Saquinavir Mesylate (1 brand name, 2 dosage forms, 1 route)
Available dosage forms: TABLET, CAPSULE.
Routes of administration: ORAL.
Brand Names
- INVIRASE
Indications and Usage
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 (see Table 6 ) and pharmacokinetic data (see Table 1 ). The efficacy of INVIRASE with ritonavir has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.
Dosage and Administration
INVIRASE must be used in combination with ritonavir, because it significantly inhibits saquinavir’s metabolism to provide increased plasma saquinavir levels.
Contraindications
INVIRASE is contraindicated in patients with clinically significant hypersensitivity (e.g. anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients including ritonavir. INVIRASE/ritonavir should not be administered concurrently with rifampin, 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/ritonavir should not be administered concurrently with drugs listed in Table 4 . Table 4 Drugs That Are Contraindicated With INVIRASE/Ritonavir Drug Class Drugs Within Class That Are Contraindicated With INVIRASE Clinical Comment Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine Potential for serious and/or threatening reactions. Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Potential for serious and life threatening reactions such as ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Antimycobacterial Agents Rifampin Rifampin should not be administered in patients taking ritonavir-boosted INVIRASE part of an ART regimen due to the risk of severe hepatocellular toxicity. GI Motility Agent Cisapride Potential for serious and/or life threatening reactions such as cardiac arrhythmias. Neuroleptics Pimozide Potential for serious and/or life threatening reactions such as cardiac arrhythmias. Sedative/Hypnotics Triazolam, orally admini
Drug Interactions
Drug interaction studies have been completed with INVIRASE and saquinavir soft gel capsules. Observations from drug interaction studies with saquinavir soft gel capsules may not be predictive for INVIRASE/ritonavir. Because ritonavir is coadministered, prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent. The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp, may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp. Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in Table 4 under CONTRAINDICATIONS. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in Table 2 , which summarizes the effect of saquinavir, administered as saquinavir soft gel capsules or INVIRASE, on the geometric mean AUC and Cmax of coadministered drugs and Table 3 , which summarizes the effect of coadministered drugs on the geometric mean AUC and Cmax of saquinavir. Clinical dose recommendations can be found in Table 5 . The magnitude of the interactions may be different when INVIRASE is given with ritonavir (see CLINICAL PHARMACOLOGY ). When coadministering INVIRASE/ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulti
Mechanism of Action
Saquinavir is an inhibitor of HIV protease. HIV protease is an enzyme required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV. Saquinavir is a peptide-like substrate analogue that binds to the protease active site and inhibits the activity of the enzyme. Saquinavir inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious virus particles.
Overdosage
There is limited experience of overdose with saquinavir. 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. Treatment of overdose with saquinavir should consist of general supportive measures including monitoring of vital signs and ECG and observations of the patient’s clinical status. Since saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.