Indinavir

Pronunciation

(in DIN a veer)

U.S. Brand Names

Crixivan®

Synonyms

Indinavir Sulfate

Generic Available

Canadian Brand Names

Crixivan®

Use

Treatment of HIV infection; should always be used as part of a multidrug regimen (at least three antiretroviral agents)

Pregnancy Risk Factor

Pregnancy Implications

Plasma levels of indinavir were 74% lower at weeks 30-32 of gestation when compared to the same women at 14-28 weeks of gestation. Plasma levels were not measurable in some patients 8 hours post dose. Hyperbilirubinemia may be exacerbated in neonates. Pregnancy and protease inhibitors are both associated with an increased risk of hyperglycemia. Glucose levels should be closely monitored. Until optimal dosing during pregnancy has been established, the manufacturer does not recommend indinavir use in pregnant patients. Healthcare professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to indinavir or any component of the formulation; concurrent use of amiodarone, cisapride, triazolam, midazolam, pimozide, or ergot alkaloids

Warnings/Precautions

Because indinavir may cause nephrolithiasis/urolithiasis the drug should be discontinued if signs and symptoms occur; risk is substantially higher in pediatric patients versus adults. Adequate hydration is recommended. May cause tubulointerstitial nephritis (rare); severe asymptomatic leukocyturia may warrant evaluation. Indinavir should not be administered concurrently with lovastatin or simvastatin (caution with atorvastatin and cerivastatin) because of competition for metabolism of these drugs through the CYP3A4 system, and potential serious or life-threatening events. Use caution with other drugs metabolized by this enzyme (particular caution with phosphodiesterase-5 inhibitors, including sildenafil). Avoid concurrent use of St John's wort (may lead to loss of virologic response and/or resistance). Patients with hepatic insufficiency due to cirrhosis should have dose reduction. Warn patients about fat redistribution that can occur. Indinavir has been associated with hemolytic anemia (discontinue if diagnosed), hepatitis, and hyperglycemia (exacerbation or new-onset diabetes). Treatment may result in immune reconstitution syndrome (acute inflammatory response to indolent or residual opportunistic infections). Use caution in patients with hemophilia; spontaneous bleeding has been reported.

Adverse Reactions

Protease inhibitors cause dyslipidemia which includes elevated cholesterol and triglycerides and a redistribution of body fat centrally to cause increased abdominal girth, buffalo hump, facial atrophy, and breast enlargement. These agents also cause hyperglycemia (exacerbation or new-onset diabetes).

10%:

Gastrointestinal: Nausea (12%)

Hepatic: Hyperbilirubinemia (14%)

Renal: Nephrolithiasis/urolithiasis (29%, pediatric patients; 12% adult patients)

1% to 10%:

Central nervous system: Headache (6%), insomnia (3%)

Gastrointestinal: Abdominal pain (9%), diarrhea/vomiting (4% to 5%), taste perversion (3%)

Neuromuscular & skeletal: Weakness (4%), flank pain (3%)

Renal: Hematuria

<1%: Malaise, dizziness, somnolence, anorexia, xerostomia, decreased hemoglobin, pancreatitis, urticaria, depression, increased serum cholesterol, fever, MI, angina

Postmarketing and/or case reports: Acute renal failure, alopecia, anaphylactoid reactions, bleeding (spontaneous in patients with hemophilia A or B), crystalluria, depression, dysuria, erythema multiforme, hemolytic anemia, hepatic failure, hepatitis, hyperglycemia, immune reconstitution syndrome, interstitial nephritis (with medullary calcification and cortical atrophy), leukocyturia (severe and asymptomatic), MI, new-onset diabetes, paresthesia (oral), pruritus, pyelonephritis, Stevens-Johnson syndrome, vasculitis

Drug Interactions

Substrate of CYP2D6 (minor), 3A4 (major); Inhibits CYP2C8/9 (weak), 2C19 (weak), 2D6 (weak), 3A4 (strong)

Amiodarone: Serum levels/toxicity may be increased by indinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

Anticonvulsants: Phenobarbital, and carbamazepine may decrease serum levels and consequently effectiveness of indinavir.

Benzodiazepines: An increase in midazolam and triazolam serum levels may occur resulting in significant oversedation when administered with indinavir. Concurrent use is contraindicated. Use caution with other benzodiazepines.

Calcium channel blockers: Indinavir may increase the serum concentrations of calcium channel blockers.

Cisapride: Indinavir inhibits the metabolism of cisapride and should not be administered concurrently due to risk of life-threatening cardiac arrhythmias.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of indinavir. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins. Dosage adjustment may be recommended; see individual agents.

CYP3A4 inhibitors: May increase the levels/effects of indinavir. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

CYP3A4 substrates: Indinavir may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Didanosine: Separate administration of indinavir from buffered formulations by at least 1 hour.

