Invirase (Saquinavir Mesylate) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Drugs That Are Mainly Metabolized by CYP3A4

Although specific studies have not been performed, coadministration with drugs that are mainly metabolized by CYP3A4 (eg, calcium channel blockers, dapsone, disopyramide, quinine, amiodarone, quinidine, warfarin, tacrolimus, cyclosporine, ergot derivatives, pimozide, carbamazepine, fentanyl, alfentanyl, alprazolam, and triazolam) may have elevated plasma concentrations when coadministered with saquinavir; therefore, these combinations should be used with caution. Since INVIRASE is coadministered with ritonavir, the ritonavir label should be reviewed for additional drugs that should not be coadministered.

Inducers of CYP3A4

Coadministration with compounds that are potent inducers of CYP3A4 (eg, phenobarbital, phenytoin, dexamethasone, carbamazepine) may result in decreased plasma levels of saquinavir.

Rifampin

In a Phase I, randomized, open-label, multiple-dose study involving 28 healthy volunteers, 11 of 17 (65%) healthy volunteers exposed concomitantly to rifampin 600 mg once daily and INVIRASE 1000 mg/ritonavir 100 mg given twice daily (ritonavir-boosted INVIRASE) developed severe hepatocellular toxicity during the 28-day study period. Therefore, rifampin should not be administered concomitantly in patients taking ritonavir-boosted INVIRASE as part of an ART regimen (see CONTRAINDICATIONS).

OVERDOSAGE

No acute toxicities or sequelae were noted in 1 patient who ingested 8 grams of INVIRASE as a single dose. The patient was treated with induction of emesis within 2 to 4 hours after ingestion. A second patient ingested 2.4 grams of INVIRASE in combination with 600 mg of ritonavir and experienced pain in the throat that lasted for 6 hours and then resolved. In an exploratory Phase II study of oral dosing with INVIRASE at 7200 mg/day (1200 mg q4h), there were no serious toxicities reported through the first 25 weeks of treatment.

CONTRAINDICATIONS

INVIRASE must be used in combination with ritonavir, which significantly inhibits saquinavir's metabolism and provides increased plasma saquinavir levels.

INVIRASE is contraindicated in patients with clinically significant hypersensitivity to saquinavir or to any of the components contained in the capsule or tablet.

INVIRASE/ritonavir should not be administered concurrently with terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam or ergot derivatives. Inhibition of CYP3A4 by saquinavir and ritonavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation (see PRECAUTIONS: Drug Interactions).

INVIRASE/ritonavir should not be given together with rifampin, due to the risk of severe hepatocellular toxicity if the three drugs are given together (see PRECAUTIONS: Drug Interactions).

INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment.

INVIRASE should not be administered concurrently with drugs listed in Table 4 (also see PRECAUTIONS: Drug Interactions, Table 5).

Table 4 Drugs That Are Contraindicated With INVIRASE/Ritonavir

Drug Class	Drugs Within Class That Are Contraindicated With INVIRASE
Antiarrhythmics	Amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines	Astemizole, terfenadine
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine
Antimycobacterial Agents	Rifampin
GI Motility Agent	Cisapride
Neuroleptics	Pimozide
Sedative/Hypnotics	Triazolam, midazolam