 unique single agent short acting opioids and at least 2 unique
combinations of short acting opioids be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: SHORT ACTING NARCOTICS
PREFERRED
NON-PREFERRED
Codeine QL
Balacet® QL (Propoxyphene napsylate/APAP)
Codeine/APAP QL
Capital with Codeine® QL (codeine/APAP)
QL
Codeine/APAP/caffeine/butalbital
Combunox® QL (oxycodone/IBU)
QL
Codeine/ASA/caffeine/butalbital
Cocet® QL (Codeine/APAP)
® QL
(hydrocodone/APAP)
Co-gesic
Darvon® QL (propoxyphene)
® QL
Endocet
(oxycodone/APAP)
Darvon-N® QL (propoxyphene napsylate)
® QL
(oxycodone/ASA)
Endodan
Darvocet ® QL A500 (propoxyphene napsylate/APAP)
QL
Hydrocodone/APAP
Darvocet-N® QL 100(propoxyphene napsylate/APAP)
QL
Hydrocodone/Ibuprofen
Demerol® QL (meperidine)
® QL
(hydrocodone/APAP)
Hydrocet
Dilaudid® QL (hydromorphone)
® QL
(hydrocodone/APAP)
Hydrogesic
Fioricet® with Codeine QL (cod/APAP/caff/butalbital)
QL
Hydromorphone
Fiorinal® with Codeine QL (cod/ASA/caff/butalbital)
® QL
(Hydrocodone/Ibuprofen)
Ibudone
Hycet® QL (hydrocodone/APAP)
® QL
(hydrocodone/APAP)
Margesic
Lorcet® QL (hydrocodone/APAP)
QL
Meperidine
Lortab® QL (hydrocodone/APAP)
® QL
(meperidine)
Meperitab
Maxidone® QL (hydrocodone/APAP)
QL
Morphine IR
Magnacet® QL (oxycodone/APAP)
QL
Oxycodone
Norco® QL (hydrocodone/APAP)
QL
Oxycodone/APAP
Nucynta TM, QL (tapentadol)
QL
Oxycodone/ASA
Opana® QL (oxymorphone)
QL
Oxycodone/IBU
OxyIR® QL (oxycodone)
® QL
Polygesic
(hydrocodone/APAP)
Panlor® DC QL (APAP/caffeine/dihydrocodeine)
QL
propoxyphene
Panlor® SS QL (APAP/caffeine/dihydrocodeine)
QL
Propoxyphene/APAP
Percocet® QL (oxycodone/APAP)
QL
Propoxyphene napsylate/APAP
Percodan® QL (oxycodone/ASA)
® QL
QL
(hydrocodone/IBU)
Reprexain
Primalev® QL (oxycodone/APAP)
® QL
(oxycodone/APAP)
Roxicet
Roxanol® QL (morphine)
® QL
(hydrocodone/APAP)
Stagesic
Roxicodone® QL (oxycodone)
® QL
(APAP/caffeine/dihydrocodeine)
Trezix
Tylenol® with Codeine QL (APAP/codeine)
® QL
(hydrocodone/APAP)
Vanacet
Tylox® QL (oxycodone/APAP)
® QL
HP (hydrocodone/APAP)
Vicodin
Vicodin® QL (hydrocodone/APAP)
Vicoprofen® QL (hydrocodone/IBU)
Vopac® (APAP/codeine)
Xodol® QL (hydrocodone/APAP)
Xolox® QL (oxycodone/APAP)
Zamicet® QL (hydrocodone/APAP)
Zydone® QL (hydrocodone/APAP)
ZerLor® QL (APAP/caffeine/dihydrocodeine)
Quantity Limits
For all hydrocodone and oxycodone products*: QL=1200mg/month, and 4 grams APAP/day
Meperidine* (Demerol): QL = 30 ampules per month; 6 tab/day
*The QL for these 3 products is determined based on recommendations from the Short Acting Narcotics
committee (April 2008)
Page 20 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
Quantity Limits
Codeine
Codeine/APAP
Codeine/APAP/caffeine/butalbital
Codeine/ASA/caffeine/butalbital
APAP/caffeine/dihydrocodeine
Hydromorphone
Morphine IR
NucyntaTM (tapentadol)
Propoxyphene
Propoxyphene/APAP
Opana (oxymorphone)
15mg 6 tab/day
30 mg 6 tab/day
60mg 12 tab/day
15/300mg 6 tab/day
30/300mg 6 tab/day
60/300mg 12 tab/day
6 tab/day
6 tab/day
Capsules (as Panlor® DC & Trezix® ) 10/day
Tablets (as Panlor® SS & ZerLor® ) 5/day
2mg 8 tab/day
4mg 8 tab/day
8mg 8 tab/day
15mg 6 tab/day
30mg 6 tab/day
50mg 6 tab/day
75mg 6 tab/day
100mg 6 tab/day
65mg 6 tab/day
100mg 6 tab/day
50/325mg 12 tab/day
65/650mg 6 tab/day
100/500mg 6 tab/day
1200mg/month
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed March, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. March, 2009.
3. MedMetrics. Short-acting narcotics class review. February 11, 2009.
4. International Association for the Study of Pain. IASP Pain Terminology. Accessed
December 29, 2008 at http://www.iasp-pain.org/terms-p.html#Pain.
5. Gimbel J, Ahdieh H. The efficacy and safety of oral immediate-release oxymorphone for
postsurgical pain. Anesth Analog. 2004; 99:1472-7.
6. Rodrigez RF, et al. Codeine/acetaminophen and hydrocodone/acetaminophen
combination tablets for the management of chronic cancer pain in adults: A 23-day,
prospective, double-blind, randomized, parallel-group study. Clin Ther. 2007; 29:581-7.
7. Chou R, et al. American Pain Society: Clinical Guidelines for the Use of Chronic Opioid
Therapy in Chronic Noncancer Pain. The Journal of Pain. 2009; 10(2):113-30.
8. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint
clinical practice guideline from the American College of Physicians and the American
Pain Society. Ann Int Med. 2007 Oct 2;147(7):478-91.
9. Final Summary Minutes: Joint Meeting of the Anesthetic and Life Support Drugs
Advisory Committee and Drug Safety and Risk Management Advisory Committee.
January 30, 2009. Available at: http://www.fda.gov/ohrms/dockets/ac/09/minutes/20094411m1-final.pdf.
10. Li Wan Po A, Zhang WY. Systematic overview of co-proxamol to assess analgesic
effects of addition of dextropropoxyphene to paracetamol. BMJ 1997;315:1565-71.
11. Collins SL, Edwards JE, Moore RA, McQuay HJ. Single dose dextropropoxyphene,
alone and with paracetamol (acetaminophen), for postoperative pain. Cochrane
Page 21 of 55
November 10, 2009 Tennessee PAC
ANALGESICS
Database Syst Rev 2000;(2):CD001440.
12. FDA briefing material. Joint meeting of the Anesthetic and Life Support Drugs Advisory
Committee and Drug Safety & Risk Management Advisory Committee. January 30,
2009. http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4411b1-01-FDA.pdf.
(Accessed April 17, 2009).
13. Simmons RL, Owen S, Abbott CJA, Bouchier-Hayes TAI, Hunt HA. Naproxen sodium
and paracetamol/dextropropoxyphene in sports injuries- A multicenter comparative
study. Brit J. Sports Med. 1982; 16(2):91-5.
14. WHO’s pain ladder. The World Health Organization. Available from:
http://www.who.int/cancer/palliative/painladder/en/ (Accessed October 2009)
Page 22 of 55
November 10, 2009 Tennessee PAC
GASTROINTESTINAL AGENTS
NEW: CHLORIDE CHANNEL ACTIVATORS
BACKGROUND
•
•
•
•
•
•
•
Constipation is a common gastrointestinal complaint. Constipation can be a symptom of
many different types of conditions. Common causes of constipation include low
fiber/poorly balanced diet, medications, hormonal and metabolic changes, irritable bowel
syndrome and some neurological diseases. Initial treatment options for constipation
include dietary changes, lifestyle modifications, and mild laxatives.
Chloride channel activators are an additional treatment option for certain types of
constipation. Lubiprostone is currently the only agent in this class.
Lubiprostone works by activating chloride channel-2, a normal constituent of the apical
membrane of the human intestine. By increasing intestinal fluid secretion, lubiprostone
increases motility of the intestine, thereby increasing the passage of stool and alleviating
symptoms associated with constipation.
Lubiprostone was approved by the FDA for the treatment of chronic idiopathic
constipation in adults and the treatment of constipation-predominate irritable bowel
syndrome (IBS) in women at least 18 years of age.
The most common adverse events noted with use of lupiprostone include nausea,
headache, and diarrhea.
o Lubiprostone is contraindicated in patients with known or suspected mechanical
gastrointestinal obstruction.
o Lubiprostone should not be used in patients with severe diarrhea
o Lubiprostone has also been associated with reports of dyspnea and some
patients have discontinued therapy.
o No drug-drug interactions have been identified with lubiprostone. Lubiprostone is
not metabolized by the cytochrome P450 isoenzymes.
There are currently no head-to-head trials comparing lubiprostone to other treatments for
constipation and the majority of information regarding the clinical efficacy and safety of
lubiprostone is not fully published. Additionally, the long-term safety of lubiprostone
remains to be established.
Lubiprostone is the only chloride channel activator available and selectively activates
intestinal chloride channels, increasing intestinal fluid secretion and delaying gastric
emptying. In clinical trials, it has demonstrated efficacy in the treatment of chronic
idiopathic constipation as well as constipation predominant irritable bowel syndrome in
women, with improvement in spontaneous bowel movements, straining, constipation
severity, stool consistency, and global assessment of constipation. The American
Society of Colon and Rectal Surgeons: Practice Parameters for the Evaluation and
Management of Constipation states the initial management of constipation is typically
dietary modification, including a high-fiber diet and fluid supplementation. Bulk and
stimulant laxatives, as well as other osmotic laxatives are also included as treatment
options for constipation.The guidelines outline treatment options to include lubiprostone
along with polyethylene glycol and tegaserod, as appropriate for the treatment of chronic
constipation in patients who have had an inadequate response to dietary management.
RECOMMENDATION
Lubiprostone is the only chloride channel activator available. In clinical trials, it has demonstrated
efficacy in the treatment of chronic idiopathic constipation as well as constipation predominant
irritable bowel syndrome in women. However, lubiprostone has not been directly compared to
conventional treatments such as dietary management and laxatives which are recommended as
first-line treatment for constipation and therefore it is typically reserved for patients in whom other
approaches have been unsuccessful. Current clinical guidelines include lubiprostone as a
treatment option when therapy with dietary management and laxatives has been unsuccessful.
Therefore, it is recommended that lubiprostone be available for use subject to clinical criteria.
Page 23 of 55
November 10, 2009 Tennessee PAC
GASTROINTESTINAL AGENTS
COMMITTEE VOTE:
APPROVED
PREFERRED
N/A
DISAPPROVED
APPROVED with MODIFICATION
NEW: CHLORIDE CHANNEL ACTIVATORS
NON-PREFERRED
Amitiza® (lubiprostone)CC
Clinical Criteria for Amitiza®
Approval for Amitiza® will be granted upon documentation of:
- Diagnosis of idiopathic chronic constipation or constipation-predominate irritable bowel
syndrome (IBS) AND
-Trial and failure of at least TWO other laxatives (bulk, osmotic, or stimulant)
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Quantity Limits for Amitiza®
8 mcg 2 per day
24 mcg 2 per day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed September, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed September, 2009.
