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Roche
Issues Drug Interaction Warning on Hepatocellular Toxicity in Healthy
Volunteers Receiving TB Drug Rifampin and Saquinavir/Ritonavir
Roche
Pharmaceuticals distributed a “Dear Health Care Provider” letter
today (February 8, 2005) with a warning regarding significant hepatocellular
toxicity among healthy volunteers in a clinical study receiving
saquinavir/ritonavir (1000/100 mg twice daily) plus rifampin (Rifadin)
once daily (600 mg). Rafampin is used in the treatment of tuberculosis.
Following
is the text of the letter released by Roche:
IMPORTANT DRUG INTERACTION WARNING:
DRUG-INDUCED HEPATITIS WITH MARKED TRANSAMINASE ELEVATIONS HAS BEEN
OBSERVED IN HEALTHY VOLUNTEERS RECEIVING RIFAMPIN* 600 MG ONCE DAILY
IN COMBINATION WITH RITONAVIR 100 MG/SAQUINAVIR 1000 MG TWICE DAILY
(RITONAVIR BOOSTED SAQUINAVIR).
In a Phase I, randomized, open-label, multiple-dose clinical pharmacology
study in healthy volunteers, 11/28 (39.3%) subjects exposed to rifampin
600 mg once daily taken together with ritonavir 100 mg / saquinavir
1000 mg given twice daily (ritonavir-boosted saquinavir) developed
significant hepatocellular toxicity during the 28 day study period.
Among
these subjects, transaminase elevations of up to > 20X upper
limit of normal values were noted and one subject was admitted to
the hospital with marked transaminase elevations. For all study
participants, dosing of all study medications was immediately terminated
and the study was discontinued. Following drug discontinuation,
liver function tests in all affected subjects are returning to normal,
clinical symptoms have abated and no deaths from this clinical study
have been reported.
The current package inserts for both INVIRASE® (saquinavir mesylate
capsules and tablets) and FORTOVASE® (saquinavir soft gelatin capsules)
contraindicate the use of rifampin together with saquinavir. This
contraindication is based on a pharmacokinetic interaction between
rifampin and saquinavir that results in reduced saquinavir plasma
levels. The clinical pharmacology study reported above was undertaken
to determine if boosting of saquinavir with ritonavir would overcome
the interaction. However, as a result of the high incidence of hepatotoxicity
in this study, Roche now advises prescribers that:
Rifampin SHOULD NOT be administered to patients also receiving saquinavir/ritonavir
(ritonavir-boosted saquinavir) as part of combination antiretroviral
therapy (ART) for HIV infection.
Roche is collaborating closely with the U.S. FDA (Food and Drug
Administration) on this issue, and appropriate changes to the package
insert will be made as soon as possible.
Health care professionals are encouraged to report any unexpected
events associated with the use of saquinavir/ ritonavir directly
to Roche Laboratories at 1-800-526-6367 or to the FDA MedWatch
program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178
or by mail (MED WATCH, 5600 Fishers Lane, Rockville, MD 20852-9787).
Please see important safety information at close of letter.
Yours sincerely,
Lars E. Birgerson, MD, PhD
Vice President, Medical Affairs
Indication
INVIRASE
in combination with ritonavir and other antiretroviral agents is
indicated for the treatment of HIV infection. The twice-daily administration
of INVIRASE in combination with ritonavir is supported by safety
data from the MaxCMin 1 study and pharmacokinetic data. The efficacy
of INVIRASE with ritonavir or FORTOVASE (with or without ritonavir
coadministration) has not been compared against the efficacy of
antiretroviral regimens currently considered standard of care.
FORTOVASE is indicated for use in combination with other antiretroviral
agents for the treatment of HIV infection. This indication is based
on studies that showed increased saquinavir concentrations and improved
antiviral activity for FORTOVASE 1200 mg tid compared to INVIRASE
600 mg tid. In treatment-naive and treatment-experienced patients,
the efficacy of FORTOVASE (with or without ritonavir coadministration)
has not been compared against the efficacy of antiretroviral regimens
currently considered standard of care.
Important Safety Information
WARNING:
INVIRASE® (saquinavir mesylate) capsules and tablets and FORTOVASE®
(saquinavir) soft gelatin capsules are not bioequivalent and cannot
be used interchangeably. INVIRASE may be used only if it is combined
with ritonavir, which significantly inhibits saquinavir's metabolism
to provide plasma saquinavir levels at least equal to those achieved
with FORTOVASE. When using saquinavir as the sole protease inhibitor
in an antiviral regimen, FORTOVASE is the recommended formulation.
INVIRASE and FORTOVASE are contraindicated in patients with clinically
significant hypersensitivity to saquinavir or to any of the components
contained in the capsule.
FORTOVASE
and INVIRASE/ritonavir should not be administered concurrently with
terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam
or ergot derivatives. Inhibition of CYP3A4 by saquinavir could result
in elevated plasma concentrations of these drugs, potentially causing
serious or life-threatening reactions, such as cardiac arrhythmias
or prolonged sedation.
FORTOVASE and INVIRASE, when administered with ritonavir, are contraindicated
in patients with severe hepatic impairment. Saquinavir drug pharmacokinetics/pharmacodynamics
have not been studied in patients with hepatic impairment and caution
should be exercised when prescribing saquinavir in this population.
Concomitant
use of INVIRASE or FORTOVASE with lovastatin or simvastatin is not
recommended. Caution should be exercised if HIV protease inhibitors,
including INVIRASE or FORTOVASE, are used concurrently with other
HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4
pathway (eg, atorvastatin). Concomitant use of INVIRASE or FORTOVASE
and St. John's wort (hypericum perforatum) or products containing
St. John's wort is not recommended. Garlic capsules should not be
used while taking unboosted saquinavir, due to the risk of decreased
saquinavir plasma concentrations. For a complete list of drugs that
should not be taken with saquinavir, please see TABLE 5 in the summary
of complete product information.
New-onset diabetes mellitus, exacerbation of preexisting diabetes
mellitus and hyperglycemia have been reported during postmarketing
surveillance in HIV-infected patients receiving protease-inhibitor
therapy. No initial dose adjustment is necessary for patients with
renal impairment. However, patients with severe renal impairment
have not been studied, and caution should be exercised when prescribing
saquinavir in this population.
There have been reports of spontaneous bleeding in patients with
hemophilia A and B treated with protease inhibitors.
Elevated
cholesterol and/or triglyceride levels have been observed in some
patients taking twice daily saquinavir in combination with ritonavir.
Redistribution/accumulation of body fat has been observed in patients
receiving ART. A causal relationship between protease-inhibitor
therapy and these events has not been established, and the long-term
consequences are currently unknown.
Varying degrees of cross-resistance among protease inhibitors have
been observed. In clinical trials with saquinavir (1000 mg) in combination
with ritonavir (100 mg) and other antiretrovirals, the grade 2,
3 and 4 adverse events occurring in 3 2% of 148 patients (considered
at least possibly related to study drug or of unknown relationship):
abdominal pain (6.1%), back pain (2%), bronchitis (2.7%), constipation
(2%), diarrhea (8.1%), diabetes mellitus/hyperglycemia (2.7%), dry
lips/skin (2%), eczema (2%), fatigue (6.1%), fever (3.4%), influenza
(2.7%), lipodystrophy (5.4%).
INVIRASE
and FORTOVASE are not cures for HIV infection or AIDS. INVIRASE
and FORTOVASE do not prevent the transmission of HIV.
02/09//05
Source
www.invirase.com http://invirase.com/Global/newspress.asp
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