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Proposed
Preferred Drug List
with
Clinical Criteria
Proposal for TennCare
May12, 2009
Page 1 of 46
May 12, 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 46
February 26, 2009, 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 46
February 26, 2009 Tennessee PAC
ANALGESIC AGENTS
NEW: NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS
BACKGROUND
•
•
•
•
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) are synthetic analogs
of naturally occurring nucleosides, which are the building blocks of deoxyribonucleic acid
(DNA) and ribonucleic acid (RNA). There are currently seven available nucleoside
reverse transcriptase inhibitors: abacavir, didanosine, emtricitabine, lamivudine,
stavudine, and zidovudine. Tenofovir is the only available nucleotide reverse
transcriptase inhibitor.
Active metabolites of NRTIs compete with endogenous substrates for the active binding
site on HIV reverse transcriptase and/or HBV DNA polymerase. Once the metabolites
become incorporated into viral DNA, synthesis of the viral DNA chain is terminated and
viral replication is inhibited.
All of the currently available NRTIs are FDA-approved for the treatment of HIV-1 infection
in combination with other antiretroviral agents. Additionally, zidovudine is approved for
the prevention of maternal-fetal HIV transmission. Lamivudine, and tenofovir are FDAapproved for the treatment of chronic hepatitis B.
In general, the most common adverse drug events observed with NRTIs are diarrhea,
fatigue, headache, nausea, vomiting, rash, and sleep disorders. Tenofovir is also often
commonly associated with depression.
o Black Box Warnings:
ƒ All NRTIs carry a black box warning regarding potentially fatal lactic
acidosis and severe hepatomegaly with steatosis. However, these
events have been more frequently reported with stavudine, didanosine
and zidovudine.
ƒ Abacavir carries a black box warning regarding serious and potentially
fatal hypersensitivity reactions.
ƒ Didanosine and stavudine carry black box warnings regarding
pancreatitis.
ƒ Tenofovir carries a black box warning regarding severe acute
exacerbations of hepatitis in HBV-infected patients who discontinue
tenofovir therapy. Severe acute exacerbations of hepatitis B have also
been reported in patients who have discontinued anti-hepatitis B therapy,
including lamivudine, and emtricitabine.
ƒ Zidovudine carries black box warnings regarding hematologic toxicity
and should be used with caution in patients who have bone marrow
compromise. In patients with advanced symptomatic human
immunodeficiency virus (HIV) disease, anemia and neutropenia were the
most significant adverse events observed. Pancytopenia, which was
reversible in most instances after discontinuation of the drug, has been
associated with zidovudine.
ƒ Zidovudine carries a black box warning regarding the risk of symptomatic
myopathy with prolonged use.
o Precautions:
ƒ In general, the NRTIs are primarily eliminated by the kidneys and, with
the exception of abacavir, dosage adjustment is recommended in
patients with renal insufficiency.
ƒ Since fatal lactic acidosis has been reported in pregnant women who
received didanosine in conjunction with stavudine, this antiretroviral
combination should be used with caution during pregnancy and only if
the potential benefit clearly outweighs the potential risk.
ƒ Lamivudine should be used cautiously in pediatric patients with a history
of prior antiretroviral nucleoside exposure, pancreatitis, or other
significant risk factors for the development of pancreatitis since fatal
pancreatitis has been reported in this population.
Page 4 of 46
February 26, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
During combination antiretroviral therapy with didanosine and stavudine,
patients with preexisting liver dysfunction have an increased frequency of
liver function abnormalities, including severe and potentially fatal hepatic
adverse events. The combination of didanosine, hydroxyurea and
stavudine should be avoided since fatal hepatic events have been
reported in patients receiving these agents concurrently.
ƒ Renal impairment has been reported with use of tenofovir, and creatinine
clearance should be calculated in all patients prior to initiating therapy
and as clinically appropriate during tenofovir therapy.
ƒ Abacavir and didanosine may be correlated with an increased risk of
myocardial infarction, particularly in patients with preexisting cardiac risk
factors. In a prospective epidemiological study designed to investigate
the rate of myocardial infarction in patients on combination antiretroviral
therapy, recent use of abacavir and didanosine was correlated with an
increased risk of myocardial infarction, particularly in patients with
preexisting cardiac risk factors. A second study also suggested an
increased risk of myocardial infarction associated with abacavir use but
not didanosine. In a sponsor-conducted pooled analysis of clinical trials,
no excess risk of myocardial infarction was observed in abacavir-treated
subjects as compared with control subjects. In totality, the available data
are inconclusive regarding the risk of myocardial infarction and abacavir
or didanosine.
ƒ Severe motor weakness resembling Guillain-Barre syndrome has been
reported rarely in patients receiving stavudine. Peripheral neuropathy
has been reported in patients receiving didanosine and stavudine.
ƒ Retinal changes and optic neuritis have been reported in patients taking
didanosine.
ƒ Tenofovir use has been associated with decreases in bone mineral
density and osteomalacia.
Drug-Drug Interactions:
ƒ Didanosine powder for oral solution should be mixed with an antacid
before administration. Drugs whose absorption can be affected by
stomach acidity or that interact with antacids may interact with
reconstituted didanosine oral solution.
ƒ Other clinically significant drug-drug interactions are listed in the table
below:
ƒ
o
Generic
Name
Nucleoside
reverse
transcriptase
inhibitors
Lamivudine,
stavudine,
zidovudine
Interacting
Medication or
Disease
Ribavirin
Interferons,
ribavirin
Didanosine
Allopurinol
Didanosine
Ganciclovir
Didanosine
Tenofovir
Page 5 of 46
Potential Result
Administration of these agents with ribavirin has resulted in fatal
and nonfatal lactic acidosis. Co-administration of these agents
with ribavirin should be undertaken with caution and only if the
potential benefit outweighs the potential risks.
HIV/hepatitis C virus (HCV) co-infected patients receiving
combination antiretroviral therapy for HIV, and interferons and
ribavirin for HCV may be at increased risk for serious side effects
(e.g., anemia, hepatic decompensation, neutropenia).
Allopurinol increases didanosine concentrations, which may
increase didanosine-associated toxicity. Concurrent use is not
recommended.
The risk of didanosine toxicity and CD4 T-cell loss or failure of
CD4 T-cell recovery may be increased.
Didanosine levels may be elevated, increasing the risk of lifethreatening adverse reactions (e.g., lactic acidosis, pancreatitis).
Coadminister with caution and monitor closely for adverse
reactions, especially in patients with renal insufficiency. A dosage
reduction of didanosine is recommended.
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
Generic
Name
Tenofovir
Interacting
Medication or
Disease
Adefovir
Tenofovir
Atazanavir
Tenofovir
Lopinavir/ritonavir
Zidovudine
Atovaquone
Zidovudine
Ganciclovir
Zidovudine
Methadone
Zidovudine
Probenecid
Zidovudine
Valproic acid
•
Potential Result
In the treatment of chronic hepatitis B, these agents should not be
administered in combination.
Tenofovir may decrease atazanavir concentrations. When
coadministered with tenofovir, dose adjustments are
recommended. Atazanavir may increase tenofovir concentrations.
When coadministered, monitor for tenofovir-associated adverse
reactions (e.g., renal impairment).
Lopinavir/ritonavir may increase tenofovir concentrations. When
coadministered, monitor for tenofovir-associated adverse
reactions.
Atovaquone may inhibit the glucuronidation of zidovudine, leading
to elevated zidovudine concentrations and increased risk of
toxicity.
Coadministration may result in life-threatening hematologic
toxicity. Coadministration should be avoided.
Monitor the effects of zidovudine during concurrent use of
methadone since zidovudine levels may be elevated.
Coadminister with caution since cutaneous eruptions, malaise,
myalgia and fever have been reported.
Valproic acid may decrease the first-pass glucuronide metabolism
of zidovudine. The dose of zidovudine may need to be adjusted
when starting, stopping or changing the dose of valproic acid.
Monitor hemoglobin and hematocrit.
Clinical trials have demonstrated safety and efficacy with various dual-NRTI combinations
when added to an NNRTI or protease inhibitor. Extensive data support inclusion of
emtricitabine or lamivudine as 1 of the 2 NRTIs.
o The 934 study compared a regimen of emtricitabine/tenofovir/efavirenz to
lamivudine/zidovudine/efavirenz in antiretroviral-naïve HIV-1 infected patients
≥18 years of age with plasma HIV-1 RNA levels >10,000 copies/mL. Through
144 weeks, significantly more patients in the emtricitabine/tenofovir/efavirenz
group reached and maintained HIV-1 RNA levels <400 copies/mL than did those
in the lamivudine/zidovudine/efavirenz group (71% vs 58%, respectively;
P=0.004). Patients receiving emtricitabine/tenofovir/efavirenz experienced a
trend toward greater CD4 cell increase over baseline at 144 weeks than
3
lamivudine/zidovudine/efavirenz (312 vs 271 cells/mm , respectively; P=0.09).
More patients receiving lamivudine/zidovudine/efavirenz than
emtricitabine/tenofovir/efavirenz discontinued their study regimen (41% vs 29%;
P=0.004). Cumulatively, there were more discontinuations attributable to
virologic failure (6% vs 2%; P=0.038) and adverse events (11% vs 5%; P=0.01).
o The 903 study compared a regimen of stavudine/lamivudine/efavirenz to
tenofovir/lamivudine/efavirenz in antiretroviral-naïve HIV-1 infected patients with
plasma HIV RNA levels >5,000 copies/mL. The combination of
tenofovir/lamivudine/efavirenz was highly effective and comparable to stavudine/
lamivudine/efavirenz (70.6% vs. 64.1%, respectively; no P value reported)
through 144 weeks.
o The CNA30024 study compared a regimen containing
abacavir/lamivudine/efavirenz to zidovudine/lamivudine/efavirenz in antiretroviralnaïve HIV-1 infected patients ≥18 years of age with plasma HIV-1 RNA levels
3
>400 copies/mL and CD4 cell counts >50 cells/mm . Virologic responses were
similar (69% vs 70% with HIV-1 RNA levels of ≤ 50 copies/mL) in both arms, the
CD4 cell count increase was greater in the abacavir regimen (209 cells/mm3 vs.
155 cells/mm3, P=0.005).
Page 6 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
•
Highly active antiretroviral therapy (HAART) that includes a minimum of three drugs is
recommended for the management of HIV in most patients. Current guidelines from the
Department of Health and Human Service (DHHS) and the International Acquired
Immunodeficeincy Syndrome Society- USA (AIDS-US) both recommend regimens that
contain two nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) with
either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted
protease inhibitor as first-line therapy in treatment-naïve patients. DHHS guidelines
recommend the preferred dual-NRTI regimen for initial combination therapy is tenofovir
and [emtricitabine (coformulated) or lamivudine]. Alternative dual-NRTI regimens include
abacavir and [lamivudine (coformulated) or emtricitabine] in patients who tested negative
for HLA-B*5701; didanosine and [lamivudine or emtricitabine]; or zidovudine and
[lamivudine (coformulated) or emtricitabine]. The 2008 IAIDS-USA guidelines
recommend [abacavir or tenofovir] with [emtricitabine or lamivudine] as the initial dualNRTI combination. The combination of lamivudine and zidovudine is an alternative dualNRTI component, although the guidelines state gastrointestinal and central nervous
system adverse effects and associations with lipoatrophy and anemia make this choice
less desirable.