3. MedMetrics. Chloride Channel Activators class review. 07/15/2009.
4. Ternent CA, Bastawrous AL, Morin NA, Ellis CN, Hyman NH, Buie W et al. Practice
Parameters for the Evaluation and Management of Constipation. Dis Colon Rectum.
2007;50:2013-22.
Page 24 of 55
November 10, 2009 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: LAXATIVES
BACKGROUND
•
•
•
•
•
Constipation is a common gastrointestinal complaint. Constipation can be a symptom of
many different types of conditions. Common causes of constipation include low
fiber/poorly balanced diet, medications, hormonal and metabolic changes, irritable bowel
syndrome and some neurological diseases. Initial treatment options for constipation
include dietary changes, lifestyle modifications, and pharmacologic therapy. Laxatives
are used for the treatment of constipation, bowel preparation prior to gastrointestinal
procedures and for the prevention and treatment of hepatic encephalopathy. Lactulose,
polyethylene glycol (PEG), and sodium phosphate (NaP) monobasic and dibasic
formulations are the currently available prescription laxatives.
Lactulose exerts its pharmacological effect to relieve constipation by producing an
osmotic effect in the colon with resultant distention promoting peristalsis. For the
treatment of hepatic encephalopathy, lactulose’s bacterial degradation results in an acidic
+
pH which causes the conversion of NH3 to NH4 inhibiting the diffusion of NH3 into the
blood.
PEG causes water retention in the stool and increases stool frequency and consistency.
NaP exerts an osmotic effect in the small intestine by drawing water into the lumen of the
gut, producing distention and promoting peristalsis and evacuation of the bowel.
FDA-Approved Indications:
Bowel
Cleansing:
Colonoscopy
Lactulose
NaP monobasic
monohydrate/
NaP dibasic anhydrous
PEG 3350
PEG
3350/KCl/NaHCO3/NaCl
PEG
3350/KCl/NaHCO3/NaCl/
Na2SO4
PEG
3350/KCl/Na2SO4/NaCl/
Na ascorbate/ascorbic acid
PEG
3350/KCl/NaHCO3/NaCl
for oral solution and
bisacodyl tablet
Treatment of
Constipation
Bowel
Cleansing:
Barium
Enema
X-ray
Examination
a
Adjunct in the
Prevention
and Treatment
of PSE
a
(Enulose®)
a
a
(>6 months of
age)
a
a
a
a
a
PSE=portal-systemic encephalopathy (also known as hepatic encephalopathy).
•
The most common adverse events observed with lactulose, PEG and NaP include:
nausea, abdominal bloating, cramping, flatulence, and diarrhea. Significant electrolyte
abnormalities have also been observed with sodium phosphate regimens.
o Sodium phosphate (NaP) monobasic and dibasic anhydrous carries a black box
warning regarding increased risk of acute phosphate nephropathy.
o All laxative agents are contraindicated in patients with known or suspected bowel
obstruction.
Page 25 of 55
November 10, 2009 Tennessee PAC
GASTROINTESTINAL AGENTS
Sodium phosphate (NaP) monobasic and dibasic anhydrous formulations are
contraindicated in patients with biopsy verified acute phosphate nephropathy.
o Lactulose solution should be used with caution in diabetic patients. Solution
contains galactose and lactulose.
o Periodic monitoring of electrolytes should be implemented for patients using
lactulose greater than 6 months and for patients with increased risk of electrolyte
abnormalities.
o NaP formulations should be used with extreme caution in patients with renal
insufficiency, bowel perforation or patients who have misused NaP products.
Significant fluid shifts, severe electrolyte abnormalities, and cardiac arrthymias
have been reported.
®
o NaP monobasic monohydrate (Visicol ) should be used with caution in patients
having difficulty swallowing or esophageal narrowing.
o NaP monobasic monohydrate (Visicol®) tablet particles have been noted in stool.
o MoviPrep® contains sodium ascorbate and ascorbic acid; this agent should be
used with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD)
deficiency.
o Significant Drug-Drug Interactions:
ƒ Due to laxatives’ cathartic effect, caution should be exercised when other
medications are administered in close proximity with laxatives as they
may not be properly absorbed.
ƒ Lactulose and NaP monobasic monohydrate/NaP dibasic anhydrous
should be used with extreme caution when concomitantly administering
other drugs that cause QT prolongation.
For the use of laxatives in bowel preparation there are numerous clinical trials
demonstrating efficacy in colon cleansing for all laxative agents. Varying patient
tolerability of bowel preparation agents is also demonstrated among different laxative
preparations. Limited head to head clinical data is available for the treatment of
constipation and hepatic encephalopathy.
One randomized trial compared NaP regimen to PEG solution (4L) regimen for patients
with scheduled colonoscopies (N=845). The primary endpoint was overall quality of colon
cleansing on a 4 point scale (1=excellent to 4=inadequate). Secondary endpoints
included distribution of colon cleansing scores, frequency of inadequate preparation, and
quality of cleansing in the ascending colon. The mean score for the overall quality of
colon cleansing demonstrated equivalence between NaP tablets and PEG (1.75 vs 1.81;
P=0.1175.) The distribution of scores 1 through 4 for colon cleansing was similar within
and between treatment groups (P value not provided). Inadequate colon cleansing was
reported for 11 patients (6 in the NaP tablet group and 5 in the PEG group). The quality
of cleansing in the ascending colon was equivalent in the two treatment groups for both
the mean score and the distribution of individual scores (P value not reported).
®
®
Another randomized trial compared 4L PEG solutions (NuLYTELY vs. GoLYTELY ) in
patients with scheduled colonoscopy (N=152). Primary endpoints were patient tolerance,
adequacy of preparation, clinical acceptability, and patient preference. Subjects reported
significantly less discomfort with NuLYTELY® with respect to fullness and cramps
(P<0.05). GoLYTELY® patients reported less nausea (P<0.05). There was no significant
difference between groups for vomiting and overall discomfort (P value not reported).
There was no difference between NuLYTELY® and GoLYTELY® groups for adequacy of
feces removal (P=0.36) or “clinical acceptability” (86.5% vs 79.3%, respectively; no P
value reported).
National treatment guidelines from the American Gastroenterological Association (AGA)
recommend milk of magnesia, stimulants, lactulose, or PEG or the treatment of
constipation if initial management when dietary modification is not adequate. The
American Society of Colon and Rectal Surgeons’ Practice Parameters for the Evaluation
and Management of Constipation also include lactulose and PEG when dietary
modifications are not adequate.
o
•
•
•
•
Page 26 of 55
November 10, 2009 Tennessee PAC
GASTROINTESTINAL AGENTS
•
•
•
The Consensus Document on Bowel Preparation for Colonoscopy by the American
Society for Gastrointestinal Endoscopy (ASGE) strongly recommend balanced electrolyte
oral solutions with PEG as a faster, more effective, and better-tolerated method for
cleansing the colon than a restricted diet combined with cathartics, high-volume gut
lavage, or mannitol. The balanced electrolyte solutions are safer than osmotic
laxatives/sodium phosphate (NaP) for patients with electrolyte or fluid imbalances, such
as renal or liver insufficiency, congestive heart failure, or liver failure and are, therefore,
preferable in these patient groups. A 2-Liter (L) PEG regimen with bisacodyl is as
effective as a standard 4 L PEG regimen, but appears to be better tolerated.
NaP regimens are comparable in safety and efficacy to 4-L balanced electrolyte oral
solutions with PEG, have fewer adverse effects and are associated with better
compliance and tolerance, however the clinical significance of this is not known and the
regimen is not recommended in patients with other significant co-morbidities. Additionally,
NaP has received a black box warning from FDA due to an association with renal toxicity.
The American Association for the Study of Liver Disease (AASLD) Management of Acute
Liver Failure recommends using lactulose in the early stages of hepatic encephalopathy.
RECOMMENDATION
Laxatives are used for the treatment of constipation, for bowel preparation prior to gastrointestinal
procedures and for the prevention and treatment of hepatic encephalopathy. Lactulose,
polyethylene glycol (PEG), and sodium phosphate (NaP) monobasic and dibasic formulations are
the prescription laxatives available. Current clinical guidelines include lactulose and polyethylene
glycol for treatment of constipation when dietary management fails. Additionally, lactulose is also
recommended for the treatment of hepatic encephalopathy. Sodium phosphate (NaP) regimens
are comparable in efficacy to PEG regimens for bowel preparation but NaP has demonstrated
more severe systemic adverse effects and it is not recommended for use in patients with renal or
liver insufficiency, congestive heart failure, or liver failure. Therefore, it is recommended that
lactulose and polyethylene glycol be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: LAXATIVES
PREFERRED
Constulose® (lactulose)
Enulose® (lactulose)
Generlac (lactulose)
®
Kristalose (lactulose packets)
Lactulose
PEG 3350 powder
PEG 3350 solution
PEG 3350 electrolyte solution
NON-PREFERRED
Colyte® (PEG 3350/KCl/NaHCO3/NaCl/Na2SO4)
GoLYTELY® (PEG 3350/KCl/NaHCO3/NaCl/Na2SO4)
®
HalfLytely (PEG 3350/KCl/NaHCO3/NaCl)
®
Moviprep (PEG 3350/KCl/Na2SO4/NaCl/Na ascorbate/ascorbic acid)
®
NuLYTELY (PEG 3350/KCl/NaHCO3/NaCl)
TM
Osmoprep (NaP monobasic monohydrate/NaP dibasic anhydrous)
®
Trilyte (PEG 3350/KCl/NaHCO3/NaCl)
Visicol® (NaP monobasic monohydrate/NaP dibasic anhydrous)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed October, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed October, 2009.
3. MedMetrics. Laxatives class review. 08/10/2009.
4. Kastenberg D, Chasen R, Choudhary C, Riff D, Steinberg S, Weiss E, et al. Efficacy
and safety of sodium phosphate tablets compared with PEG solution in colon cleansing:
two identically designed, randomized, controlled, parallel group, multicenter phase III
trials. Gastrointest Endosc. 2001;54(6):705-13.
5. DiPalma JA, Marshall JB. Comparison of a new sulfate-free polyethylene glycol
electrolyte lavage solution versus a standard solution for colonoscopy cleansing.
Gastrointest Endosc. 1990;36(3):285-9.
Page 27 of 55
November 10, 2009 Tennessee PAC
GASTROINTESTINAL AGENTS
Locke GR 3rd, Pemberton JH, Phillips SF.; American Gastroenterological Association.
American Gastroenterological Association Medical Position Statement: Guidelines on
Constipation [guideline on the Internet]. Gastroenterology 2000 Dec [cited 2009 Aug
13];119(6):1766-78. Available from: http://www.gastro.org/wmspage.cfm?parm1=4453.
7. Wexner SD, Beck DE, Baron TH, Fanelli RD, Hyman N, Shen B, et al. A consensus
document on bowel preparation before colonoscopy: prepared by a task force from the
American Society of Colon and Rectal Surgeons (ASCRS), the American Society for
Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and
Endoscopic Surgeons (SAGES). Gastrointest Endosc. 2006;63(7):894-909.
8. Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD
position paper: the management of acute liver failure. Hepatology 2005;41(5):1179-97.
