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CRIXIVAN
Overview
What is CRIXIVAN?
CRIXIVAN (indinavir sulfate) is an inhibitor of the human immunodeficiency virus (HIV) protease. CRIXIVAN Capsules are formulated as a sulfate salt and are available for oral administration in strengths of 100, 200, and 400 mg of indinavir (corresponding to 125, 250, and 500 mg indinavir sulfate, respectively). Each capsule also contains the inactive ingredients anhydrous lactose and magnesium stearate. The capsule shell has the following inactive ingredients and dyes: gelatin, titanium dioxide, silicon dioxide, and sodium lauryl sulfate.
The chemical name for indinavir sulfate is [1(1,2),5()]-2,3,5-trideoxy--(2,3-dihydro-2-hydroxy-1-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D--pentonamide sulfate (1:1) salt. Indinavir sulfate has the following structural formula:
Indinavir sulfate is a white to off-white, hygroscopic, crystalline powder with the molecular formula CHNO• HSO and a molecular weight of 711.88. It is very soluble in water and in methanol.
What does CRIXIVAN look like?
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What are the available doses of CRIXIVAN?
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What should I talk to my health care provider before I take CRIXIVAN?
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How should I use CRIXIVAN?
CRIXIVAN in combination with antiretroviral agents is indicated for the treatment of HIV infection.
This indication is based on two clinical trials of approximately 1 year duration that demonstrated: 1) a reduction in the risk of AIDS-defining illnesses or death; 2) a prolonged suppression of HIV RNA.
The recommended dosage of CRIXIVAN is 800 mg (usually 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. Alternatively, CRIXIVAN may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal, e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; or corn flakes, skim milk and sugar. (See .)
To ensure adequate hydration, it is recommended that adults drink at least 1.5 liters (approximately 48 ounces) of liquids during the course of 24 hours.
What interacts with CRIXIVAN?
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:
What are the warnings of CRIXIVAN?
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Nephrolithiasis/Urolithiasis
Nephrolithiasis/urolithiasis has occurred with CRIXIVAN therapy. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range across individual trials: 4.7% to 34.4%). 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, 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 (e.g., 1-3 days) or discontinuation of therapy may be considered.
Hemolytic Anemia
Acute hemolytic anemia, including cases resulting in death, has been reported in patients treated with CRIXIVAN. Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of CRIXIVAN.
Hepatitis
Hepatitis including cases resulting in hepatic failure and death has been reported in patients treated with CRIXIVAN. Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between CRIXIVAN and these events has not been established.
Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
Drug Interactions
Concomitant use of CRIXIVAN with lovastatin, simvastatin, or rosuvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including CRIXIVAN, are used concurrently with atorvastatin. The interaction of CRIXIVAN with pravastatin and fluvastatin is not known. The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including CRIXIVAN, are used in combination with these statin drugs (see ).
Midazolam is extensively metabolized by CYP3A4. Co-administration with CRIXIVAN with or without ritonavir may cause a large increase in the concentration of this benzodiazepine. No drug interaction study has been performed for the co-administration of CRIXIVAN with benzodiazepines. Based on data from other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore CRIXIVAN should not be co-administered with orally administered midazolam (see ), whereas caution should be used with co-administration of CRIXIVAN and parenteral midazolam. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels. If CRIXIVAN with or without ritonavir is co-administered with parenteral midazolam, it should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
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 events, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil (see and and , and the manufacturer’s complete prescribing information for sildenafil, tadalafil, or vardenafil).
Concomitant use of CRIXIVAN and St. John’s wort () or products containing St. John’s wort is not recommended. Coadministration of CRIXIVAN and St. John’s wort has been shown to substantially decrease indinavir concentrations (see and may lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors.
What are the precautions of CRIXIVAN?
General
Indirect hyperbilirubinemia has occurred frequently during treatment with CRIXIVAN and has infrequently been associated with increases in serum transaminases (see also and ). It is not known whether CRIXIVAN will exacerbate the physiologic hyperbilirubinemia seen in neonates. (See .)
