FDA approved changes to the Invirase (saquinavir mesylate) label to provide updated for drugs that are contraindicated or interact with Invirase/ritonavir.
Also a warning was added to state cobicistat is not recommended for concomitant use with Invirase. The specific changes are summarized below.
Section 2: DOSAGE AND ADMINISTRATION was updated as follows:
Cobicistat is not interchangeable with ritonavir to increase systemic exposure of saquinavir.
For patients already taking ritonavir 100 mg twice daily as part of their antiretroviral regimen, no additional ritonavir is needed.
Section 4: CONTRAINDICATIONS was updated to contraindicate the following agents.
Drugs That Are Contraindicated With INVIRASE/ritonavir
|
Drug Class |
Drugs Within Class That Are Contraindicated With INVIRASE/ritonavir |
Clinical Comment |
|
Anti-infectives |
Clarithromycin, erythromycin, halofantrine, pentamidine |
Potential for serious and/or life-threatening cardiac arrhythmia. |
|
HIV-1 Protease Inhibitor |
Atazanavir |
Potential for serious and/or life-threatening cardiac arrhythmia. |
|
Immunosuppressant |
Tacrolimus |
Potential for serious and/or life-threatening cardiac arrhythmia. |
|
Neuroleptics |
Pimozide Chlorpromazine Sertindole Clozapine Haloperidol Mesoridazine Phenothiazines Thioridazine Ziprasidone |
Potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
|
Other drugs that are CYP3A substrates |
Dapsone Disopyramide Quinine |
Potential for serious and/or life-threatening cardiac arrhythmia. |
The following statement was added to section 5: WARNINGS and PRECAUTIONS. INVIRASE is not recommended for use in combination with cobicistat.
Dosing recommendations for this combination have not been established. Cobicistat is also not recommended in combination with regimens containing
ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Please refer to the cobicistat full prescribing information for additional precautionary
measures.
The following changes were made to section 7: Drug Interactions to provide clinical comments regarding when coadministration is not recommended or
when additional monitoring is needed.
|
Concomitant Drug Class: Drug Name |
Effect on Concentration of Saquinavir or Concomitant Drug |
Clinical Comment |
|
|
HIV-1 Antiviral Agents |
|||
|
Non-nucleoside reverse transcriptase inhibitor: Delavirdineb
|
Saquinavir
Effect on delavirdine is not well established |
Appropriate doses of the combination with respect to safety and efficacy have not been established. Coadministration is not recommended. Liver function should be monitored frequently if this combination is prescribed. |
|
|
Non-nucleoside reverse transcriptase inhibitor: Efavirenza, nevirapineb |
↓ Saquinavir ↔ Efavirenz
|
Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended.
|
|
|
HIV-1 protease inhibitor: AtazanavirIndinavirb |
Saquinavir Indinavir ↔ Atazanavir
|
Atazanavir in Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended. may result in nephrolithiasis. For further details see complete prescribing information for Crixivan® (indinavir). |
|
|
HIV-1 protease inhibitor: IndinavirLopinavir/ritonavira (coformulated tablet) |
« Saquinavir « Lopinavir ↓ Ritonavir
|
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following INVIRASE/ritonavir 1000/100 mg. The recommended dose for this combination is INVIRASE 1000 mg plus lopinavir/ritonavir 400/100 mg bid.
Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.2, 5.3)]. Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and e |
|
|
HIV-1 protease inhibitor: Lopinavir/ritonavirNelfinavir |
Saquinavir |
|
|
|
Other Agents |
|||
|
Ibutilide Sotalol |
|
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)]. Coadministration of INVIRASE/ritonavir and ibutilide or sotalol is not recommended.
|
|
|
Anticonvulsants: Carbamazepineb, phenobarbitalb, phenytoinb |
¯ Saquinavir
Effect on carbamazepine, phenobarbital, and phenytoin is not well established
|
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. Coadministration is not recommended. |
|
|
Anti-infective:Streptogramin antibiotics (quinupristin/dalfopristinb) |
Streptogramin antibiotics such as quinupristin/dalfopristin inhibit CYP3A4; saquinavir concentrations may be increased |
Monitoring for saquinavir toxicity is recommended. Use with caution due to possible cardiac arrhythmias. |
|
|
Antimycobacterial: Rifabutina |
↔ Saquinavir Rifabutin ↔ Ritonavir
|
No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if INVIRASE/ritonavir is administered in combination with rifabutin.
Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events including neutropenia and liver enzyme levels is warranted in patients receiving the combination.
Consider monitoring rifabutin concentrations to ensure adequate exposure.
|
|
|
Benzodiazepinesb: Alprazolam, clorazepate, diazepam, flurazepam
|
Benzodiazepines |
Clinical significance is unknown. Careful monitoring of patients for benzodiazepine effects is warranted; a decrease in benzodiazepine dose may be needed.
|
|
|
Corticosteroid: Dexamethasoneb |
¯ Saquinavir
|
Use with caution. SaquinavirINVIRASE/ritonavir may be less effective due to decreased saquinavir plasma concentrations. Coadministration is not recommended.
|
|
|
Inhaled/nasal steroids: Fluticasoneb Budesonide |
Fluticasone |
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Several cases of Cushing’s disease associated with this interaction have been reported in the literature. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. If the combination is nevertheless considered necessary, a dose reduction of fluticasone propionate with close monitoring of local and systemic effects is recommended.
A switch to a corticosteroid which is not a substrate for CYP3A (e.g., beclomethasone) should be considered. In case of withdrawal of corticosteroids, progressive dose reduction may have to be performed over a longer period.
|
|
|
HMG-CoA reductase inhibitorsb: Atorvastatin |
Atorvastatin
|
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day. Patients should be carefully monitored for signs and symptoms of myopathy (e.g., muscle weakness, muscle pain, rising creatinine creatine kinase).
|
|
|
Immunosuppressantsb: Cyclosporine, rapamycin |
Immunosuppressants |
Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
|
|
|
Narcotic analgesic: Methadonea |
¯ Methadone |
Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
|
|
|
Tricyclic antidepressantsb: Amitriptyline, clomipramine, imipramine, maprotiline
|
Tricyclics |
Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
|
|
|
Other antidepressants: Nefazodone |
Saquinavir |
Monitoring for saquinavir toxicity is recommended. |
|
|
Herbal Products: St. John’s wortb (hypericum perforatum) |
↓ Saquinavir |
Herbal products containing St. John’s wort should not be used concomitantly with INVIRASE/ritonavir because coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
|
|
|
Other drugs that are substrates of CYP3A: Fentanylb Alfentanilb |
Fentanyl Alfentanil |
Coadministration with these drugs may accentuate the side effects reported with use of fentanyl or alfentanil including respiratory depression, apnea and bradycardia.
|
|
|
Vasodilators (peripheral): Intravenously administered Vincamine |
Vincamine |
Monitoring for vincamine toxicity is recommended. Use with caution due to potential cardiac arrhythmias. |
|
7.4 Drugs without Clinically Significant Interactions with INVIRASE/ritonavir
Based on drug interaction studies conducted with INVIRASE/ritonavir, no clinically significant effect was observed for saquinavir when coadministered
with fosamprenavir. No clinically significant effect was observed for enfuvirtide when coadministered with INVIRASE/ritonavir.
Section 12: Clinical Pharmacology was updated to include the following statement
The HIV-1 antiviral drugs didanosine, tenofovir, and zidovudine are not predicted to have any clinically significant effect on the pharmacokinetics of
saquinavir with and without ritonavir. No clinically significant effect on the pharmacokinetic parameters of enfuvirtide was observed with
coadministration of INVIRASE/ritonavir. No clinically significant effect on the pharmacokinetic parameters of saquinavir was observed with coadministration
of fosamprenavir.
You will be able to view the complete label at drugs@fda or dailymed.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
For more information about the HIV Liaison Program visit the FDA Patient Network
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