9. Ternent CA, Bastawrous AL, Morin NA, Ellis CN, Hyman NH, Buie W et al. Practice
Parameters for the Evaluation and Management of Constipation. Dis Colon Rectum.
2007;50:2013-22.
10. American College of Gastroenterology Chronic Constipation Task Force. An evidencebased approach to the management of chronic constipation in North America. Am J
Gastroenterol. 2005;100 Suppl 1:S1-4.
6.
Page 28 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: AGENTS FOR GENITAL WARTS
BACKGROUND
•
•
•
•
The agents for genital warts therapeutic class consists of four agents; imiquimod,
podofilox, and sinecatechins.
Imiquimod is an immune response modifier. It has no direct antiviral activity in cell
culture and its mechanism of action in actinic keratosis (AK) and basal cell carcinoma
(BCC) is unknown. Podofilox exerts its effect through antimitotic activity. Sinecatechins
contains a combination of catechins, or phenols that have antioxidant properties,
although the mechanism of action in the treatment of genital warts is unknown.
All of the agents in this class are FDA-approved for the topical treatment of external
genital warts. Additionally, imiquimod is indicated for the treatment of AK and superficial
BCC.
The most common adverse reactions to the agents for genital warts are dermatologic in
nature including erythema, skin irritation, burning, skin ulceration or erosion, edema and
rash.
o These agents have been associated with photosensitivity. Patients should be advised
to minimize exposure of treated areas to sunlight and sunlamps during the use of these
agents. Imiquimod has the potential to exacerbate inflammatory conditions of the
•
•
•
skin and should not be used if the wart or surrounding tissue is inflamed or
irritated.
o Drug interactions with the agents for genital warts are limited due to the topical
route of administration and the relatively low systemic bioavailability. There are
no significant drug interactions reported with these agents.
All agents in this class have shown efficacy when compared to placebo for the treatment
of genital warts. However, head-to-head studies are limited and therefore, it is difficult to
conclude that one agent is more efficacious than another.
Current therapies for external genital warts include: self-administered topical treatments
such as imiquimod, podofilox, or sinecatechins, among other provider administered
therapies (e.g. podophyllin resin, trichloroacetic acid, bichloroacetic acid, intralesional
interferons, etc.). Cryotherapy and surgical removal (including laser surgery) are
alternative interventions. The Centers for Disease Control and Prevention 2006
guidelines for the treatment of genital warts do not recommend any one regimen over
another, but do suggest consideration of patient preference and access to treatment. The
role of sinecatechins is not discussed in the guideline, as it was approved after
publication, and its place in the pharmacotherapeutic management of genital and perianal
warts is unknown.
The use of imiquimod for the treatment of AK and superficial BCC is addressed in
national and international treatment guidelines. The British Association of Dermatologists
2007 guidelines for the management of AK states that imiquimod 5% cream has been
demonstrated to be effective. The National Comprehensive Cancer Network Clinical
Practice Guidelines in Oncology 2009 guideline for basal cell and squamous cell skin
cancers states that imiquimod is an agent that may be used topically to treat low-risk
BCC when surgery or radiation is contraindicated. This guideline also notes that AK
should be treated aggressively and imiquimod is considered a treatment option. The
British Association of Dermatologists 2008 guidelines for the management of BCC notes
that topical imiquimod appears effective in the treatment of primary small superficial BCC
and may possibly have a role in the treatment of primary nodular BCC.
RECOMMENDATION
Imiquimod, podofilox, and sinecatechins are FDA-approved for the topical treatment of external
genital warts. Imiquimod is also indicated for the treatment of AK and superficial BCC. Current
clinical guidelines from the CDC for the treatment of genital warts do not recommend any one
regimen over another; however sinecatechins is not discussed in the guideline, as it was approved
after publication, and its place in the pharmacotherapeutic management of genital and perianal
Page 29 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
warts is unknown. The use of imiquimod for the treatment of AK and superficial BCC is addressed
in national and international treatment guidelines and it is recommended as a treatment option for
both disease states. Therefore, it is recommended that at least one agent for the treatment of
genital warts be available for use. Additionally, due to its role in the treatment of AK and BCC, it is
recommended that imiquimod be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: AGENTS FOR GEN(ITAL WARTS
PREFERRED
NON-PREFERRED
Condylox® (podofilox)
Aldara® (imiquimod)
podofilox (compares to Condylox®)
Veregen® (sinecatechins)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed September, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed September, 2009.
3. MedMetrics. Agents for Genital Warts class review. August 10, 2009.
4. Centers for Disease Control and Prevention. Genital warts. In: Centers for Disease
Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2006.
MMWR 2006;55(No. RR-11):1-100 [cited 2009 Aug 4]. Available from:
http://www.cdc.gov/std/treatment/2006/genital-warts.htm.
5. British Association of Dermatologists Therapy Guidelines and Audit Subcommittee.
Guidelines for the Management of Actinic Keratoses. Br J Dermatol. 2007;156(2):22230.
6. National Comprehensive Cancer Network. NCCN Clinical practice guidelines in
oncology: Basal Cell and Aquamous Cell Skin Cancers v.I.2009 [monograph on the
internet]. Jenkintown (PA): National Comprehensive Cancer Network, Inc.; 2009 [cited
2009 Aug 4]. Available from:
http://www.nccn.org/professionals/physician_gls/PDF/nmsc.pdf.
7. Telfer N, Clover G, Morton C. Guidelines for the management of basal cell carcinoma.
Br J Dermatol. 2008;159:35-48.
Page 30 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: EMOLLIENTS
BACKGROUND
•
•
•
•
•
•
Xerosis is characterized by dehydrated skin showing fine, dry scaling and accentuation of
skin lines. Dryness and impaired barrier function of the stratum corneum is associated
with skin disorders such as atopic dermatitis, psoriasis and ichthyosis. Maintaining
proper hydration in the stratum corneum is fundamental to the treatment and prevention
of dry skin.
Emollients have immediate effects on xerosis by increasing the hydration of the stratum
corneum as the skin absorbs moisture from the product and making the skin look
smoother by filling in microcracks and fissures. Emollients also work to restore the skin’s
natural barrier by sealing in moisture. In addition to these effects, some emollients
contain humectants, such as lactic acid or ammonium lactate, which have water
attracting properties and modulate skin keratinization.
Ammonium lactate is FDA-approved for the treatment of ichthyosis vulgaris and dry scaly
skin (xerosis) and temporary relieve of itching associated with these conditions. Lactic
acid and lactic acid with vitamin E are non-FDA approved marketed prescription drugs.
Common adverse events associated with the use of emollients include burning,
erythema, irritation, rash and stinging.
o Application of ammonium lactate to skin that is abraded or has fissures or
erosions may cause transient stinging or burning. Due to the potential for
irritation, caution should be advised when applying to the face. Exposure to
natural and artificial sunlight should be minimized or avoided.
o There are no significant drug interactions associated with the topical emollients.
Head to head clinical trials with the emollients are limited. Two studies evaluating the
safety and efficacy of ammonium lactate have been conducted (lactic acid vs ammonium
lactate and urea vs ammonium lactate). In both studies, all treatment groups showed
significant improvement over baseline; however, there were no significant differences
observed at the end of the study period between the groups.
Guidelines from the Joint Task Force on Practice Parameters in Collaboration with the
American College of Allergy, Asthma and Immunology (ACAAI), the American Academy
of Allergy, Asthma, and Immunology (AAAAI), and the Joint Council of Allergy, Asthma
and Immunology (JCAAI) for the care of contact dermatitis state once the diagnosis of
contact dermatitis is established, emollients, moisturizers, and/or barrier creams may be
instituted as secondary prevention strategies for continued exposure. Guidelines from the
American Academy of Dermatology for the care of atopic dermatitis state that emollients
are a standard of care, steroid-sparing and useful for both prevention and maintenance of
atopic dermatitis. Guidelines do not recommend one topical emollient over another.
Guidelines from the Joint Task Force for the management of atopic dermatitis state that
emollients should be used as first-line therapy to retain moisture and provide
symptomatic relief. All of the guidelines state that topical corticosteroids are the mainstay
of treatment for these disorders but that emollients are important in the hydration of the
skin to maintain the skin’s barrier properties and prevent irritation. Guidelines do not
recommend one topical emollient over another.
RECOMMENDATION
Emollients increase hydration of the skin to maintain the skin’s barrier properties and prevent
irritation. Current clinical guidelines recommend these agents as standard therapy for many skin
conditions, such as seborrheic dermatitis and atopic dermatitis. Guidelines do not recommend
one topical emollient over another; however, ammonium lactate is currently the only FDAapproved emollient. Therefore, it is recommended at least ammonium lactate be available for use.
COMMITTEE VOTE:
APPROVED
Page 31 of 55
DISAPPROVED
APPROVED with MODIFICATION
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: EMOLLIENTS
PREFERRED
NON-PREFERRED
Lac-Hydrin® (ammonium lactate)
ammonium lactate (compares to LacHydrin®, Lac-Lotion®)
Lac-Lotion® (ammonium lactate)
®
lactic acid (compares to Lactinol )
Lactinol® (lactic acid)
lactic acid with vitamin E (compares to
Lactinol-E® (lactic acid with vitamin E)
®
Lactinol-E )
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed September, 2009
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed September, 2009.
3. Med Metrics. Topical Emollients class review. August 26, 2009.
4. Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, et al. Guidelines of
care for atopic dermatitis. J Am Acad Dermatol. 2004;50:391-404. Available at:
http://www.aad.org/research/guidelines/index.html.
Page 32 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: TOPICAL STEROIDS
BACKGROUND
•
•
•
•
•
•
•
Millions of people are affected annually with skin disorders that cause marked discomfort,
significant morbidity, and rarely death. The prevalence of these chronic inflammatory skin
disorders is a major quality-of-life issue as they give rise to significant psychosocial
morbidity and other negative health effects. Topical anti-inflammatory agents, or topical
corticosteroids, are utilized for symptomatic relief and treatment of both acute and chronic
inflammatory dermatoses. This review will be limited to the available prescription topical
steroid agents.
Corticosteroids play an important and routine role in various dermatologic conditions
because of their anti-inflammatory and immunosuppressive effects, as well as their ability
to suppress mitotic activity and cause localized vasoconstriction.
All of the available prescription topical steroids are FDA-approved for the treatment of
inflammatory and pruritic dermatoses. Other FDA-approved indications are as follows:
o Atopic dermatitis: desonide, fluocinolone, fluticasone
o Dental use: fluocinolone, halobetasol, hydrocortisone acetate, triamcinolone
o Plaque psoriasis: clobetasol, fluocinonide
o Scalp psoriasis: clobetasol, fluocinolone
o Seborrheic dermatitis of the scalp: fluocinolone
Adverse events commonly associated with the topical steroids are mild to moderate local
reactions including: burning, itching, irritation, erythema, and dryness.
o Topical corticosteroids share similar warnings and precautions associated with
systemic administration of corticosteroids including reversible hypothalamicpituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome,
hyperglycemia, and glucosuria in some patients. Patients receiving large doses
of potent topical steroids applied to a large surface area, or under an occlusive
dressing, should be evaluated periodically for evidence of HPA axis suppression.
o Due to the limited systemic absorption when corticosteroids are administered
topically, no drug interactions are likely to occur and none are documented with
these agents.