RECOMMENDATION
For the management of HIV infections, the primary goals of antiretroviral therapy are to maximally
and durably suppress HIV viral load, preserve and/or restore immunologic function, reduce
morbidity and mortality, and improve quality of life. Highly active antiretroviral therapy (HAART)
that includes a minimum of 3 drugs is recommended for the management of HIV in most patients.
Current guidelines from the Department of Health and Human Service (DHHS) and the
International Acquired Immunodeficeincy Syndrome Society- USA (IAIDS-USA) both recommend
regimens that contain 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with either a
nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor as
first-line therapy for most patients. In their 2008 guidelines, DHHS recommends tenofovir in
combination with emtricitabine or lamivudine as the preferred initial dual-NRTI therapy. The 2008
International AIDS Society US Panel recommends [abacavir or tenofovir] in combination with
[emtricitabine or lamivudine] as the initial dual-NRTI therapy. Alternative dual-NRTI regimens
include abacavir and [lamivudine or emtricitabine]; didanosine and [lamivudine or emtricitabine]; or
zidovudine and [lamivudine or emtricitabine]. Given that all available NRTIs, with the exception of
stavudine, are recommended as first line or alternative therapies for treatment-naïve patients, and
given the need to have multiple NRTIs available for use in dual therapy, it is recommended that all
NRTIs indicated for the treatment of HIV-1 infections be available.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
NEW: NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS
PREFERRED
NON-PREFERRED
didanosine capsulesQL (compares to
Retrovir® QL (zidovudine)
®
Videx )
Videx® capsules QL (didanosine)
® QL
(emtricitabine)
Emtriva
Zerit® QL (stavudine)
® QL
(lamivudine)
Epivir
stavudineQL (compares to Zerit®)
Videx solution (didanosine)
Viread® QL (tenofovir)
Ziagen® QL (abacavir)
zidovudineQL (compares to Retrovir®)
*Note: current users of non-preferred products will be grandfathered for 90 days.
Page 7 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
Quantity Limits
didanosine capsules: 1 per day
solution: 40 mL per day
Emtriva® capsules: 1 per day
solution: 24 mL per day
Epivir® 100 mg & 300 mg tabs: 1 per day
150 mg tabs: 2 per day
5mg/mL solution: 20 mL per day
10 mg/mL solution: 30 mL per day
Retrovir® 100 mg capsule: 6 per day
300 mg tablet: 2 per day
syrup: 60 mL per day
stavudine capsules: 2 per day
solution: 80 mL per day
Videx® capsules: 1 per day
solution: 40 mL per day
Viread® 1 per day
Zerit® capsules: 2 per day
solution: 80 mL per day
Ziagen® tablet: 2 per day
solution: 30 mL per day
zidovudine 100 mg capsule: 6 per day
300 mg tablet: 2 per day
syrup: 60 mL 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 April, 2009.
2. MedMetrics. Nucleotide Analog Reverse Transcriptase Inhibitors Therapeutic Class
Review. February 25, 2009.
3. MedMetrics. Nucleoside Analog Reverse Transcriptase Inhibitors. Therapeutic Class
Review. February 26, 2009.
4. Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine,
and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naïve
patients: 144-week analysis. J Acquir Immune Defic Syndr. 2008 Jan 1;47(1):74-8.
5. Gallant JE, Staszewski S, Pozniak AL, et al; 903 Study Group. Efficacy and safety of
tenofovir DF vs stavudine in combination therapy in antiretroviral-naïve patients: a 3year randomized trial. JAMA. 2004 Jul 14;292(2):191-201.
6. Lai CL, Gane E, Liaw YF, et al; Globe Study Group. Telbivudine versus lamivudine in
patients with chronic hepatitis B. N Engl J Med. 2007 Dec 20;357(25):2576-88.
7. Liaw YF, Gane E, Leung N, et al; GLOBE Study Group. 2-Year GLOBE trial results:
telbivudine is superior to lamivudine in patients with chronic hepatitis B.
Gastroenterology. 2009 Feb;136(2):486-95.
8. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. November 3, 2008;1-139. Available at http://www.aidsinfo.nih.gov.
Accessed January 21, 2009.
9. Hammer SM, Eron JJ Jr, Reiss P, et al; International AIDS Society–USA. Antiretroviral
treatment of adult HIV infection: 2008 recommendations of the International AIDS
Society–USA panel. JAMA. 2008 Aug 6;300(5):555-70.
10. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment
Guidelines, 2006. MMWR Morb Mortal Wkly Rep. 2006;55(No. RR-11):1-101. Available
from: http://www.cdc.gov/std/treatment/default.htm. Accessed January 21, 2009.
11. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39.
Page 8 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
12. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of
chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol
Hepatol. 2008 Dec;6(12):1315-41.
NEW: PROTEASE INHIBITORS
BACKGROUND
•
•
•
•
•
In the management of human immunodeficiency virus (HIV) infections, the primary goals
of antiretroviral therapy are to maximally and durably suppress HIV viral load, to preserve
and/or restore immunologic function, to reduce morbidity and mortality, and to improve
quality of life. Highly active antiretroviral therapy (HAART) that includes a minimum of
three drugs is recommended for the management of HIV in most patients. Currently,
there are nine protease inhibitors available in the United States: atazanavir, darunavir,
fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, saquinavir, ritonavir and tipranavir.
The protease inhibitors prevent the replication of HIV-1 by inhibiting HIV protease which
results in the production of noninfectious immature virions.
All of the protease inhibitors, with the exception of tipranavir, are FDA-approved for the
treatment of HIV-1 infection in combination with other antiretroviral agents. Tipranavir is
FDA-approved in combination with other antiretroviral agents for the treatment of HIV-1
infection in treatment-experienced patients who are infected with HIV-1 strains resistant
to more than one protease inhibitor.
Darunavir, lopinavir, saquinavir and tipranavir require coadministration with ritonavir to
achieve effective serum concentrations in HIV-1 treatment. Atazanavir and
fosamprenavir require coadministration with ritonavir to achieve effective serum
concentrations in HIV-1 treatment-experienced patients.
As a class, the protease inhibitors are commonly associated with gastrointestinal side
effects and metabolic changes, such as increases in cholesterol, glucose and
triglycerides, and changes in body fat distribution. Distinguishing adverse events for the
protease inhibitors include the following: unconjugated hyperbilirubinemia with
atazanavir; hyperlipidemia with darunavir and lopinavir; rash with darunavir and
fosamprenavir; nephrolithiasis with indinavir; diarrhea with nelfinavir; gastrointestinal
intolerance with ritonavir; and mild nausea and bloating with saquinavir.
o Tipranavir has black box warnings regarding the risk of hepatotoxicity and
intracranial hemorrhage, both of which have been associated with fatalities.
o Tipranavir is contraindicated in patients with moderate or severe hepatic
dysfunction. The combination of saquinavir and ritonavir is contraindicated in
patients with severe hepatic impairment.
o Precautions:
ƒ Atazanavir and ritonavir have been shown to prolong the PR interval of
the electrocardiogram in some patients. Atazanavir and ritonavir should
be used with caution in patients at increased risk for developing cardiac
conduction abnormalities and in patients receiving other drugs that may
prolong the PR interval.
ƒ Darunavir, fosamprenavir and tipranavir contain a sulfonamide moiety
and should be used with caution in patients with a known sulfonamide
allergy.
ƒ Increased transaminases, hepatitis, and hepatic dysfunction, including
some fatalities, have been reported in patients receiving fosamprenavir,
indinavir and ritonavir alone or in combination with darunavir, lopinavir
and tipranavir. Patients with preexisting liver dysfunction, including
hepatitis B or C, who are taking multiple concomitant medications and/or
with advanced acquired immunodeficiency syndrome (AIDS) have an
increased risk for liver function abnormalities including severe hepatic
adverse events.
Page 9 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
Nephrolithiasis/urolithiasis has occurred with indinavir therapy with a
cumulative frequency of nephrolithiasis in 12% and 29% of adult and
pediatric patients, respectively. Cases of nephrolithiasis were also
reported during postmarketing surveillance in HIV-1 infected patients
receiving atazanavir therapy.
ƒ New-onset diabetes mellitus, exacerbation of preexisting diabetes
mellitus, hyperglycemia and diabetic ketoacidosis have been reported
during postmarketing surveillance in HIV-infected patients receiving
protease inhibitor therapy.
ƒ Pancreatitis has been observed in patients receiving lopinavir and
ritonavir, and some cases have been fatal. Patients with advanced HIV-1
disease may be at increased risk of elevated triglycerides and
pancreatitis, and patients with a history of pancreatitis may be at
increased risk for recurrence during lopinavir and ritonavir therapy.
Treatment with fosamprenavir, and ritonavir alone or in combination with
lopinavir, saquinavir or tipranavir have resulted in increased total
cholesterol and/or triglyceride levels.
ƒ Tipranavir plus ritonavir should be used with caution in patients who may
be at risk of increased bleeding from trauma, surgery or other medical
conditions, or who are receiving medications known to increase the risk
of bleeding. Tipranavir administered with ritonavir has been associated
with reports of both fatal and nonfatal intracranial hemorrhage. Acute
hemolytic anemia has been reported in patients treated with amprenavir
(fosamprenavir) and indinavir.
o Drug interactions are important considerations with protease inhibitors because
they are substrates, inducers and/or inhibitors of various isoenzymes of the
cytochrome P450 enzyme system. Coadministration of protease inhibitors is
contraindicated with drugs that are highly dependent on the cytochrome P450
3A4 isoenzyme for clearance, and for which elevated plasma concentrations are
associated with serious and/or life-threatening events. Ritonavir carries a black
box warning regarding these drug interactions. Coadministration of protease
inhibitors is also contraindicated with potent CYP3A4 inducers where reduced
plasma concentrations of the protease inhibitor may be associated with the
potential for loss of virologic response and possible resistance and crossresistance.
Once-daily atazanavir plus ritonavir was shown to produce similar virologic and
immunologic responses as once-daily fosamprenavir plus ritonavir and twice-daily
lopinavir plus ritonavir. In general, hyperbilirubinemia was observed more frequently in
patients treated with atazanavir plus ritonavir and increases in cholesterol and/or
triglycerides were observed more frequently in patients treated with lopinavir plus
ritonavir. Regimens containing once-daily darunavir plus ritonavir, twice-daily
fosamprenavir plus ritonavir and twice-daily saquinavir plus ritonavir were also shown to
be comparable in efficacy to twice-daily lopinavir plus ritonavir in treatment-naïve
patients. While lopinavir plus ritonavir was shown to be more effective than nelfinavir,
studies comparing fosamprenavir plus ritonavir to nelfinavir have produced mixed results
with 1 trial demonstrating greater efficacy with fosamprenavir plus ritonavir and another
showing comparable efficacy.
Several clinical trials reported that ritonavir-boosted darunavir and tipranavir were
effective in treatment-experienced patients. When added to optimized background
therapy, darunavir plus ritonavir achieved better virological and immunological responses
over 48 weeks than lopinavir plus ritonavir and the investigator-selected protease
inhibitor. Tipranavir plus ritonavir achieved better virological and immunological
responses than the investigator-selected protease inhibitor. Elevations in serum
transaminase, cholesterol and triglyceride levels were more frequent with tipranavir plus
ritonavir than the comparator protease inhibitor. There are no published studies
evaluating the efficacy of tipranavir plus ritonavir in antiretroviral-treatment naïve patients.