Tubulointerstitial Nephritis
Reports of tubulointerstitial nephritis with medullary calcification and cortical atrophy have been observed in patients with asymptomatic severe leukocyturia (>100 cells/ high power field). Patients with asymptomatic severe leukocyturia should be followed closely and monitored frequently with urinalyses. Further diagnostic evaluation may be warranted, and discontinuation of CRIXIVAN should be considered in all patients with severe leukocyturia.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy (CART), including CRIXIVAN. During the initial phase of treatment, patients responding to antiretroviral therapy whose immune system responds to CART may develop an inflammatory response to indolent or residual opportunistic infections (such as MAI, CMV, PCP, or TB), which may necessitate further evaluation and treatment.
Coexisting Conditions
Patients with hemophilia: There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established. (See .)
Patients with hepatic insufficiency due to cirrhosis: In these patients, the dosage of CRIXIVAN should be lowered because of decreased metabolism of CRIXIVAN (see ).
Patients with renal insufficiency: Patients with renal insufficiency have not been studied.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have 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.
Information for Patients
A statement to patients and health care providers is included on the product’s bottle label. A Patient Package Insert (PPI) for CRIXIVAN is available for patient information.
CRIXIVAN is not a cure for HIV infection and patients may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of CRIXIVAN are unknown at this time. CRIXIVAN has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
Patients should be advised to remain under the care of a physician when using CRIXIVAN and should not modify or discontinue treatment without first consulting the physician. Therefore, if a dose is missed, patients should take the next dose at the regularly scheduled time and should not double this dose. Therapy with CRIXIVAN should be initiated and maintained at the recommended dosage.
CRIXIVAN may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John’s wort.
For optimal absorption, CRIXIVAN should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, CRIXIVAN may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal, e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; or corn flakes, skim milk and sugar (see and ). Ingestion of CRIXIVAN with a meal high in calories, fat, and protein reduces the absorption of indinavir.
Patients receiving a phosphodiesterase type 5 (PDE5) inhibitor (sildenafil, tadalafil, or vardenafil) should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, visual changes, and priapism, and should promptly report any symptoms to their doctors ( see and ).
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
CRIXIVAN Capsules are sensitive to moisture. Patients should be informed that CRIXIVAN should be stored and used in the original container and the desiccant should remain in the bottle.
Drug Interactions
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 (see and ).
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.
Array
| Drug Class: Drug Name | Clinical Comment | |
| Alpha 1-adrenoreceptor antagonist: alfuzosin | Potentially increased alfuzosin concentrations can result in hypotension. | |
| Antiarrhythmics: amiodarone | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. | |
| 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. | |
| 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. | |
| GI motility agents:cisapride | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. | |
| Herbal products:St. John's wort () | May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors. | |
| HMG-CoA Reductase inhibitors: lovastatin, simvastatin, rosuvastatin | Potential for serious reactions such as risk of myopathy including rhabdomyolysis. | |
| Neuroleptic:pimozide | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. | |
| PDE5 inhibitor:Revatio (sildenafil) [for treatment of pulmonary arterial hypertension] | A safe and effective dose has not been established when used with CRIXIVAN. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). | |
| 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. | |
| Sedative/hypnotics:Oral midazolam, triazolam, alprazolam | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. | |
| Note: ↑= increase; ↓ = decrease | ||
| Drug Name | Effect | Clinical Comment |
| 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. |
| 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. |
| Antidepressant:Trazodone | ↑ trazodone concentration | Concomitant use of trazodone and CRIXIVAN may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as CRIXIVAN, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-gout:Colchicine | ↑ colchicine concentration | Patients with renal or hepatic impairment should not be given colchicine with CRIXIVAN. Co-administration of colchicine in patients on CRIXIVAN: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Co-administration of colchicine in patients on CRIXIVAN:If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Co-administration of colchicine in patients on CRIXIVAN: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| 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. |