The efficacy and safety of topical corticosteroids have been well documented since the
introduction of hydrocortisone in the early 1950s. Topical corticosteroids have been
evaluated in the management of multiple disease states including atopic dermatitis (AD),
eczema, and psoriasis, and results from these clinical trials demonstrate that there is no
one topical corticosteroid agent that is more efficacious than another in the class.
Additionally, clinical trials evaluating the different dosage forms did not consistently
demonstrate that a specific dosage form is more efficacious than another.
While systemic corticosteroids are typically more effective in most dermatologic
inflammatory conditions, they are typically reserved for more widespread and advanced
conditions. Topical treatment is preferred in most cases with limited or localized
involvement, and to help minimize systemic adverse effects. Topical corticosteroids are
the standard of care for the treatment of atopic dermatitis and psoriasis, according to the
American Academy of Dermatology (AAD). The Guidelines of Care for the Use of
Topical Glucocorticosteroids from the AAD state the strength and vehicle of a topical
corticosteroid should be selected dependent on the nature, location, and extent of the
skin lesions, the patient’s age, and duration of therapy.
Agents in the class are divided into potency groups according to their relative potency. In
general, usage of the lowest potency topical corticosteroid that is effective is
recommended, especially in children and infants and for the face and intertriginous areas.
Low- to medium-strength topical corticosteroids are preferred for the treatment of large
areas of the body. Short-term use of more potent topical corticosteroids is occasionally
required.
Page 33 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
Relative Potency Ratings of the Topical Anti-inflammatory Agents
Group*
(I=highest potency;
Generic Name
Strength
VII = lowest potency)
I
betamethasone dipropionate;
0.05%
augmented
I
clobetasol
0.05%
Page 34 of 55
Formulation(s)
cream, gel, lotion, ointment
I
I
I
fluocinonide
flurandrenolide
halobetasol
0.1%
4 μg/cm2
0.05%
cream, foam, gel, lotion,
ointment, shampoo, solution,
spray
cream
tape
cream, ointment
II
II
II
II
II
II
II
amcinonide
betamethasone dipropionate
desoximetasone
desoximetasone
diflorasone
fluocinonide
halcinonide
0.1%
0.05%
0.05%
0.25%
0.05%
0.05%
0.1%
lotion, ointment
ointment
gel
ointment
ointment
cream, gel, ointment, solution
ointment
III
III
III
III
III
III
III
III
III
amcinonide
betamethasone dipropionate
betamethasone valerate
desoximetasone
diflorasone
fluticasone
halcinonide
mometasone
triamcinolone
0.1%
0.05%
0.1%
0.25%
0.05%
0.005%
0.1%
0.1%
0.5%
cream
cream
ointment
cream
cream
ointment
cream
ointment
cream, ointment
IV
IV
IV
IV
IV
IV
IV
IV
betamethasone valerate
desoximetasone
fluocinolone
fluticasone
hydrocortisone valerate
mometasone
prednicarbate
triamcinolone
0.12%
0.05%
0.025%
0.05%
0.2%
0.1%
0.1%
0.1%
foam
cream
ointment
cream, lotion
ointment
cream, lotion
ointment
ointment
V
V
V
V
V
V
V
V
V
V
betamethasone dipropionate
betamethasone valerate
clocortolone
fluocinolone
flurandrenolide
hydrocortisone butyrate
hydrocortisone valerate
hydrocortisone probutate
prednicarbate
triamcinolone
0.05%
0.1%
0.1%
0.025%
0.05%
0.1%
0.2%
0.1%
0.1%
0.1%
lotion
cream, lotion
cream
cream
cream, lotion
cream, ointment, solution
cream
cream
cream
cream, lotion, paste
VI
VI
alclometasone
desonide
0.05%
0.05%
VI
fluocinolone
0.01%
cream, ointment
cream, foam, gel, lotion,
ointment
cream, oil, shampoo, solution
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
Group*
(I=highest potency;
VII = lowest potency)
VI
VII
Generic Name
Strength
triamcinolone
0.025%
hydrocortisone, hydrocortisone acetate
(all)
all strengths
Formulation(s)
aerosol, cream, lotion,
ointment
cream, gel, lotion, ointment,
packet, solution
*Potency ratings are given following the Stoughton‐Cornell classification of topical glucocorticoid potency. RECOMMENDATION
Topical corticosteroids are utilized for symptomatic relief and treatment of both acute and chronic
inflammatory dermatoses. Topical steroids are the standard of care for the treatment of atopic
dermatitis and psoriasis, according to guidelines from the AAD. Currently available clinical
guidelines do not differentiate between agents or dosage forms. Results from clinical trials
demonstrate that there is no one topical corticosteroid agent that is more efficacious than another
in the class. Additionally, clinical trials evaluating the different dosage forms did not consistently
demonstrate that a specific dosage form is more efficacious than another. All agents in this class
can be considered therapeutic alternatives to the other agents in the same potency group. It is
recommended at least six topical steroids be available for use, reflective of at least one agent in
each potency group.
COMMITTEE VOTE:
APPROVED
PREFERRED
all generic agents
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: TOPICAL STEROIDS
NON-PREFERRED
all branded agents
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed October, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed October, 2009.
3. Med Metrics. Topical Anti-inflammatory agents class review. August 10, 2009.
4. Drake LA, Dinehart SM, Farmer ER et al. Guidelines of care for the use of topical
glucocorticosteroids. J Am Acad Dermatol. 1996, 35:615-9.
5. Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, et al. Guidelines of
care for atopic dermatitis. J Am Acad Dermatol. 2004;50:391-404. Available at:
http://www.aad.org/research/guidelines/index.html.
6. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al.
Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3.
Guidelines of care for the management and treatment of psoriasis with topical therapies.
J Am Acad Dermatol. 2009;60:643-59. Available at:
http://www.aad.org/research/guidelines/index.html.
Page 35 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: ENZYME PREP AND WOUND HEALING AGENTS
BACKGROUND
•
There are currently four enzyme prep and wound healing products available in the United
States. The single entity agents include becaplermin and collagenase, and the
combination products are chlorophyllin/papain/urea and papain/urea.
• Becaplermin has activity similar to that of endogenous platelet-derived growth factor,
which promotes chemotactic recruitment and proliferation of cells involved in wound
repair and enhancing the formation of granulation tissue. Collagenase works to break
down collagen and contribute to the formation of granulation tissue and epithelization of
dermal ulcers and severely burned areas. Papain is a proteolytic enzyme that digests
nonviable protein matter. Urea provides supplementary actions to papain that result in
nonviable protein matter becoming more susceptible to enzymatic degradation.
Chlorophyllin promotes healing by inhibiting the hemagglutinating and inflammatory
properties of protein degradation products in the wound, including the products of
enzymatic digestion. These actions promote healthy granulations, control local
inflammation, and reduce wound odor.
• In 2008 the Food and Drug Administration (FDA) proposed that all topical products
containing papain be withdrawn from the market due to a lack of substantial evidence
supporting their effectiveness. Additionally the FDA noted the action affects “all topical
products containing papain because no product currently has FDA approval.” This
mandate required companies to stop manufacturing these products by November 24,
2008 and cease shipping by January 21, 2009. Any papain containing product shipped
after this date must obtain FDA approval.
• Indications:
Single Entity Agents
Combination Products
Chlorophyllin/ Papain/
Indication
Becaplermin Collagenase
papain/urea
urea
The treatment of lower extremity diabetic
neuropathic ulcers that extend into the
a*
subcutaneous tissue or beyond and have
an adequate blood supply
Debridement of necrotic tissue in dermal
a
ulcers and severe burns
Debridement of necrotic tissue and
liquefaction of slough in acute and
chronic lesions such as varicose,
diabetic, and decubitus ulcers, burns,
a†
a†
post-operative wounds, pilonidal cyst
wounds, carbuncles, and miscellaneous
wounds
*Efficacy has not been established for the treatment of pressure ulcers and venous stasis ulcers and has not been
evaluated for the treatment of diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue
(Stage I or II, IAET staging classification) or ischemic diabetic ulcers.
10
† No papain containing product currently has Food and Drug Administration approval.
•
Erythematous rash is the most common adverse reaction associated becaplermin and
collagenase. Infections such as cellulitus and osteomyelitis have also been associated
with the use of becamplermin. Adverse reactions associated with the use of the
combination products chlorophyllin/papain/urea and papain/urea include irritation and
burning sensation at the application site.
o Becaplermin carries a black box warning regarding the increased rate of mortality
secondary to malignancy in patients treated with 3 or more tubes.
o
Page 36 of 55
Chlorophyllin/papain/urea and papain/urea aerosol products should not be used
on fresh arterial clots.
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
o
Collagenase enzymatic activity may be affected by certain detergents, and heavy metal
ions such as mercury and silver which are used in some antiseptics. Additionally, papain
may be inactivated by the salts of heavy metals such as lead, silver, and mercury, and
avoidance with agents containing these metals is recommended.
There are no significant drug-drug interactions associated with the enzyme prep
and wound healing products.
A meta-analysis by Wieman et al. described the results of four clinical trials of
becaplermin. A significantly higher incidence of complete healing in the patients receiving
becaplermin 30 µg and/or 100 µg gel was demonstrated in two studies. The other two
studies either showed no significant difference between active treatment group and
placebo or good ulcer care or were not powered to detect a difference between
becaplermin and standard care. A study by Embil et al. showed that complete healing of
ulcers was achieved in 57.5% of patients receiving becaplermin 100 µg gel. All patients in
this study received active treatment.
Alvarez et al. compared the efficacy of collagenase and papain/uea in patients with
pressure ulcers. The papain/urea ointment was significantly more effective in reducing
the amount of non-viable, necrotic tissue at each evaluation compared to the collagenase
ointment and generally enhanced the level of granulation and epithelialization, though the
degree of epithelialization did not correlate to a reduction in wound area, and significant
conclusions can not be made as a result of this study.
No studies were found evaluating the efficacy of the combination of
chlorophyllin/papain/urea.
Debridement options often used in wound treatment include mechanical debridement
with gauze dressings, sharp surgical debridement, autolytic debridement with occlusive
dressings, as well as enzymatic debridement. Treatment guidelines from the Infectious
Disease Society of America state that proper care for patients with diabetic foot infections
should include off-loading of pressure, wound cleansing and debridement, and
appropriate antibiotic treatment. Furthermore, these guidelines state sharp debridement
is preferable to the use of topical debriding agents. Treatment guidelines from the
American Diabetes Association Consensus Development Conference on Diabetic Foot
Wound Care states that recombinant platelet derived growth factor has shown modest
benefit when used with off-loading, debridement, and treatment of infection but should
not be a substitute for appropriate wound care. Other enzyme prep and wound healing
products are not addressed in these guidelines. No guideline currently recommends one
agent over another.
o
•
•
•
•
RECOMMENDATION
There are currently two enzyme prep and wound healing products available in the Unites States,
becaplermin, and collagenase. Currently only becaplermin and collagenase are approved by the
FDA, and the agency has proposed that all topical products containing papain be withdrawn from
the market due to a lack of substantial evidence supporting their effectiveness. Although the
agents in this class have typically been shown to be efficacious when compared to placebo, no
guideline currently recommends one agent over another. It is recommended at least one agent in
this class indicated for the debridement of necrotic tissue in dermal ulcers and severe burns be
available for use. Additionally, becamplermin is only FDA-approved for use in lower extremity
diabetic ulcers and efficacy has not been established for the treatment of pressure ulcers and
venous stasis ulcers; therefore, it is recommended its use be restricted to treatment of lower
extremity diabetic ulcers.