ƒ
•
•
Page 10 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
•
Highly active antiretroviral therapy (HAART) that includes a minimum of three drugs is
recommended for the management of HIV in most patients. Current guidelines from the
Department of Health and Human Service (DHHS) and the International Acquired
Immunodeficeincy Syndrome Society- USA (IAIDS-USA) both recommend regimens that
contain two nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) with
either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted
protease inhibitor as first-line therapy in treatment-naïve patients. Both guidelines
recommend that initial choice of therapy should be individualized and dependent on the
drug susceptibility of the individual patient’s HIV. The following protease inhibitor
regimens are recommended for treatment-naïve patients in both the DHHS and IAIDSUSA guidelines: atazanavir plus ritonavir,darunavir plus ritonavir, fosamprenavir plus
ritonavir, and lopinavir plus ritonavir (coformulated). Guidelines from the IAIDS-USA also
consider saquinavir plus ritonavir as a first-line option while DHHS guidelines consider
this regimen as an alternative option. Protease inhibitors that are not recommended as
initial treatment, according to DHHS guidelines, include indinavir (with or without
ritonavir), nelfinavir, ritonavir alone and tipranavir plus ritonavir. In addition, the following
unboosted protease inhibitors are not recommended as initial therapy: darunavir,
indinavir and saquinavir.
RECOMMENDATION
For the management of HIV infections, the primary goals of antiretroviral therapy are to maximally
and durably suppress HIV viral load, preserve and/or restore immunologic function, reduce
morbidity and mortality, and improve quality of life. Highly active antiretroviral therapy (HAART)
that includes a minimum of 3 drugs is recommended for the management of HIV in most patients.
Current guidelines from the Department of Health and Human Service (DHHS) and the
International Acquired Immunodeficeincy Syndrome Society- USA (AIDS-US) both recommend
regimens that contain 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with either a
nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor as
first-line therapy for most patients. On the basis of clinical trial efficacy, the barrier for virologic
resistance, convenience and tolerability, the following protease inhibitor regimens are
recommended for treatment-naïve patients: atazanavir plus ritonavir, darunavir plus ritonavir,
fosamprenavir plus ritonavir, and lopinavir plus ritonavir. Guidelines from the International AIDSUS Panel also consider saquinavir plus ritonavir as a first-line option. Therefore, it is
recommended that all of these first line agents for treatment-naïve patients be available for use.
Ritonavir-boosted darunavir and tipranavir have demonstrated activity against resistant viruses
and are important options in treatment-experienced patients. Tipranavir is only FDA approved for
use in treatment-experienced patients who are infected with HIV-1 strains resistant to more than 1
protease inhibitor. Therefore, it is recommended that tipranavir be reserved for use in treatmentexperienced patients.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
NEW: PROTEASE INHIBITORS
NON-PREFERRED
Aptivus® QL (tipranavir)
Crixivan® QL (indinavir)
Viracept® QL (nelfinavir)
PREFERRED
Invirase® QL (saquinavir)
Lexiva® QL (fosamprenavir)
Kaletra® QL (lopinavir/ritonavir)
Norvir® QL (ritonavir)
Prevista® QL (darunavir)
Reyataz® QL (atazanavir)
*Note: Current users of non-preferred agents will be indefinitely grandfathered. PA will not
be required for non-preferred agents if auto-look back identifies paid claim for 1 preferred
agent.
Page 11 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
Quantity Limits
Aptivus® capsule: 4 per day
solution: 10 mL per day
Crixivan®: 6 per day
Invirase® 200 mg capsule: 10 per day
500 mg tablet: 4 per day
Lexiva® 700 mg tablet: 4 per day
suspension: 56 mL per day
Kaletra® tablets: 6 per day
solution: 15 mL per day
Norvir® capsule: 12 per day
solution: 15 mL per day Prevista®: 2 per day
Reyataz®: 100, 150, 300 mg capsules: 1 per day
200 mg capsules: 2 per day
Viracept® tablets: 4 per day
powder: 1,584 g per 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. Accessed March, 2009.
3. MedMetrics. Protease Inhibitors review. March 2, 2009.
4. Smith KY, Weinberg WG, DeJesus E, et al; ALERT (COL103952) Study Team.
Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus
tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of
ALERT. AIDS Res Ther. 2008 Mar 28;5:5.
5. Molina JM, Andrade-Villanueva J, Echevarria J, et al; CASTLE Study Team. Once-daily
atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with
tenofovir and emtricitabine, for management of antiretroviral-naïve HIV-1 infected
patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug
23;372(9639):646-55.
6. Johnson M, Grinsztejn B, Rodriguez C, et al. 96-week comparison of once-daily
atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic
failures. AIDS. 2006;20(5):711-18.
7. Ortiz R, DeJesus E, Khanlou H, et al. Efficacy and safety of once-daily
darunavir/ritonavir versus lopinavir/ritonavir in treatment-naïve HIV-1-infected patients at
week 48. AIDS. 2008 Jul 31;22(12):1389-97.
8. Eron J Jr, Yeni P, Gathe J Jr, et al; KLEAN Study Team. The KLEAN study of
fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavirlamivudine, for initial treatment of HIV infection over 48 weeks: a randomized
noninferiority trial. Lancet. 2006 Aug 5;368:476-82.
9. Walmsley S, Avihingsanon A, Slim J, et al. GEMINI: a noninferiority study of
saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J Acquir
Immune Defic Syndr. 2009 Feb 12. [Epub ahead of print]
10. Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT Study: a 48-week openlabel study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in
antiretroviral therapy-naïve HIV-1 infected patients. J Acquir Immune Defic Syndr. 2004
Jan 1;35(1):22-32.
11. Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of
once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naïve HIV-1 infected
patients. AIDS. 2004;18:1529-37.
Page 12 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
12. Walmsley S, Bernstein B, King M, et al; M98-863 Study Team. Lopinavir-ritonavir versus
13.
14.
15.
16.
17.
18.
19.
20.
nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002 Jun
27;346(26):2039-46.
Clotet B, Bellos N, Molina JM, et al; POWER 1 and 2 study groups. Efficacy and safety
of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection
in POWER 1 and 2: a pooled subgroup analysis of data from two randomized trials.
Lancet. 2007 Apr 7;369(9568):1169-78.
DeJesus E, Gottlieb MS, Gathe JC Jr, et al. Safety and efficacy of enfuvirtide in
combination with darunavir-ritonavir and an optimized background regimen in treatmentexperienced human immunodeficiency virus-infected patients: the below the level of
quantification study. Antimicrob Agents Chemother. 2008 Dec;52(12):4315-9.
Madruga JV, Berger D, McMurchie M, et al; TITAN Study Group. Efficacy and safety of
darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatmentexperienced, HIV-infected patients in TITAN: a randomized controlled phase III trial.
Lancet. 2007 Jul 7;370.49-58.
Gathe J, Cooper DA, Farthing C, et al; RESIST-1 Study Group. Efficacy of the protease
inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis
from the RESIST-1 trial. Clin Infect Dis. 2006 Nov 15;43(10):1337-46.
Cahn P, Villacian J, Lazzarin A, et al. Ritonavir-boosted tipranavir demonstrates
superior efficacy to ritonavir-boosted protease inhibitors in treatment-experienced HIVinfected patients: 24-week results of the RESIST-2 trial. Clin Infect Dis. 2006 Nov
15;43(10):1347-56.
Hicks CB, Cahn P, Cooper DA, et al; RESIST Investigator Group. Durable efficacy of
tipranavir-ritonavir in combination with an optimized background regimen of antiretroviral
drugs for treatment-experienced HIV-1 infected patients at 48 weeks in the randomized
evaluation of strategic intervention in multi-drug resistant patients with tipranavir
(RESIST) studies: an analysis of combined data from two randomized open-label trials.
Lancet. 2006 Aug 5;368:466-75.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. November 3, 2008;1-139. Available at http://www.aidsinfo.nih.gov.
Accessed January 21, 2009.
Hammer SM, Eron JJ Jr, Reiss P, et al; International AIDS Society–USA. Antiretroviral
treatment of adult HIV infection: 2008 recommendations of the International AIDS
Society–USA panel. JAMA. 2008 Aug 6;300(5):555-70.
NEW: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
BACKGROUND
•
•
•
•
There are currently 4 nonnucleoside reverse transcriptase inhibitors (NNRTIs) available
for use: delavirdine, efavirenz, etravirine, and nevirapine.
The NNRTIs inhibit replication of HIV-1 by noncompetitively binding to reverse
transcriptase at a different site than the NRTIs. The NNRTIs do not require intracellular
conversion to become pharmacologically active, do not compete against endogenous
substrates and are not incorporated into viral DNA.
NNRTIs are FDA-approved for treatment of HIV-1 infections in combination with other
antiretroviral agents. Etravirine is only approved in treatment-experienced adult patients,
who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other
antiretroviral agents.
Rash is the most common adverse event associated with all of the NNRTIs. Although
most cases of rash are mild to moderate and occur during the first few weeks of therapy,
severe and life-threatening skin reactions have been reported in patients receiving these
drugs. The NNRTIs are also associated with elevated liver function tests and caution is
advised when using in patients with hepatic impairment. Central nervous and psychiatric
symptoms are significant adverse reactions associated with efavirenz.
Page 13 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
Nevirapine carries a black box warning regarding the potential for severe, lifethreatening skin reactions, including cases of Stevens-Johnson syndrome and
toxic epidermal necrolysis.
o Nevirapine carries a second black box warning regarding the risk of
hepatotoxicity, especially in females with CD4 counts greater than 250 cells/mm3.
Due to the risk of hepatotoxicity, nevirapine is contraindicated in patients with
moderate or severe hepatic impairment.
o Convulsions have been observed in patients receiving efavirenz, generally in the
presence of known medical history of seizures. Caution must be taken in any
patient with a history of seizures.
o Efavirenz is pregnancy category D and should not be used in pregnant women
(especially during the first trimester) or women of childbearing potential who are
contemplating pregnancy or not using effective and consistent contraception.
o There are numerous significant drug interactions associated with NNRTIs as all
of the agents are metabolized in the liver by the cytochrome P450 enzyme
system, particularly by the CYP3A4 isoenzyme. The NNRTIs are substrates of
the CYP3A4 isoenzyme, as well as inducers (etravirine and nevirapine),
inhibitors (delavirdine) or mixed inducer and inhibitor (efavirenz).
Coadministration of efavirenz with astemizole, bepridil, cisapride, ergot
derivatives, midazolam, pimozide, and triazolam is contraindicated.
On the basis of large randomized, controlled trials and safety analyses, efavirenz has
emerged as the preferred NNRTI for an NNRTI-based regimen. When paired with dual
NRTI, efavirenz has demonstrated durable and potent viral suppression with a
comparable or better safety profile than the comparator regimen.
o The 2NN Study compared efavirenz vs. efavirenz/nevirapine vs. nevirapine in
antiretroviral-naïve HIV-1 infected male and female patients ≥16 years of age
with plasma HIV-1 RNA levels >5,000 copies/mL. Treatment failure occurred in
37.8% of patients receiving efavirenz, 53.1% of patients receiving efavirenz and
nevirapine, 43.6% of patients receiving nevirapine QD and 43.7% of patients
receiving nevirapine BID (overall P=0.004). The regimen containing efavirenz
and nevirapine was associated with the highest frequency of clinical adverse
events, and nevirapine QD was associated with significantly more hepatobiliary
laboratory toxicities than efavirenz.
o There are limited clinical studies evaluating the efficacy and safety of delavirdine.
