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Indinavir (Crixivan)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of indinavir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for indinavir treatment
References
Related Resources
DHHS Guidelines
Characteristics of PIs
Drug Interactions with PIs
Interactions among PIs
Interactions between NNRTIs, Maraviroc, Raltegravir, and PIs
Drugs That Should Not Be Used with PIs, NNRTIs, or CCR5 Antagonists
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Indinavir (Crixivan)
Class

Protease inhibitor

Background
U.S. Manufacturer

Merck & Co., Inc.

Approval

Indinavir received FDA approval in 1996 for use in adults with HIV infection. Initial approval was based on studies showing increases in CD4 T-lymphocyte counts and reductions in HIV viral load in individuals receiving indinavir either alone or in combination with 1 or 2 nucleoside analogues.(1) A study in patients with more advanced HIV infection showed a reduction in the rate of progression to AIDS-defining illness or death in individuals receiving indinavir + zidovidine + lamivudine compared with those receiving zidovudine + lamivudine.(2)

Formulation and Dosing

Indinavir is available in capsule form.

Dosing of Indinavir
AdultSingle PI800 mg Q 8 hrs
BoostedIndinavir 800 mg + ritonavir 100-200 mg BID*
PediatricBirth-4 yearsNot FDA approved in patients <18 years; should not be given to neonates
Age 4-15 years500 mg/m2 Q 8 hrs**
AdolescentAdult dose

Key to abbreviations: PI, protease inhibitor; Q, every; BID, twice daily.

* Other dosages are under investigation.

** Indinavir is not FDA approved for children <18 years of age. However, it has been studied in children; usual doses are indicated. In children, indinavir trough levels may be lower than those seen in adults.

Indinavir should be taken on an empty stomach or with a light snack, but not within 1 hour before or 2 hours after a full meal. When boosted with ritonavir, indinavir can be taken with food. Adequate hydration (1.5 liters per day in adults) is required to reduce the risk of nephrolithiasis.
Indinavir interacts with a number of antiretroviral medications, including other protease inhibitors, efavirenz, and nevirapine; see Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for indinavir with other antiretrovirals.
No dosage adjustment is necessary in renal insufficiency.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category C.
Clinical Use
Combinations

Regimens consisting of 2 nucleoside analogues and indinavir have been found to provide potent suppression of viral load in previously untreated patients. Several regimens containing indinavir in combination with nonnucleoside reverse transcriptase inhibitors have also been found to be effective, although adjustment in the indinavir dose is required. Combination with low-dose ritonavir allows less-frequent dosing of indinavir and elimination of food restrictions.(3,4)

Indinavir is an inhibitor of cytochrome P450 3A4 (CYP3A4), and may alter serum concentrations of other drugs metabolized by this pathway, including certain benzodiazepines, cholesterol-lowering agents, ergot derivatives, rifampin, phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, or vardenafil), and others. Because indinavir is also metabolized by CYP3A4, drugs that affect this enzyme system, such as ketoconazole, rifampin, and rifabutin, may significantly affect indinavir levels. Several protease inhibitors and the nonnucleoside reverse transcriptase inhibitors also affect indinavir concentrations. For example, indinavir concentrations are decreased by efavirenz and nevirapine; indinavir must be boosted with low-dose ritonavir when it is used in combination with nevirapine or efavirenz.

Even though both indinavir and didanosine are taken on an empty stomach, the tablet or powder formulations of didanosine should not be taken at the same time as indinavir because the buffer in these formulations may interfere with indinavir absorption. Indinavir should not be coadministered with atazanavir because of increased risk of hyperbilirubinemia.

Information on drug interactions should be consulted, as dose adjustments are frequently required, and some combinations are clearly contraindicated.

Use in Initial vs Subsequent Therapy

Treatment guidelines of the U.S. Department of Health and Human Services designate indinavir and ritonavir-boosted indinavir as "not recommended" for initial treatment of HIV infection.

Failure of a regimen containing indinavir may decrease the likelihood that subsequent protease inhibitor-containing regimens will succeed. Similarly, the response to indinavir is often diminished following virologic relapse on a regimen containing another protease inhibitor (see "Resistance").

Factors Affecting Adherence

The most common serious symptomatic side effect of indinavir is nephrolithiasis (kidney stones). The risk of stones is reduced by maintaining adequate hydration. Intake of least 48 ounces (1.5 liter) of water per 24-hour period is recommended for individuals taking indinavir, and more may be needed in hot weather or with sweating or diarrhea.

Fluid requirements, frequent dosing, and dietary restrictions make adherence to indinavir particularly challenging. Combination with ritonavir may simplify the dosing interval and dietary restrictions, but does not eliminate the risk of nephrolithiasis.

Indinavir has been associated with metabolic abnormalities including hyperglycemia, dyslipedemia, and abnormalities in fat distribution.

It is essential to assess patient motivation and discuss possible side effects and strategies for their management before treatment with indinavir is initiated.

Resistance

Resistance to indinavir is associated with the selection of 1 or more of several resistance mutations.

Implications of indinavir resistance for treatment with other antiretrovirals

Resistance mutations selected by indinavir frequently confer or contribute to resistance against other protease inhibitors. Different mutations are associated with cross-resistance to different drugs. For example, M46I is associated with cross-resistance to ritonavir, nelfinavir, and amprenavir (but not to saquinavir); V82A,F,T,S alone is associated with cross-resistance to ritonavir, but in combination with other mutations also confers resistance to nelfinavir, amprenavir, and saquinavir; and I84V contributes to resistance against to all available protease inhibitors. Although no single one of these mutations is associated with full resistance to lopinavir or tipranavir, each contributes partial resistance, and the presence of several mutations together can confer resistance.

Response to ritonavir is unlikely in the setting of resistance to indinavir.

Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing indinavir.

Implications of resistance to other antiretrovirals for indinavir treatment

Response to indinavir is unlikely in the setting of resistance ritonavir.

Response to indinavir may be diminished by resistance to saquinavir.(5)

Genotypic or phenotypic resistance testing may be useful in predicting the likelihood of response to indinavir following failure of regimens containing other protease inhibitors.

References
1.   Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Richman DD, Valentine FT, Jonas L, Meibohm A, Emini EA, Chodakewitz JA. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337:734-9.
2.   Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ, Feinberg JE, Balfour HH, Deyton LR, Chodakewitz JA, Fischl MA. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997;337:725-33.
3.   Lichterfeld M, Nischalke HD, Bergmann F, Wiesel W, Rieke A, Theisen A, Fatkenheuer G, Oette M, Carls H, Fenske S, Nadler M, Knechten H, Wasmuth JC, Rockstroh JK. Long-term efficacy and safety of ritonavir/indinavir at 400/400 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors as first line antiretroviral therapy. HIV Med. 2002 Jan;3(1):37-43.
4.   Dragsted UB, Gerstoft J, Pedersen C, Peters B, Duran A, Obel N, Castagna A, Cahn P, Clumeck N, Bruun JN, Benetucci J, Hill A, Cassetti I, Vernazza P, Youle M, Fox Z, Lundgren JD; MaxCmin1 Trial Group. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. J Infect Dis. 2003 Sep 1;188(5):635-42. Epub 2003 Aug 20.
5.   Para MF, Glidden DV, Coombs RW, Collier AC, Condra JH, Craig C, Bassett R, Leavitt R, Snyder S, McAuliffe V, Boucher C. Baseline human immunodeficiency virus type 1 phenotype, genotype, and RNA response after switching from long-term hard-capsule saquinavir to indinavir or soft-gel-capsule saquinavir in AIDS clinical trials group protocol 333. J Infect Dis 2000;182:733-43.