COMMITTEE VOTE:
APPROVED
Page 37 of 55
DISAPPROVED
APPROVED with MODIFICATION
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: ENZYME PREP AND WOUND HEALING AGENTS
PREFERRED
NON-PREFERRED
N/A
Regranex® CC (becaplermin)
Santyl® (collagenase)
Clinical Criteria for Regranex®
Regranex® will be approved only for patients having a diagnosis of lower extremity diabetic
ulcers.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed September, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed September, 2009.
3. Med Metrics. Enzyme Prep and Wound Healing Products class review. July 23, 2009.
4. Wieman T, et al. Clinical efficacy of becaplermin (rhPDGF-BB) gel. Am J Surg.
1998;176(2A):74S-79S.
5. Embil J, Papp K, Sibbald G, et al. Recombinant human platelet-derived growth factorBB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label
clinical evaluation of efficacy. Wound Repair Regen. 2000;8(3):162-8.
6. Alvarez O, Fernandez-Obregon A, Rogers R, et al. A prospective, randomized,
comparative study of collagenase and papain-urea for pressure ulcer debridement.
Wounds. 2002;14(8):293-301.
7. Lipsky B, Berendt A, Deery H, et al. Diagnosis and treatment of diabetic foot infections.
Clin Infect Dis.. 2004;39:885-910.
8. Consensus Development Conference on Diabetic Foot Wound Care: 7-8 April
1999,Boston, Massachusetts. American Diabetes Association. Diabetes Care. 1999
Aug;22(8):1354-60.
Page 38 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: ORAL RETINOIDS
BACKGROUND
•
•
•
•
•
Acne vulgaris is a chronic inflammatory dermatosis which is notable for open and/or
closed comedones (blackheads and whiteheads) and inflammatory lesions including
papules, pustules, or nodules. Psoriasis is a common, chronic inflammatory, multisystem
disease with predominately skin and joint manifestations affecting approximately 2% of
the population. Currently, there are two oral single entity retinoid agents, isotretinoin
(Accutane®, Amnesteem®, Claravis®, Sotret®), and acitretin (Soriatane®).
The mechanism of action of oral isotretinoin is unknown. However, isotretinoin reduces
sebaceous gland size and inhibits sebaceous gland activity, thus decreasing sebum
secretion. Isotretinoin also has been shown to decrease the number of Propionibacterium
acnes (P. acnes) organisms within the follicle and has anti-keratinizing and antiinflammatory actions.
The exact mechanism of action of acitretin is unknown. Studies suggest that acitretin
affects immune response, epidermal proliferation, and glycoprotein synthesis in the skin.
Specifically, acitretin helps to normalize cell differentiation and thin the cornified layer by
directly reducing the keratinocytes’ rate of proliferation. Acitretin’s anti-inflammatory and
antiproliferative actions in the skin decrease epidermal and dermal inflammation and
reduce the scaling, erythema, and thickness of psoriatic lesions.
Isotretinoin is FDA-approved for the treatment of severe recalcitrant nodular acne and
acitretin is FDA-approved for the treatment of psoriasis.
The most common (≥5%) adverse effects reported with both isotretinoin and acitretin are
alopecia, cheilitis, dry skin, increased triglycerides, and pruritus.
o Isotretinoin and acitretin both carry black box warnings regarding potent
teratogenic effects. Both drugs are classified as Pregnancy Category X and are
therefore contraindicated in female patients who are or may become pregnant.
o Because of isotretinoin’s teratogenicity and to minimize fetal exposure,
isotretinoin is approved for marketing only under a special restricted distribution
program approved by the Food and Drug Administration. This program is called
iPLEDGE. Isotretinoin must only be prescribed by prescribers who are registered
and activated with the iPLEDGE program. Isotretinoin must only be dispensed by
a pharmacy registered and activated with iPLEDGE, and must only be dispensed
to patients who are registered and meet all the requirements of iPLEDGE.
o Females of reproductive potential must not be given a prescription for acitretin
until pregnancy is excluded. Acitretin is contraindicated in females of
reproductive potential unless the patient meets all of the following conditions:
ƒ Must have had 2 negative urine or serum pregnancy tests. The first test
(a screening test) is obtained by the prescriber when the decision is
made to pursue acitretin therapy. The second pregnancy test (a
confirmation test) should be done during the first 5 days of the menstrual
period immediately preceding the beginning of acitretin therapy. For
patients with amenorrhea, the second test should be done at least 11
days after the last act of unprotected sexual intercourse (without using 2
effective forms of contraception [birth control] simultaneously).
ƒ Must have a pregnancy test repeated every month during acitretin
treatment. The patient must have a negative result from a urine or serum
pregnancy test before receiving an acitretin prescription. To encourage
compliance with this recommendation, a limited supply of the drug
should be prescribed. For at least 3 years after discontinuing acitretin
therapy, a pregnancy test must be repeated every 3 months.
ƒ Must have selected and have committed to use 2 effective forms of
contraception (birth control) simultaneously, at least 1 of which must be a
primary form, unless absolute abstinence is the chosen method, or the
patient has undergone a hysterectomy or is clearly postmenopausal.
Page 39 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
•
•
Primary forms of contraception include: tubal ligation, partner's
vasectomy, intrauterine devices, birth control pills, and
injectable/implantable/insertable/topical hormonal birth control products.
Secondary forms of contraception include latex condoms (with or without
spermicide), diaphragms and cervical caps (which must be used with a
spermicide).
ƒ Patients must use 2 effective forms of contraception (birth control)
simultaneously for at least 1 month prior to initiation of acitretin therapy,
during acitretin therapy, and for at least 3 years after discontinuing
acitretin therapy.
ƒ Must have signed a Patient Agreement/Informed Consent for Female
Patients that contains warnings about the risk of potential birth defects if
the fetus is exposed to acitretin, about contraceptive failure, about the
fact that they must not ingest beverages or products containing ethanol
while taking acitretin and for 2 months after acitretin treatment has been
discontinued, and about preventing pregnancy while taking acitretin and
for at least 3 years after discontinuing acitretin therapy.
o Isotretinoin may decrease bone mineral density. Osteoporosis, osteopenia, and
bone fractures have been reported with use. Isotretinoin and acitretin may also
cause depression, psychosis, aggressive or violent behavior, and changes in
mood; therefore, patients should be observed closely for symptoms of
depression or suicidal thoughts. Both drugs have been associated with
hepatotoxicity.
o Due to increased risk of increased intracranial pressure, use of acitretin and
tetracyclines are contraindicated. An increased incidence of pseudotumor
cerebri (benign intracranial hypertension) has been reported in patients receiving
isotretinoin and minocycline or tetracycline; therefore, co-treatment with tretinoin
and tetracyclines should be avoided. Acitretin may enhance the hepatotoxic
effect of methotrexate and this combination should be avoided. Decreased
effectiveness of hormonal contraceptives may occur when coadministered with
isotretinoin; therefore, two forms of contraception are recommended in females
of child-bearing potential during oral retinoid therapy.
Oral isotretinoin has been studied for the treatment of severe nodulocystic acne vulgaris.
o Overall, oral isotretinoin appears to be more effective than placebo with patients
experiencing up to a 98% improvement in the number of cystic lesions in one
study of patients with treatment-resistant cystic and conglobulate acne vulgaris.
o Isotretinoin was compared to a combination of azelaic acid cream plus oral
minocycline in male patients 16 years of age and older with severe inflammatory
forms of facial acne vulgaris in a parallel group study. After six months of
therapy, isotretinoin demonstrated a significantly greater reduction versus the
combination azelaic acid cream plus oral minocycline in comedones (80.0% vs
66.0%; P<0.05) and papules and pustules (97.1% vs 88.2%; P<0.05). However,
there was no statistically significant difference in the reduction of nodes or cysts
between the treatment groups. The combination was tolerated better than
isotretinoin. The incidence of local side effects observed under the combination
of azelaic acid plus minocycline (36.5%, mainly transient burning and itching of
mild or moderate intensity) was considerably lower than that seen with
isotretinoin (65.7%; P value not reported).
Acitretin has been studied for the treatment of psoriasis.
o Overall, acitretin appears to be more effective than placebo. Olsen, et al studied
acitretin in patients with moderate to severe psoriasis. After 8 weeks of therapy,
patients reported a moderate change in erythema, scaling, and induration (mean
28% to 37% improvement) but with minimal change in the percentage of body
surface area involved (P value not reported). Prolonged treatment (greater than
or equal to 20 weeks) with acitretin resulted in further significant improvement
Page 40 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
•
•
and a 44% reduction of involved surface area from baseline (P value not
reported).
The 2007 Guidelines from the American Academy of Dermatology (AAD) state that
topical therapy is the standard of care in acne vulgaris treatment. An update to these
guidelines was published in 2009 and further states that the combination of a topical
retinoid and antimicrobial agent remains the preferred treatment approach for the majority
of patients with acne vulgaris. The AAD recommends an algorithm for the treatment of
acne vulgaris as follows:
o Mild acne vulgaris (comedonal): topical retinoid, or azelaic acid, or salicylic acid.
o Mild acne vulgaris (mixed and papular/pustular): topical retinoid + topical
antimicrobial, or azelaic acid.
o Moderate acne vulgaris (mixed and papular/pustular): oral antibiotic + topical
retinoid +/- benzoyl peroxide (BPO).
o Moderate acne vulgaris vulgaris (nodular): oral antibiotic + topical retinoid + BPO,
or oral isotretinoin or alternate oral antibiotic + alternate topical retinoid (+/-)
BPO/azelaic acid.
o Severe acne (nodular/conglobate): oral isotretinoin, or high dose oral antibiotic +
topical retinoid + BPO.
o Maintenance therapy (mild to severe acne vulgaris): topical retinoid +/- BPO.
According to the AAD, approximately 80% of psoriasis patients are affected with mild to
moderate disease and the majority of cases can be successfully treated with topical
agents with topical corticosteroids as the cornerstone of treatment for the majority of
patients with psoriasis. Guidelines from the AAD state that acitretin is effective for
psoriasis when used in conjunction with ultraviolet radiation B or psoralen and ultraviolet
radiation A phototherapy or biologics. Acitretin is the treatment of choice in human
immunodeficiency virus(HIV)-positive patients with severe psoriasis due to its lack of
significant immunosuppression.
RECOMMENDATION
Acitretin and isotretinoin are oral retinoids that are currently approved for the treatment of psoriasis
and severe recalcitrant nodular acne vulgaris, respectively. Clinical trials have demonstrated the
efficacy of both medications for their approved indications. Guidelines from the AAD state that the
combination of a topical retinoid and antimicrobial agent is the preferred treatment approach for
the majority of patients with acne vulgaris and recommend isotretinoin be reserved for use in
moderate nodular and severe recalcitrant nodular acne vulgaris. AAD guidelines for the treatment
of psoriasis recommend topical corticosteroids as the cornerstone of treatment for the majority of
patients with psoriasis. Acitretin is recommended for use in combination with phototherapy or
biologics for treatment of psoriasis. Additionally, acitretin is the treatment of choice in HIV-positive
patients with severe psoriasis due to its lack of significant immunosuppression. Despite their
proven efficacy, the use of oral retinoids is limited by their adverse events, including teratogenicity
which is described in a black box warning; therefore, it is recommended that all agents in this
category be subject to clinical criteria to minimize adverse eftects and fetal exposure to the drugs.
