Dear Health Care Provider,
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
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
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.
Lars E. Birgerson, MD, PhD
Vice President,Medical Affairs
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
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
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
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
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%), nausea (10.8%), pneumonia (5.4%), pruritus
(3.4%), rash (3.4%), sinusitis (2.7%) and vomiting (7.4%).
INVIRASE and FORTOVASE are not cures for HIV infection or AIDS. INVIRASE and FORTOVASE do not prevent the transmission of HIV.