| Endothelin receptor antagonist:Bosentan | ↑ bosentan concentration | Co-administration of bosentan in patients on CRIXIVAN or co-administration of CRIXIVAN in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA ReductaseInhibitors: atorvastatin, pravastatin, fluvastatin | ↑ atorvastatin concentration pravastatin, fluvastatin-interaction not studied | Use the lowest possible dose of atorvastatin with careful monitoring. If no alternative treatment is available, use with careful monitoring. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus | ↑ immunosuppressant agents concentration | Plasma concentrations may be increased by CRIXIVAN. |
| Inhaled beta agonist:Salmeterol | ↑ salmeterol | Concurrent administration of salmeterol with CRIXIVAN is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Inhaled/nasal steroid: Fluticasone | ↑ fluticasone concentration | Concomitant use of fluticasone propionate and CRIXIVAN may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Fluticasone use is not recommended in situations where CRIXIVAN is coadministered with a potent CYP3A4 inhibitor such as ritonavir unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. |
| 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. |
| Midazolam (parenteral administration) | ↑ midazolam concentration | Concomitant use of parenteral midazolam with CRIXIVAN may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with CRIXIVAN is CONTRAINDICATED (see ). |
| Rifabutin | ↓ indinavir concentration↑ rifabutin concentration | Dose reduction of rifabutin to half the standard dose and a dose increase of CRIXIVAN to 1000 mg every 8 hours are recommended when rifabutin and CRIXIVAN are coadministered. |
| Sildenafil | ↑ sildenafil concentration(only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with CRIXIVAN) | May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of Revatio (sildenafil) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see CONTRAINDICATIONS]. Sildenafil dose should not exceed a maximum of 25 mg in a 48-hour period in patients receiving concomitant CRIXIVAN therapy. Use with increased monitoring for adverse events. |
| Tadalafil | ↑ tadalafil concentration | May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual disturbances, and priapism. The following dose adjustments are recommended for use of Adcirca (tadalafil) with CRIXIVAN:Co-administration of Adcirca in patients on CRIXIVAN or co-administration of CRIXIVAN in patients on Adcirca:Start at or adjust Adcirca to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Tadalafil dose should not exceed a maximum of 10 mg in a 72-hour period in patients receiving concomitant CRIXIVAN therapy. Use with increased monitoring for adverse events. |
| 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. |
| Venlafaxine | ↓ indinavir concentration | In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. |
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in mice and rats. In mice, no increased incidence of any tumor type was observed. The highest dose tested in rats was 640 mg/kg/day; at this dose a statistically significant increased incidence of thyroid adenomas was seen only in male rats. At that dose, daily systemic exposure in rats was approximately 1.3 times higher than daily systemic exposure in humans. No evidence of mutagenicity or genotoxicity was observed in microbial mutagenesis (Ames) tests, alkaline elution assays for DNA breakage, and chromosomal aberration studies, and mammalian cell mutagenesis assays. No treatment-related effects on mating, fertility, or embryo survival were seen in female rats and no treatment-related effects on mating performance were seen in male rats at doses providing systemic exposure comparable to or slightly higher than that with the clinical dose. In addition, no treatment-related effects were observed in fecundity or fertility of untreated females mated to treated males.
Pregnancy
Pregnancy Category C:
Developmental toxicity studies were performed in rabbits (at doses up to 240 mg/kg/day), dogs (at doses up to 80 mg/kg/day), and rats (at doses up to 640 mg/kg/day). The highest doses in these studies produced systemic exposures in these species comparable to or slightly greater than human exposure. No treatment-related external, visceral, or skeletal changes were observed in rabbits or dogs. No treatment-related external or visceral changes were observed in rats. Treatment-related increases over controls in the incidence of supernumerary ribs (at exposures at or below those in humans) and of cervical ribs (at exposures comparable to or slightly greater than those in humans) were seen in rats. In all three species, no treatment-related effects on embryonic/fetal survival or fetal weights were observed.
In rabbits, at a maternal dose of 240 mg/kg/day, no drug was detected in fetal plasma 1 hour after dosing. Fetal plasma drug levels 2 hours after dosing were approximately 3% of maternal plasma drug levels. In dogs, at a maternal dose of 80 mg/kg/day, fetal plasma drug levels were approximately 50% of maternal plasma drug levels both 1 and 2 hours after dosing. In rats, at maternal doses of 40 and 640 mg/kg/day, fetal plasma drug levels were approximately 10 to 15% and 10 to 20% of maternal plasma drug levels 1 and 2 hours after dosing, respectively.
Indinavir was administered to Rhesus monkeys during the third trimester of pregnancy (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, indinavir caused an exacerbation of the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately fourfold above controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after exposure to indinavir during the third trimester of pregnancy. In Rhesus monkeys, fetal plasma drug levels were approximately 1 to 2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily.