COMMITTEE VOTE:
APPROVED
PREFERRED
N/A
Page 41 of 55
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: ORAL RETINOIDS
NON-PREFERRED
Amnesteem® (isotretinoin)CC
Soriatane CK Kit® (acetretin)CC, QL
Sotret® (isotretinoin)CC
Claravis® (isotretinoin)CC
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
Clinical Criteria for isotretinoin
Patients will be approved for isotretinoin if both the patient and physician have registered with the
iPledge program.
(Registration with the program helps to ensure appropriate counseling has been provided to the
patient and proper procedures have been followed with regards to the risks of use in women of
child-bearing age).
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Clinical Criteria for Soriatane®
Soriatane® will be approved only for patients meeting ALL of the following criteria:
• Recipient has a diagnosis of severe psoriasis (covering at least 10-20% of body surface area).
• Recipient has tried and failed, or had an intolerance or contraindication to, ALL of the following:
– Topical corticosteroids
– Topical antipsoriatics (i.e., Dovonex®, Tazorac®, anthralin, Psoriatec®, or Taclonex®)
– Phototherapy (UVB, PUVA, etc.), if available to the patient within their geographic area.
• If the recipient is female:
– Must have had TWO negative urine or serum pregnancy tests (one performed during
the first 5 days of the menstrual period immediately preceding the beginning of
Soriatane® therapy).
– Must have committed to use 2 effective forms of contraception simultaneously, unless
absolute abstinence is chosen, or the patient has undergone a hysterectomy or
bilateral tubal ligation, or is clearly postmenopausal. The 2 selected forms of
contraception must be initiated at least 1 month prior to starting Soriatane® and
continued for 3 years after discontinuing the drug.
– Must have read and signed a Patient Agreement/Informed Consent for Female Patients
form.
• Recipient must NOT have impaired liver or kidney function, or abnormally elevated lipid levels.
• Recipient must NOT be receiving concomitant methotrexate (due to risk of hepatitis) or
tetracyclines (due to risk of increased intracranial pressure).
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed October, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed October, 2009.
3. Med Metrics. Oral Retinoids class review. September 14, 2009.
4. Peck GL, Olsen TG, Butkus D, Pandya M, Arnaud-Battandier J, Gross EG, et al.
Isotretinoin versus placebo in the treatment of cystic acne. A randomized double-blind
study [abstract]. J Am Acad Dermatol. 1982;6(4 Pt 2 Suppl):735-45.
5. Gollnick HP, Graupe K, Zaumseil RP. Comparison of combined azelaic acid cream plus
oral minocycline with oral isotretinoin in severe acne. Eur J Dermatol. 2001;11(6):53844.
6. Olsen EA, Weed WW, Meyer CJ, Cobo LM. A double-blind, placebo-controlled trial of
acitretin for the treatment of psoriasis [abstract]. J Am Acad Dermatol. 1989;21(4 Pt
1):681-6.
7. Strauss JS, Krowchuk DP, Leyden JJ, Lucky AW, Shalita AR, Siegfried EC, et al.
Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56:65163.
Page 42 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
8. Thiboutot D, Gollnick H, Bettoli V, Dreno B, Kang S, Leyden JJ et al. New insights into
the management of acne: An update from the Global Alliance to Improve Outcomes in
Acne Group. J Am Acad Dermatol. 2009;60:S1-50.
9. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al.
Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3.
Guidelines of care for the management and treatment of psoriasis with topical therapies.
J Am Acad Dermatol. 2009;60:643-59.
Page 43 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: TOPICAL RETINOIDS
BACKGROUND
•
•
•
•
•
•
Acne vulgaris is a chronic inflammatory dermatosis characterized by open and/or closed
comedones (blackheads and whiteheads) and inflammatory lesions including papules,
pustules, or nodules. Currently there are three topical single entity retinoid agents,
adapalene, tazarotene, and tretinoin. In addition to the single entity products, two
combination products are available in which a retinoid has been combined with an
antibiotic (clindamycin or benzoyl peroxide).
The comedolytic and anti-comedogenic properties associated with topical retinoids result
in a reduction in the formation of microcomedones and comedones. Additionally, topical
retinoids normalize desquamation, which facilitates penetration of other topical agents.
All topical retinoids are FDA-approved for the treatment of acne vulgaris. Tazarotene is
also FDA-approved for the management of plaque psoriasis. The combination products
are both FDA-approved for the treatment of acne vulgaris in patients 12 years of age or
®
older. Additionally, tretinoin as Renova is indicated as an adjunctive agent for use in the
mitigation of fine wrinkles.
Initially, cutaneous signs and symptoms, including erythema, dryness, scaling, burning,
or pruritis may be experienced by patients who use any of the topical retinoid products.
These adverse effects tend to lessen with continued use.
o Tazarotene is a Pregnancy Category X drug.
o Patients administering topical retinoids have a heightened sensitivity to sunlight
therefore exposure to sunlight should be minimized. Additionally, weather
extremes, such as wind or cold, may be irritating to patients administering topical
retinoids.
®
o Atralin (tretinoin) gel should be used with caution in patients who are allergic to
fish due to the potential for allergenicity to fish protein.
o Concomitant dermatologic medications and cosmetics that have strong drying
effects should be avoided with topical retinoids.
All agents included in this review are FDA-approved for the treatment of acne vulgaris
and clinical trials have demonstrated their effectiveness compared to a placebo vehicle.
In addition, there have been few trials evaluating the comparative efficacy of the agents
in the class.
o Two separate trials compared tretinoin vs adapalene in patients with acne
vulgaris and similar efficacy was seen with the two agents. Cunliffe, et al found
no significant differences in efficacy existed except at week 1 when adapalene
demonstrated significantly greater reduction in both inflammatory and total
lesions (P<0.05). Analysis demonstrated that therapy with adapalene has a more
rapid effect very early on in therapy, but the two therapies produce very similar
changes in lesion counts at other time points. However, Cunliffe et al reported
greater tolerability with adapalene while Tu et al reported greater tolerability with
tretinoin.
o Tretinoin microsphere gel was compared to tazarotene in patients aged 12 years
or older for the treatment of mild to moderate acne vulgaris. Although tazarotene
produced a more rapid improvement in papule count, by the end of the study
period there was no statistical difference between the treatment groups in closed
comedones, investigator global assessment or papule count.
The only retinoid FDA-approved for the treatment of psoriasis is tazarotene.
o One trial showed no significant difference between tazarotene and calcipotriene
for the treatment of psoriasis. However, when combined with a corticosteroid,
tazarotene in combination with a mid- or high-potency corticosteroid showed a
trend toward greater improvement in plaque elevation compared with tazarotene
plus placebo (P values not reported). Treatment success rates (defined as the
percent of patients with a moderate response, a marked response, almost
cleared, or completely cleared [about 50% improvement to completely cleared])
Page 44 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
•
•
were reported at week 2. Response rates of 42%, 49%, 73%, and 58% were
observed in the tazarotene 0.1% gel/placebo, tazarotene 0.1% gel/low-potency
corticosteroid group, tazarotene 0.1% gel/mid-potency corticosteroid group, and
the tazarotene 0.1% gel/high-potency corticosteroid group, respectively.
The 2007 Guidelines from the American Academy of Dermatology (AAD) state that
topical therapy is the standard of care in acne vulgaris treatment. An update to these
guidelines was published in 2009 and further states that the combination of a topical
retinoid and antimicrobial agent is the preferred treatment approach for the majority of
patients with acne vulgaris. The guidelines do not differentiate between the available
topical retinoids and state the relative efficacy between agents is unclear. The AAD
recommends an algorithm for the treatment of acne vulgaris as follows:
o Mild acne vulgaris (comedonal): topical retinoid, or azelaic acid, or salicylic acid.
o Mild acne vulgaris (mixed and papular/pustular): topical retinoid + topical
antimicrobial, or azelaic acid.
o Moderate acne vulgaris (mixed and papular/pustular): oral antibiotic + topical
retinoid +/- benzoyl peroxide (BPO).
o Moderate acne vulgaris vulgaris (nodular): oral antibiotic + topical retinoid + BPO,
or oral isotretinoin or alternate oral antibiotic + alternate topical retinoid (+/-)
BPO/azelaic acid.
o Severe acne (nodular/conglobate): oral isotretinoin, or high dose oral antibiotic +
topical retinoid + BPO.
o Maintenance therapy (mild to severe acne vulgaris): topical retinoid +/- BPO.
According to the AAD, approximately 80% of psoriasis patients are affected with mild to
moderate disease and the majority of cases can be successfully treated with topical
agents with topical corticosteroids as the cornerstone of treatment for the majority of
patients with psoriasis. Other topical agents, including tazarotene, are used adjunctively
to either ultraviolet light or systemic medications for resistant lesions in patients with more
severe disease.
RECOMMENDATION
Topical retinoids are indicated for treatment of acne vulgaris and current guidelines from the AAD
state that the combination of a topical retinoid and antimicrobial agent is the preferred treatment
approach for the majority of patients with acne vulgaris. In studies comparing the agents, no one
agent was consistently more efficacious than any other and clinical guidelines do not distinguish
between the agents in this class for the treatment of acne vulgaris. Tazarotene is the only topical
retinoid agent FDA-approved for the treatment of psoriasis. Clinical trials have demonstrated its
efficacy alone as well as in combination with other antipsoriatic agents. Current AAD guidelines
recommend the use of tazarotene as an adjunct to topical corticosteroids which are the
cornerstone of therapy. Therefore, it is recommended at least two topical retinoids be available for
use, one of which should be tazarotene. In order to prevent use of topical retinoids for the
mitigation of fine wrinkles, it is recommended that the topical retinoids be subject to clinical criteria
to ensure medical necessity.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: TOPICAL RETINOIDS
PREFERRED
NON-PREFERRED
Avita® CC (tretinoin)
Atralin® CC (tretinoin)
Epiduo® CC (adapalene/benzoyl peroxide)
Differin® CC (adapalene)
® CC
(tazarotene)
Tazorac
Retin-A® CC (tretinoin)
CC
®
®
tretinoin (compares to Atralin , Avita ,
Retin-A Micro® CC (tretinoin)
®
Retin-A )
Tretin-X® CC (tretinoin)
Ziana® CC (clindamycin/tretinoin)
Page 45 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
Clinical Criteria for tretinoin
o
For a diagnosis of acne, keratosis follicularis, verruca plana, or actinic keratosis:
ƒ Recipients less than 31 years old will be approved.
ƒ Recipients 31 years of age and older will be approved as follows:
• For a diagnosis of keratosis follicularis (or Darier’s disease) - approved for 12
months.
• For a diagnosis of verruca plana - approved for 2 months.
• For a diagnosis of actinic keratosis for the prevention of future lesions - approved
for 12 months.
• For a diagnosis of acne vulgaris, will only be approved if the patient has tried and
failed at least two of the following:
– Benzoyl peroxide
– Salicylic acid
– Topical antibiotics (clindamycin, erythromycin, tetracycline)
– Oral antibiotics (tetracycline, minocycline, erythromycin, doxycycline,
SMP/TMX),
– Azelaic acid
– Sulfur products
Provided the patient has tried and failed two of the above agents, a PA will be
approved for 12months.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Clinical Criteria for Tazorac®
o
o
For a diagnosis of psoriasis, will be approved if the recipient has had a failure of, intolerance
to, or contraindication to, at least one topical steroid.
