Indinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.
Indinavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.
Hepatic. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites.
CRIXIVAN is contraindicated in patients with clinically significant hypersensitivity to any of its components.
Inhibition of CYP3A4 by CRIXIVAN can result in elevated plasma concentrations of the following drugs, potentially
causing serious or life-threatening reactions:
Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of CRIXIVAN and drugs primarily
metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or
prolong its therapeutic and adverse effects.
Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance
of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of CRIXIVAN and other drugs
that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of
indinavir.
|
Table 8
|
|
Drugs That Should Not Be Coadministered with CRIXIVAN
|
|
Drug Class:
|
Drug Name Clinical Comment
|
|
Antiarrhythmics: amiodarone
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac
arrhythmias.
|
|
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity
characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
|
|
Sedative/hypnotics:
midazolam, triazolam
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or
increased sedation or respiratory depression.
|
|
GI motility agents:
cisapride
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac
arrhythmias.
|
|
Neuroleptic:
pimozide
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac
arrhythmias.
|
|
Herbal products:
St. John’s wort (Hypericum perforatum)
|
May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease
inhibitors.
|
|
Antimycobacterial:
rifampin
|
May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease
inhibitors or other coadministered antiretroviral agents.
|
|
HMG-CoA Reductase inhibitors:
lovastatin, simvastatin
|
Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
|
|
Protease inhibitor:
atazanavir
|
Both CRIXIVAN and atazanavir are associated with indirect (unconjugated) hyperbilirubinemia. Combinations of
these drugs have not been studied and coadministration of CRIXIVAN and atazanavir is not recommended.
|
|
Table 9
|
|
Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen
May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
|
|
Drug Name
|
Effect
|
Clinical Comment
|
|
HIV Antiviral Agents
|
|
Delavirdine
|
↑ indinavir concentration
|
Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered when taking delavirdine 400 mg three
times a day.
|
|
Didanosine
|
|
Indinavir and didanosine formulations containing buffer should be administered at least one hour apart on an
empty stomach.
|
|
Efavirenz
|
¯indinavir concentration
|
The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the
indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to
efavirenz.
|
|
Nelfinavir
|
↑ indinavir concentration
|
The appropriate doses for this combination, with respect to efficacy and safety, have not been
established.
|
|
Nevirapine
|
¯ indinavir concentration
|
Indinavir concentrations may be decreased in the presence of nevirapine. The appropriate doses for this
combination, with respect to efficacy and safety, have not been established.
|
|
Ritonavir
|
↑ indinavir concentration
↑ ritonavir concentration
|
The appropriate doses for this combination, with respect to efficacy and safety, have not been established.
Preliminary clinical data suggest that the incidence of nephrolithiasis is higher in patients receiving
indinavir in combination with ritonavir than those receiving CRIXIVAN 800 mg q8h.
|
|
Saquinavir
|
↑ saquinavir concentration
|
The appropriate doses for this combination, with respect to efficacy and safety, have not been
established.
|
|
Other Agents
|
|
Antiarrhythmics: bepridil, lidocaine (systemic) and quinidine
|
↑ antiarrhythmic agents concentration
|
Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when
coadministered with CRIXIVAN.
|
|
Anticonvulsants: carbamazepine, phenobarbital, phenytoin
|
¯ indinavir concentration
|
Use with caution. CRIXIVAN may not be effective due to decreased indinavir concentrations in patients taking
these agents concomitantly.
|
|
Calcium Channel Blockers, Dihydropyridine: e.g., felodipine, nifedipine, nicardipine
|
↑ dihydropyridine calcium channel blockers concentration
|
Caution is warranted and clinical monitoring of patients is recommended.
|
|
Clarithromycin
|
↑ clarithromycin concentration
↑ indinavir concentration
|
The appropriate doses for this combination, with respect to efficacy and safety, have not been
established.
|
|
HMG-CoA Reductase Inhibitor: atorvastatin
|
↑ atorvastatin concentration
|
Use lowest possible dose of atorvastatin with careful monitoring, or consider HMG-CoA reductase inhibitors
that are not primarily metabolized by CYP3A4, such as pravastatin, fluvastatin, or rosuvastatin in combination
with CRIXIVAN.
|
|
Immunosuppressants: cyclosporine, tacrolimus, sirolimus
|
↑ immunosuppressant agents concentration
|
Plasma concentrations may be increased by CRIXIVAN.
|
|
Itraconazole
|
↑ indinavir concentration
|
Dose reduction of CRIXIVAN to 600 mg every 8 hours is recommended when administering itraconazole
concurrently.
|
|
Ketoconazole
|
↑ indinavir concentration
|
Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered.
|
|
Rifabutin
|
¯ indinavir concentration
↑ rifabutin concentration
|
Dose reduction of rifabutin to half the standard dose and a dose increase of CRIXIVAN to 1000 mg (three
333-mg capsules) every 8 hours are recommended when rifabutin and CRIXIVAN are coadministered.
|
|
Sildenafil
|
↑ sildenafil concentration
|
Sildenafil dose should not exceed a maximum of 25 mg in a 48- hour period in patients receiving concomitant
indinavir therapy.
|
|
Tadalafil
|
↑ tadalafil concentration
|
Tadalafil dose should not exceed a maximum of 10 mg in a 72- hour period in patients receiving concomitant
indinavir therapy.
|
|
Vardenafil
|
↑ vardenafil concentration
|
Vardenafil dose should not exceed a maximum of 2.5 mg in a 24-hour period in patients receiving concomitant
indinavir therapy.
|
|
Note: ↑ = increase; ¯ = decrease
|