Hyperbilirubinemia has occurred during treatment with CRIXIVAN (see and ). It is unknown whether CRIXIVAN administered to the mother in the perinatal period will exacerbate physiologic hyperbilirubinemia in neonates.
There are no adequate and well-controlled studies in pregnant patients. CRIXIVAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
A CRIXIVAN dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). Given the substantially lower antepartum exposures observed and the limited data in this patient population, indinavir use is not recommended in HIV-infected pregnant patients (see ).
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant patients exposed to CRIXIVAN, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
Studies in lactating rats have demonstrated that indinavir is excreted in milk. Although it is not known whether CRIXIVAN is excreted in human milk, there exists the potential for adverse effects from indinavir in nursing infants. Mothers should be instructed to discontinue nursing if they are receiving CRIXIVAN. This is consistent with the recommendation by the U.S. Public Health Service Centers for Disease Control and Prevention that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
Pediatric Use
The optimal dosing regimen for use of indinavir in pediatric patients has not been established. A dose of 500 mg/m every eight hours has been studied in uncontrolled studies of 70 children, 3 to 18 years of age. The pharmacokinetic profiles of indinavir at this dose were comparable to profiles previously observed in adults receiving the recommended dose (see ). Although viral suppression was observed in some of the 32 children who were followed on this regimen through 24 weeks, a substantially higher rate of nephrolithiasis was reported when compared to adult historical data (see ). Physicians considering the use of indinavir in pediatric patients without other protease inhibitor options should be aware of the limited data available in this population and the increased risk of nephrolithiasis.
Geriatric Use
Clinical studies of CRIXIVAN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.
What are the side effects of CRIXIVAN?
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 and .)
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.
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.
| Study 028Considered Drug-Related and of Moderate or Severe Intensity | Study ACTG 320 of Unknown Drug Relationship and of Severe or Life-threatening Intensity | ||||
| CRIXIVAN | CRIXIVANplusZidovudine | Zidovudine | CRIXIVAN plus Zidovudine plus Lamivudine | ZidovudineplusLamivudine | |
| Adverse Experience | Percent (n=332) | Percent(n=332) | Percent(n=332) | Percent(n=571) | Percent(n=575) |
| Abdominal pain | 16.6 | 16.0 | 12.0 | 1.9 | 0.7 |
| Asthenia/fatigue | 2.1 | 4.2 | 3.6 | 2.4 | 4.5 |
| Fever | 1.5 | 1.5 | 2.1 | 3.8 | 3.0 |
| Malaise | 2.1 | 2.7 | 1.8 | 0 | 0 |
| Nausea | 11.7 | 31.9 | 19.6 | 2.8 | 1.4 |
| Diarrhea | 3.3 | 3.0 | 2.4 | 0.9 | 1.2 |
| Vomiting | 8.4 | 17.8 | 9.0 | 1.4 | 1.4 |
| Acid regurgitation | 2.7 | 5.4 | 1.8 | 0.4 | 0 |
| Anorexia | 2.7 | 5.4 | 3.0 | 0.5 | 0.2 |
| Appetite increase | 2.1 | 1.5 | 1.2 | 0 | 0 |
| Dyspepsia | 1.5 | 2.7 | 0.9 | 0 | 0 |
| Jaundice | 1.5 | 2.1 | 0.3 | 0 | 0 |
| Anemia | 0.6 | 1.2 | 2.1 | 2.4 | 3.5 |
| Back pain | 8.4 | 4.5 | 1.5 | 0.9 | 0.7 |
| Headache | 5.4 | 9.6 | 6.0 | 2.4 | 2.8 |
| Dizziness | 3.0 | 3.9 | 0.9 | 0.5 | 0.7 |
| Somnolence | 2.4 | 3.3 | 3.3 | 0 | 0 |
| Pruritus | 4.2 | 2.4 | 1.8 | 0.5 | 0 |
| Rash | 1.2 | 0.6 | 2.4 | 1.1 | 0.5 |
| Cough | 1.5 | 0.3 | 0.6 | 1.6 | 1.0 |