For a diagnosis of acne, keratosis follicularis, verruca plana, or actinic keratosis:
ƒ Recipients less than 31 years old will be approved.
ƒ Recipients 31 years of age and older will be approved as follows:
• For a diagnosis of keratosis follicularis - approved for 12 months.
• For a diagnosis of verruca plana - approved for 2 months.
• For a diagnosis of actinic keratosis for the prevention of future lesions - approved
for 12 months.
• For a diagnosis of acne vulgaris, will only be approved if the patient has tried and
failed at least two of the following:
– Benzoyl peroxide
– Salicylic acid
– Topical antibiotics (clindamycin, erythromycin, tetracycline)
– Oral antibiotics (tetracycline, minocycline, erythromycin, doxycycline,
SMP/TMX),
– Azelaic acid
– Sulfur products
Provided the patient has tried and failed two of the above agents, a PA will be
approved for 12months.
COMMITTEE VOTE:
APPROVED
Page 46 of 55
DISAPPROVED
APPROVED with MODIFICATION
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed October, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed October, 2009.
3. Med Metrics. Topical Retinoids Therapeutic Class Review. September 14, 2009.
4. Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A comparison of the efficacy and
tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne
vulgaris: a meta-analysis of five randomized trials. Br J Dermatol. 1998;139 Suppl
52:48-56.
5. Tu P, Li GQ, Zhu XJ, Zheng J, Wong WZ. A comparison of adapalene gel 0.1% vs.
tretinoin gel 0.025% in the treatment of acne vulgaris in China. J Eur Acad Dermatol
Venereol. 2001;15 Suppl 3:31-6.
6. Kircik LH. Tretinoin microsphere gel pump 0.04% versus tazarotene cream 0.05% in the
treatment of mild-to-moderate facial acne vulgaris. J Drugs Dermatol. 2009;8(7):650-4.
7. Schiener R, Behrens-Williams S, Pillekamp H, et al. Calcipotriol vs. tazarotene as
combination therapy with narrowband ultraviolet B (311 nm): efficacy in patients with
severe psoriasis. Br J Dermatol. 2000;143:1275-8.
8. Strauss JS, Krowchuk DP, Leyden JJ, Lucky AW, Shalita AR, Siegfried EC, et al.
Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56:65163.
9. Thiboutot D, Gollnick H, Bettoli V, Dreno B, Kang S, Leyden JJ et al. New insights into
the management of acne: An update from the Global Alliance to Improve Outcomes in
Acne Group. J Am Acad Dermatol. 2009;60:S1-50.
10. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al.
Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3.
Guidelines of care for the management and treatment of psoriasis with topical therapies.
J Am Acad Dermatol. 2009;60:643-59.
Page 47 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: TOPICAL KERATOLYTIC AGENTS
BACKGROUND
•
•
•
•
•
•
This review contains only the prescription salicylic acid and urea based topical keratolytic
agents. Of note, there are numerous other salicylic acid and urea based keratolytic
products that are available over-the-counter.
Topical keratolytic agents induce sloughing of cornified epithelium. These agents cause
peeling of the skin by softening and destroying the stratum corneum by increasing
endogenous hydration. In turn this causes the cornified epithelium of the skin to swell,
soften, and then desquamate.
Salicylic acid is FDA-approved as a topical aid in the removal of excessive keratin in
hyperkeratotic skin disorders, including common and plantar warts, psoriasis, calluses
and corns. Urea is FDA-approved for debridement and promotion of normal healing of
hyperkeratotic surface lesions, treatment of hyperkeratotic conditions, and treatment of
damaged, ingrown, and devitalized nails.
Systemic adverse drug events are unlikely with the topical keratolytic agents, since the
systemic bioavailability associated with these agents is extremely low. Adverse events
are usually limited to localized reactions including erythema and scaling with salicyclic
acid and burning, irritation, itching and stinging with urea.
o Due to the potential risk of developing Reye’s syndrome, salicylate products
should not be used in children and teenagers with varicella or influenza, unless
directed by a physician.
o Drug interactions with the topical keratolytic agents are limited due to the topical
route of administration and the relatively low systemic bioavailability.
The agents within this class have been used safely and effectively for many years;
however, there is limited data available evaluating the efficacy of these products for their
approved indications.
The American Academy of Dermatology (AAD) recently released their Guidelines of Care
for the Management of Psoriasis and Psoriatic Arthritis in which topical corticosteroids
are considered the cornerstone of psoriasis treatment; however, other topical agents may
be used. In addition to topical corticosteroids, other topical psoriasis treatment options
recommended by the AAD include, but are not limited to, vitamin D analogues,
tazarotene, tacrolimus, pimecrolimus, nonmedicated topical moisturizers, salicylic acid,
anthralin, coal tar, and combination products. These guidelines further state salicylic acid
has a long standing efficacy and safety profile and is typically used in combination with
other topical products. For the treatment of seborrheic dermatitis, salicylic acid products
are used to soften thick scales. Salicylic acid products can also be used for the
management of cutaneous warts however no treatment has a high treatment success
rate.
RECOMMENDATION
Topical keratolytic agents, such as salicylic acid and urea, are effective and safe therapies for a
number of skin conditions such as seborrheic dermatitis, psoriasis, warts, corns, and calluses.
These agents can be used alone or in combination with other topical therapies, including
corticosteroids. These topical agents are generally well tolerated, with associated side effects
limited to local skin reactions. Additionally, no significant drug interactions have been reported.
The agents within this class have been used safely and effectively for many years; however, there
is limited data available evaluating the efficacy of these products for their approved indications. It
is recommended that at least one topical keratolytic agent be available for use.
COMMITTEE VOTE:
APPROVED
Page 48 of 55
DISAPPROVED
APPROVED with MODIFICATION
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: TOPICAL KERATOLYTIC AGENTS
PREFERRED
NON-PREFERRED
all generic urea products
all branded urea products
all generic salicylic acid products
all branded salicylic acid products
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed September, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed September, 2009.
3. Med Metrics. Topical Keratolytic Agents class review. July 23, 2009.
4. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al.
Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3.
Guidelines of care for the management and treatment of psoriasis with topical therapies.
J Am Acad Dermatol. 2009;60:643-59. Available at:
http://www.aad.org/research/guidelines/index.html.
Page 49 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: TOPICAL ANESTHETICS
BACKGROUND
•
•
•
•
•
•
•
The topical anesthetics include medications for a variety of indications. They are often
used to alleviate itching and pain caused by insect bites, minor burns, sunburns, atopic
dermatitis, or eczema. Additionally, some of these agents may be used to provide an
anesthetic effect during minor surgical procedures and diagnostic tests. Agents
discussed in this review will be limited to the topical anesthetics available by prescription
only.
Lidocaine and prilocaine block both initiation and conduction of nerve impulses by
decreasing ionic flux through the neuronal membrane. The penetration of topical
anesthetics through intact skin will produce an analgesic effect but is not sufficient to
produce complete sensory block.
Lidocaine is FDA approved for use as a local anesthetic in laser, cosmetic and outpatient
surgeries as well as relief of pain from minor cuts, burns and abrasions. The topical
lidocaine patch is FDA approved for relief of allodynia and chronic pain in post herpetic
neuralgia (PHN). The combination of lidocaine and hydrocortisone is FDA-approved as
an anti-inflammatory and anesthetic for skin disorders. The combination of lidocaine and
prilocaine is FDA approved for providing local analgesia on intact skin as well as
providing local analgesia on genital mucosal membranes for superficial minor surgery.
The most common adverse effects associated with the topical anesthetics include
application site reactions such as burning, dermatitis, and erythema. Allergic reactions
are rare and may include bronchospasm, angioedema, pruritis, urticaria, and shock.
o Topical anesthetic products are contraindicated in patients with a known
hypersensitivity to local anesthetics of the amide type.
o Excessive dosing by applying topical anesthetic products to larger areas or for
longer than is recommended could result in increased absorption of lidocaine or
other topical anesthetics, leading to serious adverse effects. Longer duration of
application, application of more than the recommended dose, smaller patients, or
impaired elimination may all contribute to increasing the blood concentration of
topical anesthetic products.
o Prilocaine may contribute to the formation of methemoglobin when used
concomitantly with drugs associated with inducing methemoglobin (i.e.
sulfonamides, acetaminophen, benzocaine, chloroquine, dapsone, nitrates,
nitrites, nitrofurantoin, phenobarbital, phenytoin, and quinine).
The variety of products, dosage forms, and indications present in the topical anesthetics
class of medications makes direct, head-to-head comparisons of these agents difficult.
There are no head-to-head trials evaluating lidocaine 5% patches against the oral
medications that are also indicated for the treatment of pain associated with PHN.
Consensus guidelines for the use of topical anesthetics are lacking, with the exception of
guidelines for the treatment of postherpetic neuralgia. Guidelines from the American
Academy of Neurology (AAN) recommend the use of topical lidocaine, as well as oral
medications such as tricyclic antidepressants, gabapentin, pregabalin, and opioids, for
the treatment of pain associated with PHN, but do not indicate that topical lidocaine
patches are recommended over oral therapies.
RECOMMENDATION
The topical anesthetics include medications for a variety of indications. With the exception of
lidocaine patches, they are often used to alleviate itching and pain caused by insect bites, minor
burns, sunburns, atopic dermatitis, or eczema. Additionally, these agents are commonly used to
provide an anesthetic effect during minor surgical procedures and diagnostic tests. The variety of
products, dosage forms, and indications present makes direct, head-to-head comparisons of these
agents difficult. Additionally, clinical guidelines for the use of topical anesthetics are lacking;
therefore, it is difficult to determine therapeutic alternatives in this category. Based on their FDAapproved indications and place in therapy, it is thought that all topical anesthetics (with the
Page 50 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
exception of lidocaine patches) are similar in safety and efficacy. Therefore, it is recommended at
least one topical anesthetic be available for use..
The topical lidocaine patch has a unique indication for the treatment of pain associated with
postherpetic neuralgia. Guidelines from the American Academy of Neurology (AAN) recommend
the use of topical lidocaine, as well as oral medications such as tricyclic antidepressants,
gabapentin, pregabalin, and opioids, for the treatment of pain associated with PHN, but do not
indicate that topical lidocaine patches are recommended over oral therapies. In addition, there are
no head-to-head trials evaluating lidocaine patches against the oral medications that are also
indicated for the treatment of pain associated with PHN. Due to their high cost and limited
indications, it is recommended that topical lidocaine patches be subject to clinical criteria in order
to ensure appropriate use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: TOPICAL ANESTHETICS
PREFERRED
NON-PREFERRED
lidocaine
all brand lidocaine products
lidocaine HC
EMLA® (lidocaine/prilocaine)
Lidoderm® CC (lidocaine transdermal patch)
lidocaine viscous
®
Lidamantle HC® (lidocaine/hydrocortisone)
lidocaine/prilocaine (compares to EMLA )
Clinical Criteria for Lidoderm®
Lidoderm® will be approved for patients with a diagnosis of neuropathic pain who have had a
failure of, contraindication to, or intolerance of at least one agent in ALL of the following classes:
• Tricyclic antidepressants
• Anticonvulsants
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed September, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed September, 2009.
