Invirase

INVIRASE- saquinavir mesylate tablet, film coated
Genentech, Inc.

1 INDICATIONS AND USAGE

INVIRASE in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV-1 infection in adults (over the age of 16 years).

The following points should be considered when initiating therapy with INVIRASE/ritonavir:

The twice daily administration of INVIRASE in combination with ritonavir is supported by safety data from the MaxCmin 1 trial [see Adverse Reactions (6.1)] and pharmacokinetic data [see Clinical Pharmacology (12.3)].
The efficacy of INVIRASE with ritonavir has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.
The number of baseline primary protease inhibitor mutations affects the virologic response to INVIRASE/ritonavir.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

INVIRASE must be used in combination with ritonavir because ritonavir significantly inhibits saquinavir’s metabolism to provide increased plasma saquinavir levels.

Cobicistat is not interchangeable with ritonavir to increase systemic exposure of saquinavir [see Warnings and Precautions (5.1)].

  • The standard recommended dose of INVIRASE is 1,000 mg twice daily in combination with ritonavir 100 mg twice daily.
  • For treatment-naïve patients initiating treatment with INVIRASE/ritonavir, the recommended starting dose of INVIRASE is 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment. After 7 days, the recommended dose of INVIRASE is 1,000 mg twice daily with ritonavir 100 mg twice daily [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)].
  • Patients switching immediately (no washout period) from treatment with another ritonavir containing regimen or from a non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen (not including delavirdine, rilpivirine) should initiate and continue INVIRASE/ritonavir at the standard recommended dose of 1,000 mg twice daily with ritonavir 100 mg twice daily. For patients switching from a regimen containing delavirdine, the recommended dose is 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment [see Warnings and Precautions (5.4) and Drug Interactions (7.3)].
  • Ritonavir should be taken at the same time as INVIRASE.
  • INVIRASE and ritonavir should be taken within 2 hours after a meal.
  • For patients already taking ritonavir 100 mg twice daily as part of their antiretroviral regimen, no additional ritonavir is needed.
  • Pediatric dose recommendations that are both reliably effective and below thresholds of concern for QT and PR interval prolongation could not be determined.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 500-mg light orange to greyish or brownish orange, oval cylindrical, biconvex film-coated with ROCHE and SQV 500 imprinted on the tablet face

4 CONTRAINDICATIONS

INVIRASE/ritonavir is contraindicated in patients with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia, and in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)].

INVIRASE/ritonavir is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or patients who are at high risk of complete AV block [see Warnings and Precautions (5.3)].

INVIRASE/ritonavir is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients.

INVIRASE/ ritonavir is contraindicated in patients with severe hepatic impairment.

INVIRASE/ritonavir is contraindicated with drugs that are CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions [see Warnings and Precautions (5.2), Drug Interactions (7) and Clinical Pharmacology (12.3)].

INVIRASE/ritonavir is contraindicated in patients receiving the following co-administered drugs; however, it should be noted that this list is not intended to be exhaustive [see Drug Interactions (7) and Clinical Pharmacology (12.3)]

Alpha 1-adrenoreceptor antagonist: alfuzosin
Antiarrhythmics: amiodarone, bepridil, dofetilide, flecainide, lidocaine (systemic), propafenone, quinidine
Antidepressant: trazodone
Anti-infectives: clarithromycin, erythromycin, halofantrine, pentamidine
Antimycobacterial Agents: rifampin
Antipsychotics: lurasidone, clozapine, haloperidol, pimozide, sertindole, ziprasidone, phenothiazines (e.g. chlorpromazine, mesoridazine, thioridazine).
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine
HIV-1 Protease Inhibitor: atazanavir
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin
Immunosuppressant: tacrolimus
Non-nucleoside reverse transcriptase inhibitor (NNRTI): rilpivirine (concomitant use and switching from rilpivirine to INVIRASE/ritonavir without a washout period of at least 2 weeks is contraindicated)
PDE5 Inhibitors: sildenafil (Revatio®)[for treatment of pulmonary arterial hypertension]
Sedative/Hypnotics: triazolam, and orally administered midazolam
Tyrosine kinase inhibitors: dasatinib, sunatinib
Other drugs that are CYP3A substrates: disopyramide, quinine

5 WARNINGS AND PRECAUTIONS

5.1 Importance of Co-administration with Ritonavir

INVIRASE must be used in combination with ritonavir. Refer to the ritonavir full prescribing information for additional precautionary measures.

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. Refer to the cobicistat full prescribing information for additional precautionary measures.

5.2 Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of INVIRASE/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving INVIRASE/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of INVIRASE/ritonavir, respectively. These interactions may lead to:

  • Clinically significant adverse reactions potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.
  • Clinically significant adverse reactions from greater exposures of INVIRASE/ritonavir.
  • Loss of therapeutic effect of INVIRASE/ritonavir and possible development of resistance.

See Table 2 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during INVIRASE/ritonavir therapy; review concomitant medications during INVIRASE/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].

If a serious or severe toxicity occurs during treatment with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir. For concomitantly used drugs including antiretroviral agents used in combination with INVIRASE/ritonavir, prescribers should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.

5.3 PR Interval Prolongation

INVIRASE/ritonavir prolongs the PR interval in a dose-dependent fashion. Cases of second or third degree atrioventricular block have been reported rarely. Patients with underlying structural heart disease, pre-existing conduction system abnormalities, cardiomyopathies and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities. ECG monitoring is recommended in these patients [see Warnings and Precautions (5.4)]. Discontinue INVIRASE/ritonavir if significant arrhythmias, QT or PR prolongation occur.

The impact on the PR interval of coadministration of INVIRASE/ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, coadministration of INVIRASE/ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A, and clinical monitoring is recommended [see Clinical Pharmacology (12.2)].

For concomitantly used drugs, including antiretroviral agents used in combination with INVIRASE/ritonavir, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.

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