Regimens containing delavirdine and 2 NRTIs showed modest, but not always
significant, antiviral activity and CD4 cell count benefit compared with 2-drug
regimens with these agents. There are no published head-to-head studies
comparing the clinical efficacy of delavirdine to the other NNRTIs.
o Etravirine received FDA approval based on analyses of 24-week data from 2
ongoing clinical studies in treatment-experienced HIV-1 infected patients with
NNRTI resistance (DUET-1and DUET-2). When added to optimized background
therapy, etravirine achieved better virological suppression at week 24 than did
placebo. The safety and tolerability profile of etravirine was generally comparable
with placebo. There are no published studies evaluating the efficacy of etravirine
in antiretroviral-treatment naïve patients or comparing etravirine to other NNRTIs.
Current guidelines from the Department of Health and Human Service (DHHS) and the
International Acquired Immunodeficeincy Syndrome Society- USA (AIDS-US)
recommend efavirenz as the preferred NNRTI as part of initial antiretroviral therapy.
However, both guidelines recognize that efavirenz is not recommended for women in the
first trimester of pregnancy or women who are contemplating therapy. Nevirapine is
recommended as an alternative agent in adult females with pretreatment CD4 cell counts
3
3
≤250 cells/mm or in adult males with pretreatment CD4 cell counts ≤400 cells/mm .
Guidelines from the DHHS further emphasize that delavirdine is not recommended as
part of an initial regimen because it has the least supportive clinical data, appears to have
the least antiviral activity and it is dosed three times daily. Additionally, etravirine is not
recommended as part of initial therapy because it has not been studied in large,
randomized trials in treatment-naïve participants.
o
•
•
Page 14 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
RECOMMENDATION
On the basis of clinical trials and safety analyses, national guidelines recommend efavirenz as the
preferred NNRTI for initial antiretroviral therapy. Efavirenz should not be used in pregnant women
or women of childbearing potential who are contemplating pregnancy or not using effective and
consistent contraception. Nevirapine may be used as an alternative to efavirenz for the initial
NNRTI-based regimen. Due to an increased risk of hepatotoxicity, nevirapine is not recommended
in adult females or males with pretreatment CD4 cell counts >250 cells/mm3 or >400 cells/mm3,
respectively. Delavirdine is not recommended as part of an initial regimen because it has the least
supportive clinical data, appears to have the least antiviral activity and is dosed three times daily.
Etravirine is not recommended for initial therapy due to lack of large, randomized trials in
treatment-naïve patients. Since it has demonstrated activity against some NNRTI-resistant viral
strains, etravirine may provide increased virologic activity in treatment-experienced patients,
depending on the amount of NNRTI-resistance. Etravirine may be an important adjunct to a new
regimen in treatment-experienced patients but it must be supported by a potent backbone.
Therefore, it is recommended that efavirenz and nevirapine should be available for initial
antiretroviral therapy as part of HAART. Additionally, etravirine and delavirdine should be
reserved for use in treatment-experienced patients.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
NEW: NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
PREFERRED
NON-PREFERRED
Intelence® QL (etravirine)
Sustiva® QL (efavirenz)
® QL
(nevirapine)
Viramune
Rescriptor® QL (delavirdine)
*Note: Current users of non-preferred agents will be indefinitely grandfathered. Prior
authorization will not be required for non-preferred agents if auto-lookback verifies paid
claim of one preferred agent.
Quantity Limits
Intelence®: 4 per day
Rescriptor® 100 mg tablet: 12 per day
200 mg tablet: 6 per day
Sustiva® 50 mg capsule: 7 per day
200 mg capsule: 2 per day
600 mg capsule: 1 per day
Viramune®: 200 mg tablet: 2 per day
suspension: 40 mL 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 April, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 2009.
3. MedMetrics. Nonnucleoside Reverse Transcriptase Inhibitors therapeutic class review.
February 28, 2009.
4. van Leth F, Phanuphak P, Ruxrungtham K, et al; 2NN Study Team. Comparison of firstline antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs,
plus stavudine and lamivudine: a randomized open-label trial, the 2NN Study. Lancet.
2004 Apr 17;363:1253-63.
5. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in
treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a
randomized, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):29-38.
Page 15 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
6.
Lazzarin A, Campbell T, Clotet B, et al; DUET-2 Study Group. Efficacy and safety of
TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24week results from a randomized, double-blind, placebo-controlled trial. Lancet. 2007 Jul
7;370(9581):39-48.
NEW: NRTI COMBINATION PRODUCTS
BACKGROUND
•
•
•
•
•
•
•
A number of combination antiretroviral products are currently available including
combinations of two or three NRTIs or two NRTIs plus a NNRTI. Components currently
available in a combination product include: abacavir, lamivudine, zidovudine,
emtricitabine, tenofovir, and efavirenz.
Active metabolites of NRTIs compete with endogenous substrates for the active binding
site on HIV reverse transcriptase and/or HBV DNA polymerase. Once the metabolites
become incorporated into viral DNA, synthesis of the viral DNA chain is terminated and
viral replication is inhibited.
The NNRTIs inhibit replication of HIV-1 by noncompetitively binding to reverse
transcriptase at a different site than the NRTIs. The NNRTIs do not require intracellular
conversion to become pharmacologically active, do not compete against endogenous
substrates and are not incorporated into viral DNA.
All of the combination nucleoside analog reverse transcriptase inhibitors are FDA
approved for the treatment of HIV-1 infections, either alone or in combination with other
antiretroviral agents.
Adverse drug events reported with the combination products are similar to those
associated with each of the individual components.
o In addition to black box warning associated with individual components, all of the
combination products carry a black box warning regarding potentially fatal lactic
acidosis and severe hepatomegaly with steatosis. All of the combination
products also carry a black box warning regarding severe acute exacerbations of
hepatitis B in patients who are co-infected with HBV and HIV and have
discontinued emtricitabine, lamivudine or tenofovir.
o Combination products are intended only for patients whose antiretroviral regimen
would otherwise include their respective components and should not be coadministered with other combination or single entity products that contain the
same active ingredient. Due to the similarities between emtricitabine and
®
®
lamivudine, Atripla and Truvuda should not be co-administered with other
products containing lamivudine.
o For contraindications, precautions and drug-drug interactions, please refer to the
class review for individual components of each combination product.
In a meta-analysis of 11 randomized controlled trials, encompassing over 3,000 patients,
Parienti et al reported that adherence rates were better with once-daily antiretroviral
regimens than twice-daily regimens (+2.9%; 95% CI, 1.0 to 4.8%; P<0.003). This modest
effect was more pronounced at the time when therapy was initiated and for regimens in
which all medications were taken once per day. Patients on an antiretroviral regimen that
consisted entirely of medications with once-daily administration had significantly
improved adherence (+4.5%; P<0.004) and better virologic outcomes (+5.7%; P<0.001).
Through a questionnaire, Stone et al evaluated factors related to perceived adherence to
HAART. Of all of the factors evaluated, treatment-experienced HIV-infected patients
responded that pill count, dosing frequency and adverse events had the greatest
perceived impact on adherence to HAART.
Page 16 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
•
Highly active antiretroviral therapy (HAART) that includes a minimum of three drugs is
recommended for the management of HIV in most patients. Current guidelines from the
DHHS and the International AIDS-US both recommend regimens that contain two NRTIs
with either a NNRTI or a ritonavir-boosted PI as first-line therapy in treatment-naïve
patients. DHHS guidelines also emphasize the importance of adherence to HAART and
note that adherence to antiretroviral therapy has been strongly correlated with HIV viral
suppression, reduced rates of resistance, increased survival and improved quality of life.
DHHS guidelines further recommend regimen simplification in selected patients in order
to improve the patient’s quality of life, improve medication adherence, avoid long-term
toxicities, and reduce the risk of virologic failure.
RECOMMENDATION
Highly active antiretroviral therapy (HAART) that includes a minimum of three drugs is
recommended for the management of HIV in most patients. Current guidelines from the DHHS
and the International AIDS-US Panel both recommend regimens that contain two NRTIs with
either a NNRTI or a ritonavir-boosted PI as first-line therapy in treatment-naïve patients.
Abacavir/lamivudine/ zidovudine (coformulated) contains three NRTIS and DHHS guidelines
recommend it should be used only when a preferred or an alternative NNRTI-based or a protease
inhibitor-based regimen is less desirable because of concerns about toxicities or drug interactions.
Adherence to antiretroviral therapy has been strongly correlated with HIV viral suppression,
reduced rates of resistance, increased survival and improved quality of life. Some studies in HIVinfected patients have shown higher levels of adherence and patient satisfaction with regimens
that have a reduced dosing frequency and/or contain fewer pills. Therefore, it is recommended
that combination products containing first line agents for treatment-naïve patients, as
recommended in current clinical guidelines, should be available for use. The combination
lamivudine/zidovudine should also be available since it is the preferred option for treatment of
pregnant women. Additionally, abacavir/lamivudine/ zidovudine (coformulated) should be subject
to clinical criteria to limit its use to patients who cannot be on an NNRTI-based or protease
inhibitor-based regimen.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
NEW: NRTI COMBINATION PRODUCTS
PREFERRED
NON-PREFERRED
Atripla® QL (emtricitabine/tenofovir/efavirenz)
Trizivir® CC, QL (abacavir/lamivudine/zidovudine)
® QL
(lamuvudine/zidovudine)
Combivir
Epzicom® QL (abacavir/lamivudine)
Truvada® QL (emtricitabine/tenofovir)
*Note current users of non-preferred products will be indefinitely grandfathered.
Quantity Limits
Atripla®: 1 per day
Combivir®: 2 per day
Epzicon®: 1 per day
Trizivir®: 2 per day
Truvada®: 1 per day
COMMITTEE VOTE:
APPROVED
Page 17 of 46
DISAPPROVED
APPROVED with MODIFICATION
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
Clinical Criteria for Trizivir®
Trizivir will be approved only for patients who cannot be on an NNRTI-based or a protease
inhibitor-based regimen due to concerns about toxicities or drug interactions
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed April, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 2009.
3. MedMetrics. Nucleoside Analog Reverse Transcriptase Inhibitors Combination
Products Therapeutic Class Review. February 27, 2009.
4. Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better adherence with once-daily
antiretroviral regimens: a meta-analysis. Clin Infect Dis. 2009 Feb 15;48:484-8.
5. Stone VE, Jordan J, Tolson J, Miller R, Pilon T. Perspectives on adherence and
simplicity for HIV-infected patients on antiretroviral therapy: self-report of the relative
importance of multiple attributes of highly active antiretroviral therapy (HAART)
regimens in predicting adherence. J Acquir Immune Defic Syndr. 2004 Jul 1;36(3):80816.
6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. November 3, 2008;1-139. Available at http://www.aidsinfo.nih.gov.
Accessed January 21, 2009.
7. Hammer SM, Eron JJ Jr, Reiss P, et al; International AIDS Society–USA. Antiretroviral
treatment of adult HIV infection: 2008 recommendations of the International AIDS
Society–USA panel. JAMA. 2008 Aug 6;300(5):555-70.
NEW: INTEGRASE INHIBITORS
BACKGROUND
•
•
•
•
Raltegravir is currently the only HIV integrase strand transfer inhibitor commercially
available in the United States.
Through the inhibition of HIV-1 integrase, raltegravir prevents the insertion of HIV DNA
into human DNA. This disrupts the formation of the HIV-1 provirus and thus prevents the
propagation of the viral infection.
Raltegravir is FDA approved for use in combination with other antiretroviral agents for the
treatment of HIV-1 infection in treatment-experienced adult patients who have evidence
of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The safety
and efficacy of raltegravir have not been established in treatment-naïve adults or
pediatric patients.