3. Med Metrics. Topical Anesthetics class review. July 23, 2009.
4. Dubinsky R, Kabbani H, El-Chami Z, Boutwell C, Ali H, et al. Practice parameter:
treatment of postherpetic neuralgia: an evidence-based report of the quality standards
subcommittee of the American Academy of Neurology. Neurology. 2004;63:959-65.
Page 51 of 55
November 10, 2009 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: DERMATOLOGICS/TOPICAL ANTINEOPLASTICS
BACKGROUND
• The topical antineoplastic therapeutic class consists of four agents; alitretinoin,
bexarotene, diclofenac gel, and fluorouracil. The agents are used to treat several
dermatologic conditions including acquired immunodeficiency syndrome(AIDS)-related
Kaposi’s sarcoma, cutaneous T-cell lymphoma, actinic keratosis (AK), and superficial
basal cell carcinomas (BCC)
• Alitretinoin is a naturally occurring endogenous retinoid that is thought to affect the
expression of genes that inhibit cell proliferation, induce cell differentiation, and trigger
apoptosis; its exact mechanism of action is not fully understood.
• Bexarotene is a synthetic retinoid analog that selectively binds with and activates retinoid
X receptor subtypes impacting the expression of genes controlling cellular differentiation,
apoptosis, and proliferation.
• Diclofenac, as 3% gel is a nonsteroidal anti-inflammatory agent; its mechanism of action
in the treatment of AK is not fully understood. Proposed mechanisms include reduced
inflammation by inhibiting chemotaxis, altering lymphocyte activity and inhibiting
neutrophil aggregation/activation.
• Fluorouracil is a fluorinated pyrimidine antagonist that exerts its antimetabolite action by
interfering with deoxyribonucleic acid synthesis.
• FDA-Approved Indications:
Indication
AIDS-related Kaposi’s sarcoma
Cutaneous T-cell lymphoma (stage
IA and IB) refractory or persistent
after other therapies; or patents
unable to tolerate other therapies
Actinic keratosis
Superficial basal cell carcinomas
when conventional methods are
unable to be utilized
o
Bexarotene
Diclofenac
Fluorouracil
a
a
a®
Efudex 5%
only
a
The most common adverse effects include:
ƒ
Aliretinoin: paresthesias, dermatitis, erythema, irritation, rash, and
burning, pain and scaling
ƒ
Bexarotene: headache, dermatitis, rash, and pain
ƒ
Diclofenac: paresthesias, dermatitis, exfoliation, puritis, rash
ƒ
Fluorouracil: erosion, erythema, edema, burning and pain
o
Fluorouracil should not be used in patients with dihydropyrimidine
dehydrogenase (DPD) enzyme deficiency. A significant portion of fluorouracil is
catabolized by the enzyme DPD; this deficiency may result in cytotoxic activity
and potential toxicities.
o
All topical antineoplastics have been associated with photosensitivity. Patients
should minimize exposure of treated areas to sunlight and sunlamps during the
use of these agents.
o
Application of fluorouracil to mucous membranes should also be avoided due to
the possibility of local inflammation and ulceration.
o
Significant Drug-Drug Interactions:
ƒ
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Alitretinoin
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Use of aliretinoin can cause increase in absorption of N,N-diethyl-mtoluamide (DEET)
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Head to head clinical trial comparisons are difficult for the category of agents due to
differing indications except for actinic keratosis. However there are no direct head to
head comparisons between diclofenac and fluorouracil for the treatment of AK.
o Alitretinoin has been proven to be effective in treating Kaposi’s sarcoma in
placebo-controlled trials.
o Topical bexarotene for the treatment of cutaneous T-cell lymphoma has been
shown to be effective in an open-label trial evaluating its use in patients who
have failed other therapies.
o No placebo-controlled studies evaluating the use of fluorouracil 5% cream or
fluorouracil 5% solution in the treatment of superficial basal cell carcinomas were
identified.
o Diclofenac 3% gel and fluorouracil both have demonstrated efficacy in treatment
of AK when compared to placebo.
o Additionally, newer strengths and formulations of fluorouracil like the 0.5% cream
®
(Carac ) were included in efficacy studies in patients with AK, where they were
compared to both placebo and the 5% cream commercially available as Efudex®.
These studies show comparable efficacy between the 5% cream and the 0.5%
cream in reducing the number and percentage of AK lesions compared to
baseline values, though some of them suggest better tolerability of the 0.5%
formulation.
o Loven et al. did not show a significant difference between the two formulations of
fluorouracil, with total clearance of AK lesions occurring at the same rate (43%)
in a group of patients who used both formulations simultaneously, the 0.5%
cream on one side of the face and the 5% cream on the other side. A higher
proportion of patients preferred the 0.5% cream (85% vs 15%). This study also
observed no significant difference in the incidence of burning, erosion, pruritis,
pain, or edema between the two treatments, though a lower cumulative
proportion of patients reported these symptoms in the 0.5% group and a
significantly greater portion of patients expressed a willingness to re-treat with
the 0.5% cream (P=0.031).
o Tanghetti et al. compared fluorouracil to imiquimod for the treatment of AK. The
total AK lesion count was significantly different between the groups in favor of
fluorouracil at weeks 8, 12, 16, and 24 (P<0.05). This significant difference was
also documented in the mean reduction in total AK count at weeks 8, 12, 16, and
24 with the total AK count reduced by 94% from baseline in the fluorouracil group
vs 66% in the imiquimod group (P<0.05). The differences between the groups in
the mean scores for the physicians’ global assessment was also significantly
different in favor of fluorouracil at weeks 4, 8, 12, 16, and 24 (P<0.05). In terms of
adverse events, erythema was initially higher in the fluorouracil group; however it
lasted longer in the imiquimod group.
o Diclofenac gel was also compared to imiquimod for the treatment of AK in a
study by Kose et al. This trial found no significant difference between the agents
in terms of efficacy, safety, or tolerability.
For the treatment of AIDS-related Kaposi’s sarcoma, the National Cancer Institute (NCI)
guidelines include the use of alitretinoin gel as effective local disease control in clinical
trials of localized tumors. NCI identifies radiation and systemic chemotherapy as first line
therapy.
For the treatment of cutaneous T cell lymphomas (CTCL) of the skin, the NCI and the
National Comprehensive Cancer Network (NCCN) include bexarotene in treatment
recommendations for stages I through IV for CTCL.
For the treatment of actinic keratosis, the British Association of Dermatologists includes
topical fluorouracil, diclofenac gel, imiquimod cream, cryosurgery, and phototherapy as
treatment options for AK. However, the guidelines do not give preference to one
treatment over another. It is difficult to make direct comparisons of these agents for the
treatment of AK based on the lack of head-to-head trials for this indication. Overall,
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therapeutic decisions in the treatment of AK should be based on clinical guidelines,
adverse effects, and the tolerability of each agent.
For the treatment of BCC, the NCCN recommend use of fluorouracil and other topical
therapies when BCC is low risk or when surgery or radiation therapy is contraindicated
and the British Association of Dermatologists include topical fluorouracil in treatment
options for multiple superficial basal cell carcinoma on the trunk and lower extremities.
However it is noted that cure rates may be lower with topical treatments versus surgery
or radiation therapy.
RECOMMENDATION
The topical antineoplastics are a diverse group of agents with different indications including
treatment of AIDS-related Kaposi’s sarcoma, cutaneous T cell lymphomas, actinic keratosis, and
basal cell carcinoma. Clinical trial data demonstrate efficacy of agents with respect to unique
indications, and current clinical guidelines include use of alitretinoin, bexarotene, diclofenac 3%
gel, and various formulations of fluorouracil in treatment options, however no single agent has
been recommended over another. Therefore it is recommended that at least one agent for each
unique indication be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: DERMATOLOGICS/TOPICAL ANTINEOPLASTICS
PREFERRED
NON-PREFERRED
Efudex® 5% cream
Fluorouracil
Carac® (fluorouracil 0.5% cream)
Efudex® 2% solution
®
Fluoroplex (fluorouracil 1% cream)
Efudex® 5% solution
®
Panretin (alitretinoin)
Solaraze® (diclofenac 3% gel)
Targretin® (bexarotene)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed October, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed October, 2009.
3. MedMetrics. Topical Antineoplastics class review. 07/30/2009.
4. Heald P, Mehlmauer M, Martin A, et al. Topical bexarotene therapy for patients with
refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III
clinical trial. J Am Acad Dermatol. 2003;49(5):801-5.
5. Walmsley S, Northfelt D, Melosky B, et al. Treatment of AIDS-related Kaposi’s sarcoma
with topical alitretinoin (9-cis-retinoic acid) gel. J Acquir Immune Defic Syndr.
1999;22(3):235-53.
6. Bodsworth N, Bloch M, Bower M, et al. Phase III vehicle-controlled, multi-centered study
of topical alitretinoin gel 0.1% in cutaneous AIDS-related Kaposi’s sarcoma. Am J Clin
Dermatol. 2001;2(2):77-8.
7. Loven K, Stein L, Furst K, Levy S. Evaluation of the efficacy and tolerability of 0.5%
fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients
with actinic keratosis. Clin Ther. 2002;24(6):990-1000.
8. Tanghetti E, Werschler P. Comparison of 5% 5-fluorouracil cream and 5% imiquimod
cream in the management of actinic keratoses on the face and scalp. JDD.
2007;6(2):144-7.
9. Krawtchenko N, Roewert-Huber J, Mann I, Sterry W, Stockfleth E. British Journal of
Dermatology. 2007;157(suppl 2):34-40.
10. National Cancer Institute, PDQ (Physician Data Query) Comprehensive Cancer
®
Database. Kaposi Sarcoma Treatment (PDQ ) [Internet]. Bethesda (MD): National
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11.
12.
13.
14.
Institutes of Health (US), National Cancer Institute; 2009 March 3 [cited 2009 July 24].
Available from:
http://www.cancer.gov/cancertopics/pdq/treatment/kaposis/healthprofessional/allpages.
National Cancer Institute, PDQ (Physician Data Query) Comprehensive Cancer
Database. Mycosis Fungoides and the Sezary Syndrome Treatment (PDQ®) [Internet].
Bethesda (MD): National Institutes of Health (US), National Cancer Institute; 2008 May
22 [cited 2009 July 24]. Available from:
http://www.cancer.gov/cancertopics/pdq/treatment/mycosisfungoides/HealthProfessional.
National Comprehensive Cancer Network. NCCN Clinical practice guidelines in
oncology: Mycosis Fungoides/Sézary Syndrome v.2.2009 [monograph on the internet].
Jenkintown (PA): National Comprehensive Cancer Network, Inc.; 2009 [cited 2009 July
24]. Available from: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.
British Association of Dermatologists Therapy Guidelines and Audit Subcommittee.
Guidelines for the Management of Actinic Keratoses. Br J Dermatol. 2007
Feb;156(2):222-30.
National Comprehensive Cancer Network. NCCN Clinical practice guidelines in
oncology: Basal Cell and Aquamous Cell Skin Cancers v.I.2009 [monograph on the
internet]. Jenkintown (PA): National Comprehensive Cancer Network, Inc.; 2009 [cited
2009 July 24]. Available from:
http://www.nccn.org/professionals/physician_gls/PDF/nmsc.pdf.
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