Ergot alkaloids: Serum levels/toxicity may be increased by indinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

HMG-CoA reductase inhibitors: Indinavir may increase levels of HMG-CoA reductase inhibitors, increasing the risk of myopathy. Lovastatin and simvastatin should not be coadministered with indinavir (per manufacturer). Atorvastatin may be used with careful monitoring, in the lowest dose possible. Fluvastatin and pravastatin may have lowest risk.

Immunosuppressants: Indinavir may increase the serum levels of cyclosporine, sirolimus or tacrolimus.

Itraconazole or ketoconazole: May increase the serum concentrations of indinavir. Dosage adjustment of indinavir is recommended.

Non-nucleoside reverse transcriptase inhibitors: When used with delavirdine, serum levels of indinavir are increased. The serum concentrations of indinavir may be decreased by efavirenz or nevirapine. Dosage adjustment of indinavir may be required for these combinations.

Phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil, vardenafil): Serum concentrations/effects may be substantially increased by indinavir. Dosage restriction/limitation is recommended.

Pimozide: Serum levels/toxicity may be increased by indinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

Protease inhibitors: Serum levels of both nelfinavir and indinavir are increased with concurrent use. Serum concentrations of indinavir may be increased by ritonavir. Serum levels of ritonavir and saquinavir may be increased. Dosage adjustments of both agents may be required during concurrent therapy. Concurrent use of atazanavir may increase the risk of hyperbilirubinemia.

Quinidine: Serum levels/toxicity may be increased by indinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

Rifabutin: A 200% increase in rifabutin plasma AUC has been observed when coadministered with indinavir. Rifabutin may decrease the serum concentrations of indinavir. Dosage adjustment of both agents required.

Rifampin: Rifampin decreases indinavir's serum concentrations; loss of virologic response and resistance may occur; the two drugs should not be administered together.

St John's wort (Hypericum perforatum ): Appears to induce CYP3A enzymes and may lead to reduction in trough serum concentrations, which may lead to treatment failures. Alternatively, changes may involve P-glycoprotein. The two drugs should not be used together.

Ethanol/Nutrition/Herb Interactions

Food: Indinavir bioavailability may be decreased if taken with food. Meals high in calories, fat, and protein result in a significant decrease in drug levels. Indinavir serum concentrations may be decreased by grapefruit juice.

Herb/Nutraceutical: St John's wort (Hypericum) appears to induce CYP3A enzymes and has lead to 57% reductions in indinavir AUCs and 81% reductions in trough serum concentrations, which may lead to treatment failures; should not be used concurrently with indinavir.

Stability

Capsules are sensitive to moisture; medication should be stored and used in the original container and the desiccant should remain in the bottle

Mechanism of Action

Indinavir is a human immunodeficiency virus protease inhibitor, binding to the protease activity site and inhibiting the activity of this enzyme. HIV protease is an enzyme required for the cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV. Inhibition prevents cleavage of these polyproteins resulting in the formation of immature noninfectious viral particles.

Pharmacodynamics/Kinetics

Absorption: Administration with a high fat, high calorie diet resulted in a reduction in AUC and in maximum serum concentration (77% and 84% respectively); lighter meal resulted in little or no change in these parameters.

Protein binding, plasma: 60%

Metabolism: Hepatic via CYP3A4; seven metabolites of indinavir identified

Bioavailability: Good

Half-life elimination: 1.8 ± 0.4 hour

Time to peak: 0.8 ± 0.3 hour

Excretion: Urine and feces

Dosage

Children (investigational): 500 mg/m² every 8 hours (patients with smaller BSA may require lower doses of 300-400 mg/m² every 8 hours)

Adults: Oral: 800 mg every 8 hours

Note: Dosage adjustments for indinavir when administered in combination therapy:

Delavirdine, itraconazole, or ketoconazole: Reduce indinavir dose to 600 mg every 8 hours

Efavirenz: Increase indinavir dose to 1000 mg every 8 hours

Lopinavir and ritonavir (Kaletra™): Indinavir 600 mg twice daily

Nevirapine: Increase indinavir dose to 1000 mg every 8 hours

Rifabutin: Reduce rifabutin to ¹ /2 the standard dose plus increase indinavir to 1000 mg every 8 hours

Ritonavir: Adjustments necessary for both agents:

Ritonavir 100-200 mg twice daily plus indinavir 800 mg twice daily or

Ritonavir 400 mg twice daily plus indinavir 400 mg twice daily

Dosage adjustment in hepatic impairment: Mild-moderate impairment due to cirrhosis: 600 mg every 8 hours or with ketoconazole coadministration

Administration

Drink at least 48 oz of water daily. Administer with water, 1 hour before or 2 hours after a meal. Administer around-the-clock to avoid significant fluctuation in serum levels.

Monitoring Parameters

Monitor viral load, CD4 count, triglycerides, cholesterol, glucose, liver function tests, CBC, urinalysis (severe leukocyturia should be monitored frequently).

Dietary Considerations

Should be taken without food but with water 1 hour before or 2 hours after a meal. Administration with lighter meals (eg, dry toast, skim milk, corn flakes) resulted in little/no change in indinavir concentration. If taking with ritonavir, may take with food. Patient should drink at least 48 oz of water daily.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Indinavir is not a cure for AIDS. Take as directed, around-the-clock, with a large glass of water, preferably 1 hour before or 2 hours after meals. May take with light meal (eg, dry toast, skim milk, corn flakes) to reduce GI upset. Capsules are sensitive to moisture medication should be stored and used in the original container and the desiccant should remain in the bottle. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Indinavir may be prescribed with a combination of other medications; time these medications as directed by prescriber. You may be advised to check your glucose levels (this drug can cause exacerbation of diabetes or new-onset diabetes). You may experience body changes due to redistribution of body fat, facial atrophy, or breast enlargement (normal effects of drug); nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); muscle weakness or flank pain (consult prescriber for approved analgesic); or headache or insomnia (consult prescriber for medication). Report chest pain or palpitations, difficult or painful urination, persistent diarrhea or vomiting, or other persistent adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Abnormal taste.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause insomnia; may rarely cause dizziness or drowsiness

Mental Health: Effects on Psychiatric Treatment

Contraindicated with midazolam and triazolam; use caution with other benzodiazepines; may produce additive sedation and respiratory depression. Concomitant use of indinavir and St John's wort is not recommended. Coadministration of protease inhibitors (indinavir) with St John's wort is expected to substantially decrease protease inhibitor serum concentrations leading to a loss of virologic response and possible resistance to indinavir or to the class of protease inhibitors.

Dosage Forms

Capsule: 100 mg, 200 mg, 333 mg, 400 mg

References

CDC and the National Foundation for Infectious Disease, "Update: Provisional Public Health Service Recommendations for Chemoprophylaxis After Occupational Exposure to HIV," MMWR Morb Mortal Wkly Rep , 1996, 45(22):468-80.

Deeks SG, Smith M, Holodniy M, et al, "HIV-1 Protease Inhibitors. A Review for Clinicians," JAMA , 1997, 277(2):145-53.

Hilts AE and Fish DN, "Dosage Adjustment of Antiretroviral Agents in Patients With Organ Dysfunction," Am J Health Syst Pharm , 1998, 55:2528-33.

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, Panel on Clinical Practices for Treatment of HIV Infection," February 5, 2001. Available at: http://www.aidsinfo.nih.gov. Accessed February 14, 2001.

Kakuda TN, Struble KA, and Piscitelli SC, "Protease Inhibitors for the Treatment of Human Immunodeficiency Virus Infection," Am J Health Syst Pharm , 1998, 55(3):233-54.

Kaufman MB and Simionatto C, "A Review of Protease Inhibitor-Induced Hyperglycemia," Pharmacotherapy , 1999, 19(1):114-7.

Kaul DR, Cinti SK, Carver PL, et al, "HIV Protease Inhibitors: Advances in Therapy and Adverse Reactions, Including Metabolic Complications," Pharmacotherapy , 1999, 19(3):281-98.

McDonald CK and Kuritzkes DR, "Human Immunodeficiency Virus Type 1 Protease Inhibitors," Arch Intern Med , 1997, 157(9):951-9.

Mueller BU, Smith S, Sleasman J, et al, "A Phase I/II Study of the Protease Inhibitor Indinavir (MK-0639) in Children With HIV Infection," Int Conf AIDS , 1996, 11:37.

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.

Rana KZ and Dudley MN, "Human Immunodeficiency Virus Protease Inhibitors," Pharmacotherapy , 1999, 19(1):35-59.

Stein DS, Fish DG, Bilello JA, et al, "A 24-Week Open-Label Phase I/II Evaluation of the HIV Protease Inhibitor MK-639 (Indinavir)," AIDS , 1996, 10(5):485-92.

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection," March 1, 1999. Available at: http://www.aidsinfo.nih.gov.

International Brand Names

Crixivan® (AR, AT, AU, BE, BR, CA, CH, CL, CO, CR, CZ, DE, DK, ES, FI, FR, GB, GT, HN, HR, IE, IT, LU, MX, NL, NO, NZ, PA, PL, PT, RO, RU, SE, SG, SI, SV, TH, TR, YU, ZA); Forli® (AR); Indilea® (AR)

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