The most common adverse reactions (incidence >10%) reported with raltegravir were
diarrhea, fever, headache, and nausea, and the incidence of these events was
comparable to placebo.
o Raltegravir should be used cautiously in patients at increased risk of myopathy or
rhabdomyolysis since these events have been reported in patients receiving
raltegravir.
o Various cancers were reported in treatment-experienced patients who initiated
raltegravir with optimized background therapy. The types and rates of specific
cancers were those expected in a highly immunodeficient population and
included Kaposi’s sarcoma, lymphoma, squamous cell carcinoma, hepatocellular
carcinoma and anal cancer. It is unknown if these cancer diagnoses were related
to raltegravir use.
Page 18 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
Caution should be used when co-administering raltegravir with strong inducers of
uridine diphosphate glucuronosyltransferase (i.e. rifampin) due to reduced
plasma concentrations of raltegravir.
Raltegravir was FDA approved on the basis of this 48-week dose ranging study and a 24week interim analysis of the BENCHMRK (Blocking Integrase in Treatment Experienced
Patients with a Novel Compound against HIV, Merck) 1 and 2 studies. Patients with HIV1 virus resistant to at least 1 drug from each of 3 antiretroviral drug classes received
optimized background therapy with either raltegravir or placebo. Raltegravir 400 mg twice
daily produced a rapid and potent antiretroviral effect that was greater than optimized
background therapy alone in treatment-experienced patients. Increased CD4 cell counts
were also observed during raltegravir therapy. Subgroup analyses noted a consistently
favorable treatment effect of raltegravir over placebo in patients with baseline high HIV-1
RNA levels, low CD4 cell counts, and low genotypic or phenotypic sensitivity scores.
Overall, adverse events were generally similar for the raltegravir and placebo regimens.
Higher cancer rates in the raltegravir groups vs the placebo groups at a 16-week
analyses of the BENCHMRK studies prompted a comprehensive review of all cancers
occurring in the four phase 2-3 trials of raltegravir. The relative risk of cancer associated
with raltegravir vs placebo was 1.2 (95% CI, 0.4 to 4.1), with a composite rate of 2.2
cancers per 100 patient-years in the raltegravir groups (vs 1.8 per 100 patient-years in
the placebo groups).
In a small study of 198 treatment-naïve patients with HIV-1 infection, Markowitz et al
compared the efficacy of raltegravir to efavirenz in combination with tenofovir and
lamivudine. Raltegravir exhibited potent and durable antiretroviral activity similar to that of
efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more
rapid rate. Additional studies are needed comparing raltegravir to other antiretroviral
agents and evaluating the use of raltegravir in treatment-naïve patients.
Current guidelines from the DHHS and the International AIDS-US both recommend
regimens that contain two NRTIs with either a NNRTI or a ritonavir-boosted protease
inhibitor as first-line therapy in treatment-naïve patients. For the management of virologic
failure, clinical guidelines recommend regimens should ideally include at least 2, and
preferably 3, fully active drugs on the basis of drug history, resistance testing, or new
mechanistic class. With a unique mechanism of action and documented short-term
efficacy and safety, raltegravir should be considered a fully active antiretroviral agent in
treatment-experienced patients who are naïve to HIV integrase inhibitors. Guidelines
from the International AIDS-US further emphasize that raltegravir has a relatively low
genetic barrier to resistance and, thus, needs to be protected by the addition of other
agents to prevent virologic breakthrough.
o
•
•
•
RECOMMENDATION
Raltegravir is currently the only HIV integrase strand transfer inhibitor commercially available in the
United States and is FDA-approved for use in combination with other antiretroviral agents for the
treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral
replication and HIV-1 strains resistant to multiple antiretroviral agents. Current guidelines from the
DHHS and the International AIDS-US Panel both recommend regimens that contain two NRTIs
with either a NNRTI or a ritonavir-boosted protease inhibitor as first-line therapy in treatment-naïve
patients. Raltegravir is not recommended as initial therapy due to insufficient data in treatmentnaïve patients. For the management of virologic failure, clinical guidelines recommend regimens
should ideally include at least 2, and preferably 3, fully active drugs on the basis of drug history,
resistance testing, or new mechanistic class. With a unique mechanism of action and documented
short-term efficacy and safety, raltegravir should be considered a fully active antiretroviral agent in
treatment-experienced patients who are naïve to HIV integrase inhibitors. Therefore, it is
recommended that raltegravir be subject to step therapy to reserve its use to treatmentexperienced HIV patients.
COMMITTEE VOTE:
APPROVED
Page 19 of 46
DISAPPROVED
APPROVED with MODIFICATION
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
NEW: INTEGRASE INHIBITORS
NON-PREFERRED
Isentress® ST, QL (raltegravir)
PREFERRED
N/A
*Note: Current users of non-preferred products will be indefinitely grandfathered.
Quantity Limits
Isentress®: 2 per day COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Step Therapy for Isentress®
Isentress will be approved upon verification of trial of, contraindication, intolerance or resistance
to:
o
At least two NRTIS AND
o
One PI OR NNRTI
NOTE: If 60-day auto-lookback verifies paid claims for above, prior authorization will not be
required. COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed April, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 2009.
3. MedMetrics. Integrase Inhibitors Therapeutic Class Review. February 24, 2009.
4. Steigbigel RT, Cooper DA, Kumar PN, et al; BENCKMRK Study Teams. Raltegravir with
optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008 Jul
24;359(4):339-54.
5. Cooper DA, Steigbigel RT, Gatell JM, et al; BENCHMRK Study Teams. Subgroup and
resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008 Jul
24;359(4):355-65.
6. Markowitz M, Nguyen BY, Gotuzzo E, et al; Protocol 004 Part II Study Team. Rapid and
durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of
combination therapy in treatment-naïve patients with HIV-1 infection: results of a 48week controlled study. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):125-33.
7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. November 3, 2008;1-139. Available at
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December
10, 2008.
8. Hammer SM, Eron JJ Jr, Reiss P, et al; International AIDS Society–USA. Antiretroviral
treatment of adult HIV infection: 2008 recommendations of the International AIDS
Society–USA panel. JAMA. 2008 Aug 6;300(5):555-70.
Page 20 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
NEW: FUSION INHIBITORS
BACKGROUND
•
•
•
•
•
•
Enfuvirtide is currently the only fusion inhibitor commercially available in the US.
Enfuvirtide is a synthetic peptide that interferes with the entry of HIV-1 into target cells by
inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the HIV-1
glycoprotein and blocks the conformational changes required for fusion of the virus to
CD4 cells.
Enfuvirtide is FDA approved for use in combination with other antiretroviral agents for the
treatment of HIV-1 infection in treatment-experienced patients who have evidence of viral
replication despite ongoing antiretroviral therapy. The safety of enfuvirtide has not been
established in pediatric patients less than 6 years of age.
Local injection site reactions were the most frequently reported adverse events with
almost all patients (98%) reporting at least 1 local injection site reaction during the
enfuvirtide treatment period. Injection site reactions included ecchymosis, erythema,
induration, nodule or cyst formation, pain, and/or pruritus. Less commonly, serious
systemic hypersensitivity reactions have been associated with enfuvirtide therapy.
o An increased rate of bacterial pneumonia was observed in subjects treated with
enfuvirtide; however, it is unclear if the increased incidence of pneumonia was
related to enfuvirtide use. Patients should be monitored closely for signs and
symptoms of pneumonia.
o Nerve pain, which may last up to 6 months, bruising and hematomas have also
®
occurred with use of the Biojector 2000 needle-free device for administration of
enfuvirtide. Patients on anticoagulants or with coagulation disorders, such as
hemophilia, may have a higher risk of post-injection bleeding.
o No clinically significant drug-drug interactions have been identified at this time.
Enfuvirtide received FDA approval based on results from the TORO (T-20 vs Optimized
Regimen Only) 1 and 2 studies which were conducted in treatment-experienced, HIV-1
infected patients. The studies enrolled patients who had received at least 3-6 months of
previous treatment with NRTIs, NNRTIs and protease inhibitors; a documented
resistance to these drugs; or both. In addition, patients were enrolled if they had evidence
of HIV-1 replication despite ongoing antiretroviral therapy. The addition of enfuvirtide to
an optimized antiretroviral regimen provided significant antiretroviral and immunologic
benefit through 48 weeks. Enfuvirtide continued to demonstrate durable efficacy and
safety over 96 weeks of therapy through an extension of these studies.
Current guidelines from the DHHS and the International AIDS-US both recommend
regimens that contain two NRTIs with either a NNRTI or a ritonavir-boosted protease
inhibitor as first-line therapy in treatment-naïve patients. Enfuvirtide is not recommended
as initial therapy due to insufficient data in treatment-naïve patients as well as
inconvenience caused by twice daily dosing of subcutaneous injections. For the
management of virologic failure, clinical guidelines recommend regimens should ideally
include at least 2, and preferably 3, fully active drugs on the basis of drug history,
resistance testing, or new mechanistic class. DHHS guidelines do no address the
specific role of enfuvirtide in the management of treatment-experienced patients.
Guidelines from the International AIDS-US state that enfuvirtide is an important agent for
persons with multi-drug resistant HIV despite the inconvenience of subcutaneous dosing.
Page 21 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
RECOMMENDATION
Enfuvirtide is currently the only fusion inhibitor commercially available in the US and is FDA
approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection
in treatment-experienced patients who have evidence of viral replication despite ongoing
antiretroviral therapy. Current guidelines from the DHHS and the International AIDS-US Panel both
recommend regimens that contain two NRTIs with either a NNRTI or a ritonavir-boosted protease
inhibitor as first-line therapy in treatment-naïve patients. Enfuvirtide is not recommended as initial
therapy due to insufficient data in treatment-naïve patients as well as inconvenience caused by
twice daily dosing of subcutaneous injections. For the management of virologic failure, clinical
guidelines recommend regimens should ideally include at least 2, and preferably 3, fully active
drugs on the basis of drug history, resistance testing, or new mechanistic class. While the role of
enfuvirtide in treatment-experienced patients has not been specified in current clinical guidelines, it
is clear that this agent has been proven effective in the management of HIV patients experiencing
virologic failure despite ongoing antiretroviral therapy. Therefore, it is recommended that
enfuvirtide be subject to step therapy to reserve its use to treatment-experienced patients.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
NEW: FUSION INHIBITORS
NON-PREFERRED
Fuzeon® ST, QL (enfuvirtide)
PREFERRED
N/A
*Note: Current users of non-preferred products will be indefinitely grandfathered.
Quantity Limits
Fuzeon®: 1 kit per month (2 vials per day) COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Step Therapy for Fuzeon®
Fuzeon® will be approved upon verification of trial of, contraindication, intolerance or resistance
to:
o
At least two NRTIS AND
o
One PI OR NNRTI
NOTE: If 60-day auto-lookback verifies paid claims for above, prior authorization will not be
required. COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed April, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 2009.
3. MedMetrics. Fusion Inhibitors Therapeutic Class Review. February 27, 2009.
4. Lalezari JP, Henry K, O’Hearn M, et al; TORO 1 Study Group. Enfuvirtide, an HIV-1
fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J
Med. 2003 May 29;348(22):2175-85.
5. Lazzarin A, Clotet B, Cooper D, et al; TORO 2 Study Group. Efficacy of enfuvirtide in
patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med. 2003
May 29;348(22):2186-95.
Page 22 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
Nelson M, Arasteh K, Clotet B, et al. Durable efficacy of enfuvirtide over 48 weeks in
heavily treated-experienced HIV-1 infected patients in the T-20 versus optimized
background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr. 2005 Dec
1;40(4):404-12.
7. Trottier B, Walmsley S, Reynes J, et al. Safety of enfuvirtide in combination with an
optimized background of antiretrovirals in treatment-experienced HIV-1 infected adults
over 48 weeks. J Acquir Immune Defic Syndr. 2005 Dec 1;40(4):413-21.
8. Reynes J, Arasteh K, Clotet B, et al. TORO: ninety-six-week virologic and immunologic
response and safety evaluation of enfuvirtide with an optimized background of
antiretrovirals. AIDS Patient Care STDS. 2007 Aug;21(8):533-43.
9. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. November 3, 2008;1-139. Available at
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December
10, 2008.
10. Hammer SM, Eron JJ Jr, Reiss P, et al; International AIDS Society–USA. Antiretroviral
treatment of adult HIV infection: 2008 recommendations of the International AIDS
Society–USA panel. JAMA. 2008 Aug 6;300(5):555-70.
6.
NEW: CHEMOKINE RECEPTOR 5 (CCR5) ANTAGONISTS
BACKGROUND
•
•
•
•
Maraviroc is currently the only CC chemokine receptor 5 (CCR5) antagonist commercially
available in the US.
HIV enters host cells by attaching to the CD4 T-cell receptor using either CCR5 or CX
chemokine receptor 4 (CXCR4). Maraviroc selectively binds to CCR5 on the cell
membrane and prevents the interaction of HIV-1 glycoprotein 120 and CCR5 necessary
for CCR5-tropic HIV-1 to enter human cells.
Maraviroc is FDA approved for use in combination with other antiretroviral drugs for the
treatment of adults infected with CCR5-tropic HIV-1, who have evidence of viral
replication and HIV-1 strains resistant to multiple antiretroviral agents.
The most common adverse events associated with maraviroc are cough, dizziness,
pyrexia, rash and upper respiratory tract infections.
o Maraviroc carries a black box warning regarding a potential risk for
hepatotoxicity, which may be preceded by signs of a systemic allergic reaction.
o Maraviroc should be administered cautiously to patients with an increased risk for
cardiovascular events or a history of postural hypotension, or on a concomitant
medication known to lower blood pressure.
o Maraviroc antagonizes the CCR5 located on some immune cells, and therefore
could potentially increase the risk of developing infections. Patients should be
monitored closely for evidence of infections while receiving maraviroc. While no
increase in malignancy has been observed with maraviroc, maraviroc could
affect immune surveillance and lead to an increased risk of malignancy.
o Maraviroc is a substrate of CYP3A and P-glycoprotein; therefore, dose
adjustment may be required during co-administration with inhibitors and inducers
of these enzymes and transporters.
Page 23 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
•
•
•
•
Maraviroc received FDA approval based on a 24-week interim analyses of the
MOTIVATE (Maraviroc Versus Optimized Therapy in Viremic Antiretroviral TreatmentExperienced Patients) 1 and 2 clinical trials which were conducted in triple-class,
treatment-experienced patients with detectable viremia with only HIV-1 CCR5-tropic viral
strains. At the end of 48 weeks, more patients receiving maraviroc QD or BID had HIV-1
RNA levels of <50 copies/mL (42% and 47%, respectively, vs 16% in the placebo group
in MOTIVATE 1; 45% in both maraviroc groups vs 18% in MOTIVATE 2; P<0.001 for
both comparisons in each study). The changes from baseline in CD4 cell counts were
also greater with maraviroc QD or BID than with placebo (increases of 113 and 122
cells/mm3, respectively, vs 54 cells/mm3 in MOTIVATE 1; increases of 122 and 128
cells/mm3, respectively, vs 69 cells/mm3 in MOTIVATE 2; P<0.001 for both comparisons
in each study) at the end of 48 weeks. The frequency of adverse events was similar
among the groups.
Preliminary results of the MERIT trial noted that maraviroc was “noninferior” to efavirenz
in attaining plasma HIV-1 ribonucleic acid (RNA) load of <400 copies/mL (75.3% vs
78.9%; P value not reported), but not for those with <50 copies/mL (65.2% vs 69.2%; P
value not reported) at 48 weeks in combination with zidovudine and lamivudine as initial
therapy in drug-naive HIV-infected patients with CC chemokine receptor 5 (CCR5) virus.
More patients discontinued maraviroc because of lack of efficacy than efavirenz (11.9%
vs 4.2%; P value not reported); however, fewer patients discontinued maraviroc than
efavirenz because of adverse events (4.2% vs 13.6%; P value not reported).
While maraviroc is not FDA approved for use in treatment-naïve patients, some authors
have suggested a potential advantage of utilizing CCR5 inhibitors early in disease when
CCR5 tropic viruses are more prevalent and more sensitive to CCR5 inhibitors. Because
CCR5 inhibitors can prevent entry of HIV-1 into host cells and CCR5 tropic viruses are
generally responsible for the establishment of new HIV infections, the use of CCR5
antagonists as pre-exposure and post-exposure prophylaxis is currently being
investigated.
Current guidelines from the DHHS and the International AIDS-US both recommend
regimens that contain two NRTIs with either a NNRTI or a ritonavir-boosted protease
inhibitor as first-line therapy in treatment-naïve patients. Maraviroc is not recommended
as initial therapy due to insufficient data in treatment-naïve patients. For the management
of virologic failure, clinical guidelines recommend regimens should ideally include at least
2, and preferably 3, fully active drugs on the basis of drug history, resistance testing, or
new mechanistic class. With a unique mechanism of action and documented short-term
efficacy and safety, maraviroc should be considered a fully active antiretroviral agent in
treatment-experienced patients who have only R5 virus and who are naïve to CCR5
inhibitors. Guidelines from both DHHS and the International AIDS-US emphasize the
importance of tropism testing prior to utilization of maraviroc, due to its activity being
limited to only R5 virus types.
RECOMMENDATION
Maraviroc is currently the only CC chemokine receptor 5 (CCR5) antagonist commercially
available in the US. It is FDA approved for use in combination with other antiretroviral drugs for
the treatment of adults infected with CCR5-tropic HIV-1, who have evidence of viral replication and
HIV-1 strains resistant to multiple antiretroviral agents. Current guidelines from the DHHS and the
International AIDS-US both recommend regimens that contain two NRTIs with either a NNRTI or a
ritonavir-boosted protease inhibitor as first-line therapy in treatment-naïve patients. Maraviroc is
not recommended as initial therapy due to insufficient data in treatment-naïve patients. For the
management of virologic failure, clinical guidelines recommend regimens should ideally include at
least 2, and preferably 3, fully active drugs on the basis of drug history, resistance testing, or new
mechanistic class. With a unique mechanism of action and documented short-term efficacy and
safety, maraviroc should be considered a fully active antiretroviral agent in treatment-experienced
patients who have only R5 virus and who are naïve to CCR5 inhibitors. As maraviroc is not
recommended as initial therapy and it is only active again R5 virus, it is recommended maravoric
should be subject to clinical criteria to reserve its use to treatment-experienced HIV patients who
have only R5 virus.
Page 24 of 46
May 12, 2009 Tennessee PAC
HIV ANTIVIRAL AGENTS
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
NEW: CCR5 ANTAGONISTS
NON-PREFERRED
Selzentry® ST, QL (maraviroc)
PREFERRED
N/A
*Note: current users of non-preferred products will be indefinitely grandfathered.
Quantity Limits
Selzentry® 150 mg tabs: 2 per day
300 mg tabs: 4 per day COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Clinical Criteria for Selzentry®
Selzentry® will be approved for:
o
Diagnosis of CCR5-tropic HIV-1 via a co-receptor tropism, AND
o
Verification of trial of, contraindication, intolerance or resistance to:
ƒ At least two NRTIS AND ƒ One PI OR NNRTI COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed April, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 2009.
3. MedMetrics. CCR5 Antagonists Therapeutic Class Review. February 24, 2009.
4. Gulick RM, Lalezari J, Goodrich J, et al; MOTIVATE Study Teams. Maraviroc for
previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008 Oct
2;359(14):1429-41.
5. Fatkenheuer G, Nelson M, Lazzarin A, et al; MOTIVATE 1 and MOTIVATE 2 Study
Teams. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N
Engl J Med. 2008 Oct 2;359(14):1442-55.
6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. November 3, 2008;1-139. Available at
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December
10, 2008.
7. Hammer SM, Eron JJ Jr, Reiss P, et al; International AIDS Society–USA. Antiretroviral
treatment of adult HIV infection: 2008 recommendations of the International AIDS
Society–USA panel. JAMA. 2008 Aug 6;300(5):555-70.
Page 25 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
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.
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
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
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 lightheadness. More severe adverse effects
include: bradycardia, palpitations, syncope, disorientation, hallucinations, weakness, and
bronchospasm.
Page 26 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
o
o
o
o
o
o
o
o
o
Black Box warnings:
ƒ Propoxyphene: related to fatal reactions when used in combination with
other CNS depressant drugs; caution in patients with concomitant
alcohol use or use of propoxyphene in patients who are suicidal or
addiction prone.
ƒ Hydromorphone injection: related to caution with high concentration of
injection formulation.
ƒ Morphine injection: related to use in patients intrathecally or as an
epidural and high concentration of Infumorph®.
Short acting opioid agonists are contraindicated in patients with significant
respiratory depression.
Short acting opioids should be used with caution in patients with pre-existing
respiratory impairments: asthma, chronic obstructive pulmonary disease (COPD).
Short acting opioids can affect cerebrospinal fluid and should be used with
caution in patients with head injuries, intracranial lesions or elevated intracranial
pressure.
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.
All short acting opiate usage should be monitored closely for possible abuse,
addiction or diversion.
Use of all short acting opiates and concomitant CNS depressants should be
avoided and/or used with extreme caution.
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.)
There are numerous potential drug interactions with short acting opioids.
Significant interactions include:
Drug
All agents
Hydrocodone,
Meperidine,
Morphine,
Oxycodone
All agents
•
Interacting
Medication
CNS
depressants
Monoamine
oxidase
inhibitors
(MAOIs)
Anticholinergics
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.
Page 27 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
•
•
•
•
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),
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.
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.
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.
o 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).
o One randomized, parallel group trial, compared naproxen sodium to
dextropropoxyphene/APAP in 184 patients who had experienced acute
musculoskeletal disorders or acute traumatic sports injuries. Primary outcomes
were severity of pain, tenderness, swelling and limitation of movement. Naproxen
sodium was significantly better than dextropropoxyphene/APAP in pain at the
day 7 assessment (P<0.05). For those patients who completed 14 days of
treatment, the total symptom score was significantly different in favor of naproxen
(P<0.05). There were no significant differences between the two treatment
groups at day 7 and the day 14 follow-up for scores of tenderness, swelling, and
limitations of movement.
Page 28 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
•
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. The short acting opioids are
similar in their adverse effects and many of the adverse effects subside with continued
dosing as tolerance builds.