| Difficulty breathing/ dyspnea/ shortness of breath | 0 | 0.6 | 0.3 | 1.8 | 1.0 |
| Nephrolithiasis/urolithiasis | 8.7 | 7.8 | 2.1 | 2.6 | 0.3 |
| Dysuria | 1.5 | 2.4 | 0.3 | 0.4 | 0.2 |
| Taste perversion | 2.7 | 8.4 | 1.2 | 0.2 | 0 |
| Study 028 | Study ACTG 320 | ||||
| CRIXIVAN | CRIXIVANplusZidovudine | Zidovudine | CRIXIVAN plusZidovudineplusLamivudine | ZidovudineplusLamivudine | |
| Percent(n=329) | Percent(n=320) | Percent(n=330) | Percent(n=571) | Percent(n=575) | |
| Hematology | |||||
| Decreased hemoglobin <7.0 g/dL | 0.6 | 0.9 | 3.3 | 2.4 | 3.5 |
| Decreased platelet count <50 THS/mm | 0.9 | 0.9 | 1.8 | 0.2 | 0.9 |
| Decreased neutrophils <0.75 THS/mm | 2.4 | 2.2 | 6.7 | 5.1 | 14.6 |
| Blood chemistry | |||||
| Increased ALT >500% ULN | 4.9 | 4.1 | 3.0 | 2.6 | 2.6 |
| Increased AST >500% ULN | 3.7 | 2.8 | 2.7 | 3.3 | 2.8 |
| Total serum bilirubin >250% ULN | 11.9 | 9.7 | 0.6 | 6.1 | 1.4 |
| Increased serum amylase >200% ULN | 2.1 | 1.9 | 1.8 | 0.9 | 0.3 |
| Increased glucose >250 mg/dL | 0.9 | 0.9 | 0.6 | 1.6 | 1.9 |
| Increased creatinine >300% ULN | 0 | 0 | 0.6 | 0.2 | 0 |
Post-Marketing Experience
Body As A Whole:
Cardiovascular System:
Digestive System:
Hematologic:
Endocrine/Metabolic:
Hypersensitivity:
Musculoskeletal System:
Nervous System/Psychiatric:
Skin and Skin Appendage:
Urogenital System:
Laboratory Abnormalities
Increased serum triglycerides; increased serum cholesterol.
What should I look out for while using CRIXIVAN?
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:
ALERT: Find out about medicines that should NOT be taken with CRIXIVAN.
What might happen if I take too much CRIXIVAN?
There have been more than 60 reports of acute or chronic human overdosage (up to 23 times the recommended total daily dose of 2400 mg) with CRIXIVAN. The most commonly reported symptoms were renal (e.g., nephrolithiasis/urolithiasis, flank pain, hematuria) and gastrointestinal (e.g., nausea, vomiting, diarrhea).
It is not known whether CRIXIVAN is dialyzable by peritoneal or hemodialysis.
How should I store and handle CRIXIVAN?
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].CRIXIVAN Capsules are available as follows:No. 3755 — 100 mg capsules: semi-translucent white capsules coded in green.No. 3756 — 200 mg capsules: semi-translucent white capsules coded in blue. No. 3758 — 400 mg capsules: semi-translucent white capsules coded in green. They are supplied by as follows:CRIXIVAN Capsules are available as follows:No. 3755 — 100 mg capsules: semi-translucent white capsules coded in green.No. 3756 — 200 mg capsules: semi-translucent white capsules coded in blue. No. 3758 — 400 mg capsules: semi-translucent white capsules coded in green. They are supplied by as follows:CRIXIVAN Capsules are available as follows:No. 3755 — 100 mg capsules: semi-translucent white capsules coded in green.No. 3756 — 200 mg capsules: semi-translucent white capsules coded in blue. No. 3758 — 400 mg capsules: semi-translucent white capsules coded in green. They are supplied by as follows:CRIXIVAN Capsules are available as follows:No. 3755 — 100 mg capsules: semi-translucent white capsules coded in green.No. 3756 — 200 mg capsules: semi-translucent white capsules coded in blue. No. 3758 — 400 mg capsules: semi-translucent white capsules coded in green. They are supplied by as follows:CRIXIVAN Capsules are available as follows:No. 3755 — 100 mg capsules: semi-translucent white capsules coded in green.No. 3756 — 200 mg capsules: semi-translucent white capsules coded in blue. No. 3758 — 400 mg capsules: semi-translucent white capsules coded in green. They are supplied by as follows:
