Selected Precationary Information

CRIXIVAN^® (indinavir sulfate) in combination with other antiretroviral agents is indicated for the treatment of HIV infection. This indication is based on 2 clinical trials of approximately 1 year’s duration that demonstrated (1) a reduction in the risk of AIDS-defining illness or death and (2) a prolonged suppression of HIV RNA.

CRIXIVAN:

• Does not cure HIV infection
• Does not reduce the transmission of HIV
• Should only be taken in combination with other drugs for HIV

IMPORTANT SAFETY INFORMATION

Contraindications

CRIXIVAN is contraindicated in patients with clinically significant hypersensitivity to any of its components.

Selected Warnings

• ALERT: Find out about medicines that should NOT be taken with CRIXIVAN.
• Nephrolithiasis/urolithiasis has occurred in clinical studies in adult patients (12.4%; range across individual trials, 4.7% to 34.4%) and in pediatric patients (29%) receiving CRIXIVAN. The cumulative frequency of nephrolithiasis events increases with increasing exposure to CRIXIVAN; however, the risk over time remains relatively constant. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure and pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur (including flank pain with or without hematuria or microscopic hematuria), temporary interruption (eg, 1 to 3 days) or discontinuation of therapy may be considered. Adequate hydration (at least 48 ounces daily for adults) is recommended in all patients treated with CRIXIVAN.
• In patients treated with CRIXIVAN, acute hemolytic anemia, including death in some patients, and hepatitis, including hepatic failure and death, have been reported.
• There have also been reports of hyperglycemia and new onset or exacerbation of preexisting diabetes mellitus in patients receiving protease inhibitors.
• Concomitant use of CRIXIVAN with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including CRIXIVAN, are used concurrently with other HMG-CoA reductase inhibitors metabolized by the CYP3A4 pathway (eg, atorvastatin).
• Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving indinavir. Coadministration of CRIXIVAN with these medications is expected to substantially increase plasma concentrations of sildenafil, tadalafil, and vardenafil and may result in an increase in adverse reactions, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil.

Selected Drug Interactions

Selected Precautions

• Indirect hyperbilirubinemia has occurred frequently (in approximately 14% of patients treated with CRIXIVAN in clinical studies) and has infrequently been associated with increases in serum transaminases.
• Reports of tubulointerstitial nephritis with medullary calcification and cortical atrophy have been observed in patients with asymptomatic severe leukocyturia (>100 cells/high-power field).
• There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.
• In patients with hepatic insufficiency due to cirrhosis, the dosage of CRIXIVAN should be lowered because of decreased metabolism of CRIXIVAN. Patients with renal insufficiency have not been studied.
• Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, has been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
• Indinavir is an inhibitor of the cytochrome P-450 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 (see CONTRAINDICATIONS and WARNINGS).
• 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.
• Use of CRIXIVAN is not recommended in pregnant patients.

Established and Other Potentially Significant Drug Interactions

Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction.

Note: ↑ = increase; ↓ = decrease.

Adverse Reactions

Clinical Trials in Adults

Nephrolithiasis/urolithiasis, including flank pain with or without hematuria (including microscopic hematuria), has been reported in approximately 12.4% (301/2429; range across individual trials: 4.7% to 34.4%) of patients receiving CRIXIVAN at the recommended dose in clinical trials with a median follow-up of 47 weeks (range: 1 day to 242 weeks; 2238 patient-years follow-up). The cumulative frequency of nephrolithiasis events increases with duration of exposure to CRIXIVAN; however, the risk over time remains relatively constant. Of the patients treated with CRIXIVAN who developed nephrolithiasis/urolithiasis in clinical trials during the double-blind phase, 2.8% (7/246) were reported to develop hydronephrosis and 4.5% (11/246) underwent stent placement. Following the acute episode, 4.9% (12/246) of patients discontinued therapy. (See WARNINGS and DOSAGE AND ADMINISTRATION, Nephrolithiasis/Urolithiasis.)

Asymptomatic hyperbilirubinemia (total bilirubin >2.5 mg/dL), reported predominantly as elevated indirect bilirubin, has occurred in approximately 14% of patients treated with CRIXIVAN. In <1% this was associated with elevations in ALT or AST.

Hyperbilirubinemia and nephrolithiasis/urolithiasis occurred more frequently at doses exceeding 2.4 g/day compared to doses <2.4 g/day.

Clinical adverse experiences reported in >2% of patients treated with CRIXIVAN alone, CRIXIVAN in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 10.

* Including renal colic, and flank pain with and without hematuria

In Phase I and II controlled trials, the following adverse events were reported significantly more frequently by those randomized to the arms containing CRIXIVAN than by those randomized to nucleoside analogues: rash, upper respiratory infection, dry skin, pharyngitis, taste perversion.

Selected laboratory abnormalities of severe or life-threatening intensity reported in patients treated with CRIXIVAN alone, CRIXIVAN in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 11.

* Upper limit of the normal range.

Dosage and administration of CRIXIVAN

The recommended dosage of CRIXIVAN is 800 mg (usually two 400-mg capsules) orally every 8 hours. CRIXIVAN must be taken at intervals of 8 hours. For optimal absorption, CRIXIVAN should be administered without food but with water 1 hour before or 2 hours after a meal. CRIXIVAN may be administered with other liquids or with a light meal.