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. Propoxyphene has been associated with more severe adverse
effects and clinical trials have not demonstrated consistent efficacy. The FDA is currently
reviewing the safety and efficacy of propoxyphene. An advisory committee to the FDA has
recently recommended its withdrawal from the market. Therefore propoxyphene can be
considered an inferior agent in this class. 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 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
Page 29 of 46
DISAPPROVED
APPROVED with MODIFICATION
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
RE-REVIEW: SHORT ACTING NARCOTICS
PREFERRED
NON-PREFERRED
Codeine
Balacet® (Propoxyphene napsylate/APAP)
Codeine/APAP
Capital with Codeine® (codeine/APAP)
Combunox® QL (oxycodone/IBU)
Codeine/APAP/caffeine/butalbital
QL
Darvon® (propoxyphene)
Hydrocodone/APAP
QL
Hydrocodone/Ibuprofen
Darvon-N® (propoxyphene napsylate)
Hydromorphone
Darvocet ® A500 (propoxyphene napsylate/APAP)
QL
Darvocet-N® 100(propoxyphene napsylate/APAP)
Meperidine
Morphine IR
Demerol® QL (meperidine)
QL
Dilaudid® (hydromorphone)
Oxycodone
QL
Oxycodone/APAP
Fioricet® with Codeine (cod/APAP/caff/butalbital)
QL
Oxycodone/ASA
Fiorinal® with Codeine (cod/ASA/caff/butalbital)
® QL
(hydrocodone/APAP)
Co-gesic
Hycet® QL (hydrocodone/APAP)
®
QL
Reprexain (hydrocodone/IBU)
Hydrocet® QL (hydrocodone/APAP)
® QL
(oxycodone/APAP)
Roxicet
Lorcet® QL (hydrocodone/APAP)
® QL
(hydrocodone/APAP)
Stagesic
Lortab® QL (hydrocodone/APAP)
® QL
(hydrocodone/APAP)
Vanacet
Maxidone® QL (hydrocodone/APAP)
® QL
HP (hydrocodone/APAP)
Vicodin
Magnacet® QL (oxycodone/APAP)
Meperitab® QL (meperidine)
Norco® QL (hydrocodone/APAP)
Opana® (oxymorphone)
Oxydose® QL (oxycodone)
OxyFast® QL (oxycodone)
OxyIR® QL (oxycodone)
Panlor® DC (APAP/caffeine/dihydrocodeine)
Panlor® SS (APAP/caffeine/dihydrocodeine)
Percocet® QL (oxycodone/APAP)
Percodan® QL (oxycodone/IBU)
Propoxyphene/APAP
Propoxyphene napsylate/APAP
Roxanal® QL
Roxicodone® QL
Tylenol® with Codeine (APAP/codeine)
Tylox® QL (oxycodone/APAP)
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® (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
*QL are determined based on recommendations of the Short Acting Narcotics committee
(April 2008)
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.
Page 30 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
International Association for the Study of Pain. IASP Pain Terminology. Accessed
December 29, 2008 at http://www.iasp‐pain.org/terms‐p.html#Pain.
Gimbel J, Ahdieh H. The efficacy and safety of oral immediate-release oxymorphone for
postsurgical pain. Anesth Analog. 2004; 99:1472-7.
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.
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.
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.
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.
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.
Collins SL, Edwards JE, Moore RA, McQuay HJ. Single dose dextropropoxyphene,
alone and with paracetamol (acetaminophen), for postoperative pain. Cochrane Database
Syst Rev 2000;(2):CD001440.
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).
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.
RE-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.
Page 31 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
•
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
Potassium
Diclofenac
Sodium
Etodolac
a
Fenoprofen
a
Calcium
Flurbiprofen
Ibuprofen
a
Indomethacin
Ketoprofen
a
a
a
a
a
a
a
a
a
a
a
a
a
a
Ketorolac
a
Meclofenamate
a
Mefenamic acid
a
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
Sodium
Sulindac
a
Tolmetin sodium
a
a
Combination Agent
Diclofenac Sodium/
a
misoprostol
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)
ƒ Review of specific contraindications
ƒ Dose should be adjusted for age and renal function
Page 32 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
o
o
o
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
(CABD) surgery.
ƒ Patients with known nasal polyps, angioedema or bronchospastic
reactivity to aspirin or other NSAIDs.
Fenoprofen and mefenamic acid are contraindicated in patients with any preexisting renal disease.
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.
There are numerous drug-drug interactions; significant interactions are included
below:
(NSAIDs)
(all)
NSAIDs
(all)
NSAIDs
(all)
NSAIDs
(all)
•
•
•
•
Interacting
Medication
ACE inhibitors,
angiotensin II
receptor blockers
(ARBs)
Anti-platelet
agents, low
molecular weight
heparins, warfarin
Aspirin
Diuretics (all)
Potential Result
NSAIDs may decrease the antihypertensive effect
of ACE inhibitors and ARBs and could precipitate
renal failure.
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.
NSAIDs may reduce the effectiveness of diuretics
and cause hyperkalemia or nephrotoxicity.
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, double dummy randomized trial compared meloxicam (7.5mg and
15mg dosage) to mefenamic acid in female patients with primary dysmenorrhea during
last 3 consecutive menstrual cycles. The primary outcome was reduction in lumbar and
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.
Page 33 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
•
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
The treatment of pain can be variable and individual to the specific patient. 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 make 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 more severe adverse effects and an
additional black box warning compared to other NSAIDs. Due to these safety concerns, it is
recommended that ketorolac therapy be reserved to no more than 5 days of therapy, as per the
prescribing information. With the exception of ketorolac, it is recommended that all other generic
NSAID agents be available for use, if cost effective to the State. 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.
COMMITTEE VOTE:
APPROVED
Page 34 of 46
DISAPPROVED
APPROVED with MODIFICATION
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
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® (sulidac)
Etodolac
Daypro® (oxaprozin)
Etodolac ER
EC-Naprosyn® (naproxen)
Flurbiprofen
Feldene® (piroxicam)
Ibuprofen
Fenoprofen
Indomethacin
Flector® CC, QL (diclofenac epolamine)
Ketoprofen
KetorolacQL
Ketoprofen ER
Meclofen® (meclofenamate)
Mefenamic acid
ST, QL
Mobic® ST, QL (meloxicam)
Meloxicam
Nabumetone
Motrin® (ibuprofen)
Naproxen
Nalfon® (fenoprofen)
Naprelan® (naproxen sodium ER)
Naproxen sodium
Naprosyn® (naproxen)
Oxaprozin
Ponstel® (mefenamic acid)
Sulindac
Voltaren® (diclofenac sodium)
Tolmetin
Voltaren® GelCC (diclofenac sodium)
Voltaren® XR (diclofenac sodium)
Clinical Criteria: Arthotec®
-PA approval not required for patients > 60 years old.
For recipients under 60 years of age, trial and failure of two preferred NSAIDs is required.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Clinical Criteria: Flector® patch & Voltaren® gel
• Approval will be granted for the following conditions:
-Patient must fail 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:
– 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:
Page 35 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
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 March, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed March, 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):667-73.
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.
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.
9.
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
Page 36 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
•
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
Interacting
Medication
ACE inhibitors,
angiotensin II
receptor blockers
(ARBs)
Anti-platelet
agents, low
molecular weight
heparins, warfarin
Aspirin
Celecoxib
Diuretics
Celecoxib
Celecoxib
•
•
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 cardioprotective effect of
low-dose uncoated aspirin and may cause a higher
risk of gastric irritation.
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
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
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
versus (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).
Page 37 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
•
•
•
•
•
•
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 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
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 NASIDs. 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.
Page 38 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
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
APPROVED with MODIFICATION
RE-REVIEW: COX-II INHIBITORS
NON-PREFERRED
N/A
PREFERRED
Celebrex ® ST, QL
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
– 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/1 per day
200mg/2 per day
400mg/2 per day
COMMITTEE VOTE:
APPROVED
Page 39 of 46
DISAPPROVED
APPROVED with MODIFICATION
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed April, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 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.
NEW: SALICYLATES/NON-NARCOTIC ANALGESIC COMBINATIONS
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 and the treatment options for pain and inflammatory
conditions can also vary widely. Salicylates and non-narcotic combination agents are two
classes of medication that are commonly used as analgesics.
The salicylates included in this review are prescription strength aspirin, diflunisal, and
salsalate.
Page 40 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
•
•
•
The non-narcotic combination agents included in this review are as follows:
o Choline/magnesium salicylates
o Magnesium salicylate
o Acetaminophen (APAP)/phenyltoloxamine
o Phenyltoloxamine/magnesium salicylate
o APAP/phenyltoloxamine/caffeine
o APAP/salicylamide/phenyltoloxamine
o APAP/salicylamide/phenyltoloxamine/caffeine
o APAP/aspirin/salicylamide/caffeine
o APAP/magnesium salicylate/phenyltoloxamine/ caffeine
Mechanisms of action vary based on components of medication.
o Salicylates: inhibition of cyclooxygenase enzyme (COX)
o Non-narcotic combination agents:
ƒ Acetaminophen: in central nervous system (CNS) has active metabolite
of phenacetin and acts as a anti-pyretic and analgesic; in periphery acts
as weak COX inhibitor.
ƒ Choline: acts as pre-cursor to the neurotransmitter acetylcholine
ƒ Phenyltoloxamine: blocks histamine
ƒ Caffeine: CNS stimulant, vasoconstrictor
FDA approved indications:
Drug
Pain
Salicylates
Aspirin
a
Diflunisal
a
Salsalate
a
Non-Narcotic Combination agents
Choline/magnesium salicylates
a
Magnesium salicylate
a
APAP/phenyltoloxamine
a
Phenyltoloxamine/magnesium
a
salicylate
APAP/phenyltoloxamine/
a
caffeine
APAP/salicylamide/
a
phenyltoloxamine
APAP/salicylamide/
a
phenyltoloxamine/caffeine
APAP/aspirin/salicylamide/
a
caffeine
APAP/magnesium salicylate/
a
phenyltoloxamine/caffeine
•
HA
Allergic
Symptoms
Migraine
Arthritis
a
a
Fever
AntiInflammatory
a
a
a
a
a
a
a
a
a
a
a
a
a
The most common adverse effects seen with salicylates include: gastric mucosal
irritation, dyspepsia, nausea, vomiting, tachycardia, and hypotension. More severe
adverse effects include: gastric bleeding/ulceration, bronchospasm, anaphylaxis, Reye’s
syndrome, metabolic disturbances, and hepatotoxicity.
o Diflunisal and salsalate carry a black box warning, common to all NSAIDs, in
regards to increased risk of cardiovascular events and increased risk of serious
gastrointestinal adverse effects.
o The most common adverse effects seen with the non-narcotic combination
agents include:
ƒ APAP and phenyltoloxamine: dizziness, drowsiness, puritis, rash,
nausea, blurred vision and diaphoresis.
ƒ APAP and salicylate: see previous listing for common salicylate adverse
reactions.
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May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
Caffeine: agitation, restlessness, insomnia, gastrointestinal irritation, and
palpitations.
o Aspirin is contraindicated in patients with Reye’s syndrome.
o Diflunisal and salsalate are contraindicated in treatment of peri-operative pain
after coronary artery bypass graft surgery.
o Phenyltoloxamine should be used with caution in patients with angle closure
glaucoma, bladder neck obstruction, urinary retention or prostatic hypertrophy.
o Aspirin, diflunisal, and salsalate should be used with caution in patients with
asthma, any hematologic disorders, and hepatic, gastrointestinal or renal
dysfunction.
o Significant Drug-Drug interactions include:
ƒ Use of aspirin, diflunisal or salsalate with concomitant non-steroidal antiinflammatory agents (NSAIDs): effects can be additive and increase
possible adverse effects.
ƒ Use of aspirin, diflunisal or salsalate with other anticoagulants: possible
increase in anticoagulant effect.
Salicylates and non-narcotic combination agents have been studied in a number of
clinical trials to evaluate and compare their analgesic effects. However, the majority of
the trials are dated and lack statistical significance to demonstrate superior agents.
Aspirin is considered the gold standard for the salicylate class and as such there is
limited focus on its proven efficacy as an analgesic in the current literature, rather that of
its effects as a cardioprotective agent.
Phenyltoloxamine is an antihistamine that is used in few cold, allergy, pain and cough
formulations. Although not FDA approved for pain as a single agent, studies have shown
that in combination with acetaminophen (APAP), phenyltoloxamine is able to produce
significant augmentation of the analgesic activity of APAP. Many of the original trials
looking at efficacy and safety date back into the late 1950’s.
Caffeine is used in combination with many headache and migraine medications. Caffeine
has also been used as an adjuvant for enhancement of analgesia.
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 APAP as well as NSAIDs as
first line therapy for mild to moderate pain. Currently guidelines do not give preference to
one agent over another.
Salicylates have been used as effective analgesics for many years. Some of the agents
such as aspirin have taken on other indications such as the treatment and prevention for
various cardiovascular events. Salicylates work through inhibition of COX, which results
in a decreased formation of prostaglandin precursors; antipyretic, analgesic, and antiinflammatory properties. Aspirin binds irreversibly COX-1 and COX-2 enzymes and
subsequently has the additional anti-platelet activity the remainder of the class lacks.
The non-narcotic analgesic combination products contain multiple ingredients that allow
for a broader spectrum of activity. Stimulants such as caffeine and antihistamines such
as phenyltoloxamine have been added to these combination products for increased
efficacy by targeting specific symptoms. Although limited current clinical trials exist, the
efficacy and safety of these medications have been well established.
ƒ
•
•
•
•
•
•
•
RECOMMENDATION
Salicylates and non-narcotic combination analgesics have been used as effective analgesics for
many years. Non-narcotic combination agents utilize different mechanisms of action to enhance
their analgesic effect. The American College of Rheumatology, the ACP and APS all recommend
APAP and NSAIDs as first line therapy options for mild to moderate pain. Currently available
treatment guidelines do not give preference to one agent over another and therefore available
agents can be considered therapeutic alternatives. It is recommended that at least 3 unique
agents in the salicylates and non-narcotic combination agents class be available for use.
Page 42 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
COMMITTEE VOTE:
APPROVED
DISAPPROVED
PREFERRED
Aspirin CRQL (RX only)
APAP/phenyltoloxamineQL
QL
Diflunisal
Choline/magnesium salicylateQL
QL
Magnesium salicylate
QL
Salsalate
APPROVED with MODIFICATION
NON-PREFERRED
® QL
(APAP/phenyltoloxamine)
Acuflex
® QL
Alpain
(APAP/phenyltoloxamine)
® QL
(salsalate)
Amigesic
® QL
Anabar
(APAP/salicylamide/phenyltoloxamine)
® QL
(APAP/salicylamide/phenyltoloxamine)
Be-Flex Plus
®
Cafgesic cap QL (APAP/mag salicylate/phenyltoloxamine/caff)
®
QL
Cafgesic tab (APAP/salicylamide/phenyltoloxamine/caff)
® QL
(diflunisal)
Dolobid
Dologesic® QL (APAP/phenyltoloxamine)
® QL
(APAP/salicylamide/phenyltoloxamine)
Dolorex
Durabac® QL (APAP/salicylamide/phenyltoloxamine/caffeine)
®
QL
Durabac Forte (APAP/mag
salicylate/phenyltoloxamine/caff)
® QL
(APAP/salicylamide/phenyltoloxamine)
Ed-Flex
Flextra® QL (APAP/phenyltoloxamine/caffeine)
®
QL
Flextra DS (APAP/phenyltoloxamine)
Lagesic® QL (APAP CR/phenyltoloxamine)
® QL
(APAP/aspirin/salicylamide/caffeine)
Levacet
®
MST 600 QL (magnesium salicylate)
® QL
(APAP CR/phenyltoloxamine)
Q-Flex
Rhinoflex® QL (APAP/phenyltoloxamine)
® QL
(Phenyltoloxamine/magnesium salicylate)
Tetra-Mag
® QL
Vistra
(APAP/phenyltoloxamine)
® QL
(APAP CR/phenyltoloxamine)
Zgesic
Zorprin® QL (aspirin CR)
Quantity Limits
Aspirin 4g/day
Diflunisal 1500mg/day
Salasalate 3g/day
Choline salicylate 3g/day
Magnesium salicylate 2400mg/day
Phenyltoloxamine 180mg/day
Salicylamide 4500mg/day
Caffeine 1200/day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed April, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 2009.
3. MedMetrics. Salicylates and Non-Narcotic Combination agents class review. April 1,
2009.
4. 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.
5.
Medical Letter, Inc. Treatment guidelines from the Medical Letter: Drugs for Pain.
2007;5(56):23-32.
Page 43 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
6.
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.
NEW: AGENTS FOR OPIOID DETOXIFICATION
BACKGROUND
•
•
•
•
•
Opioid dependence is a chronic medical illness marked by high rates of relapse.
Detoxification is the first step in treatment of opioid dependence with longer term
pharmacological therapies used to sustain abstinence and prevent relapse. Long term
addiction treatment can take many forms including opioid antagonist use which prevents
the user from experiencing beneficial effects with subsequent opioid use. This review will
focus on the use of naltrexone, a pure opioid antagonist, in the treatment of opioid
dependence. Naltrexone is the only oral opioid antagonist currently available.
Naltrexone is a pure opioid antagonist that acts to competitively bind opioid receptors.
Naltrexone is FDA indicated for the treatment of alcohol dependence and the treatment of
opioid dependence.
The most common adverse effects experienced with naltrexone include: nausea,
vomiting, abdominal cramps, headache, anxiety, and nervousness.
o Naltrexone carries a black boxed warning related to the increased risk of
hepatotoxicity.
o Naltrexone is contraindicated in patients receiving opioid analgesics, patients
currently dependent on opioids, or patients in acute opioid withdrawal.
o Naltrexone is also contraindicated in any individual with acute hepatitis or liver
failure.
o Naltrexone should only be used in patients who have been opioid-free for a
minimum of 7 to 10 days; a urine drug screen as well as a naltrexone challenge
should be completed prior to initiation of therapy.
ƒ Naltrexone challenge test:
• The naltrexone challenge test should not be performed in a
patient showing clinical signs or symptoms of opioid withdrawal,
or in a patient whose urine contains opioids.
• Small doses can be given intravenously or administered
subcutaneously and then patient should be observed for 20
minutes for any signs or symptoms of withdrawal.
• If signs or symptoms of withdrawal appear, the test is positive
and no additional naloxone should be administered and the
course of oral treatment should not be administered.
o Naltrexone given in the setting of opioid use will precipitate withdrawal symptoms
including but not limited to: nausea, vomiting, dysphoria, sweating, poor appetite,
disruptive sleep pattern, an inability to focus, anxiety, and tremors.
o No significant drug-drug interactions have been reported other than the
withdrawal symptoms previously noted with the concomitant use of naltrexone
and other opioid agents. Caution should be used with any drug and its use with
naltrexone.
Results of clinical trials for the use of naltrexone for opioid dependence are inconclusive.
A Cochrane review of oral naltrexone maintenance treatment for opioid dependence
concluded that there was no clear benefit of naltrexone in terms of retention in treatment,
side effects, or relapse. This was based on a review of ten studies with 696 total
participants. In another systematic review, eleven clinical trials were reviewed and the
authors arrived at a similar conclusion; that there is insufficient evidence to justify the use
of naltrexone in the maintenance treatment of opioid addicts.
Page 44 of 46
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
•
•
•
There are limitations to the clinical trials conducted with naltrexone.
o Number of participants is small due to increased drop out and loss to follow up
with population.
o Many studies do not compare naltrexone to other agents or placebo. Use of
placebo can be challenged by patients who inject or ingest opioid to determine if
they have active medication.
The National Institutes for Health and Clinical Excellence (NICE) published guidelines in
2007 specifically addressing the use of naltrexone in opioid dependence. NICE
recommends naltrexone as a treatment option in detoxified formerly opioid-dependent
people who are highly motivated to remain in an abstinence program. The guidelines
also recommend naltrexone should only be administered under adequate supervision to
people who have been fully informed of the potential adverse effects of treatment. It
should be given as part of a program of supportive care and effectiveness in preventing
opioid misuse and individuals being treated should be evaluated regularly.
Naltrexone is an orally administered opioid antagonist that may be used in the treatment
of opioid addiction. In patients that have successfully detoxified from opioids, naltrexone
can be utilized as maintenance therapy to prevent relapse. Its antagonist mechanism of
action blocks receptors from opioids and therefore the patient receives no pleasurable
effect when opioids are administered. However, its utility has proven to be limited and in
a number of studies, no more effective than placebo or psychosocial behavior.
Naltrexone does however provide an alternative pharmacological therapy for
maintenance of opioid abstinence and may be useful in those patients that cannot take
buprenorphine or that are highly motivated to remain opioid free.
.
RECOMMENDATION
Naltrexone is an opioid antagonist that is used in the treatment of opioid addiction. In patients that
have successfully detoxified from opioids, naltrexone can be utilized as maintenance therapy to
prevent relapse. Current clinical guidelines recommend naltrexone therapy as a treatment for
opioid dependence and recommend adequate supervision of treatment due to the potential for
significant adverse effects and withdrawal symptoms with concomitant use of naltrexone and
opioid agents. Treatment should not be administered unless the patient is opioid-free. Abstinence
from opioids in opioid addicts must be objectively verified. Therefore, it is recommended that
naltrexone be available for use subject to clinical criteria.
COMMITTEE VOTE:
APPROVED
PREFERRED
NaltrexoneCC
DISAPPROVED
APPROVED with MODIFICATION
NEW: AGENTS FOR OPIOID DETOXIFICATION
NON-PREFERRED
ReVia® CC (naltrexone)
Clinical Criteria: Naltrexone (ReVia® )
• Naltrexone will be approved for recipients who meet ALL of the following criteria:
–Diagnosis of opioid dependency.
–Documentation that patient is opioid free (must document negative urine drug screen or
naltrexone challenge test within the last 30 days).
–Physician must have reviewed the Controlled Substances Database within the past 30 days to
ensure that concomitant narcotic use is not occurring.
COMMITTEE VOTE:
APPROVED
Page 45 of 46
DISAPPROVED
APPROVED with MODIFICATION
May 12, 2009 Tennessee PAC
ANALGESIC AGENTS
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2009.
Accessed April, 2009.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 2009.
3. MedMetrics. Agents for Opioid Detoxification class review. February 4, 2009.
4. Minozzi S, Amato L, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance
treatment for opioid dependence. Cochrane Database of Systematic Reviews 2006,
Issue 1. Art. No.: CD001333. DOI: 10.1002/14651858.CD001333.pub2.
5. Kirchmayer U., Davoli M., Verster AD., Amato L., Ferri M., Perucci CA. A systematic
review on the efficacy of naltrexone maintenance treatment in opioid dependence.
Addiction. 2002; 97:1241-9.
6. Cornish JW, et al. Naltrexone pharmacotherapy for opioid dependent federal
probationers. Journal of Substance Abuse Treatment. 1997;14(6):529-34.
7. National Institute for Health and Clinical Excellence (NICE). Naltrexone for the
management of opioid dependence. London (UK): National Institute for Health and
Clinical Excellence (NICE); 2007 Jan. (Technology appraisal guidance; no.115).
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May 12, 2009 Tennessee PAC