Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Protease Inhibitors (PIs)
Last Updated: April 27, 2017; Last Reviewed: April 27, 2017
|Indinavir (IDV, Crixivan)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
|Capsules: 100 mg, 200 mg, and 400 mg|
|Dosing Recommendations||Selected Adverse Events|
Neonate and Infant Dose:
Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)
- Metabolism: CYP3A4 is the major enzyme responsible for metabolism. There is potential for multiple drug interactions.
- Avoid other drugs that cause hyperbilirubinemia, such as atazanavir.
- Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions with indinavir.
- More common: Nephrolithiasis/urolithiasis with indinavir crystal deposit (higher in children (29%) than in adults (12.4%).1 Nausea, abdominal pain, headache, metallic taste, dizziness, asymptomatic hyperbilirubinemia (10%), lipid abnormalities, pruritus, and rash.
- Less common (more severe): Fat maldistribution.
- Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting diabetes mellitus, spontaneous bleeding in hemophiliacs, acute hemolytic anemia, and hepatitis (life-threatening in rare cases).
The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).
Indinavir has not been approved by the Food and Drug Administration for use in the pediatric population. Although indinavir was one of the first protease inhibitors to be studied in children, its use in pediatrics has never been common and is currently very rare.2 Indinavir is not recommended by Panel members for use in children because of its unfavorable toxicity profile, limited efficacy data, and uncertain pharmacokinetics.
Efficacy and Pharmacokinetics
Both unboosted and ritonavir-boosted indinavir have been studied in children with HIV infection. An unboosted indinavir dose of 500 to 600 mg/m2 body surface area given every 8 hours results in peak blood concentrations and area under the curve slightly higher than those in adults, but considerably lower trough concentrations. A significant proportion of children have trough indinavir concentrations less than the 0.1 mg/L value associated with virologic efficacy in adults.3-6 Studies in small groups of children of a range of indinavir/ritonavir doses have shown that indinavir 500 mg/m2 body surface area plus ritonavir 100 mg/m2 body surface area twice daily is probably too high,7 that indinavir 234 to 250 mg/m2 body surface area plus low-dose ritonavir twice daily is too low,8,9 and that indinavir 400 mg/m2 body surface area plus ritonavir 100 to 125 mg/m2 body surface area twice daily results in exposures approximating those seen with 800 mg indinavir/100 mg ritonavir twice daily in adults, albeit with considerable inter-individual variability and high rates of toxicity.9-11
- Crixivan (indinavir sulfate) [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020685s077lbl.pdf.
- Van Dyke RB, Patel K, Siberry GK, et al. Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr. 2011;57(2):165-173. Available at http://www.ncbi.nlm.nih.gov/pubmed/21407086.
- Burger DM, van Rossum AM, Hugen PW, et al. Pharmacokinetics of the protease inhibitor indinavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. 2001;45(3):701-705. Available at http://www.ncbi.nlm.nih.gov/pubmed/11181346.
- Fletcher CV, Brundage RC, Remmel RP, et al. Pharmacologic characteristics of indinavir, didanosine, and stavudine in human immunodeficiency virus-infected children receiving combination therapy. Antimicrob Agents Chemother. 2000;44(4):1029-1034. Available at http://www.ncbi.nlm.nih.gov/pubmed/10722507.
- Gatti G, Vigano A, Sala N, et al. Indinavir pharmacokinetics and parmacodynamics in children with human immunodeficiency virus infection. Antimicrob Agents Chemother. 2000;44(3):752-755. Available at http://www.ncbi.nlm.nih.gov/pubmed/10681350.
- Mueller BU, Sleasman J, Nelson RP, Jr., et al. A phase I/II study of the protease inhibitor indinavir in children with HIV infection. Pediatrics. 1998;102(1 Pt 1):101-109. Available at http://www.ncbi.nlm.nih.gov/pubmed/9651421.
- van Rossum AM, Dieleman JP, Fraaij PL, et al. Persistent sterile leukocyturia is associated with impaired renal function in human immunodeficiency virus type 1-infected children treated with indinavir. Pediatrics. 2002;110(2 Pt 1):e19. Available at http://www.ncbi.nlm.nih.gov/pubmed/12165618.
- Plipat N, Cressey TR, Vanprapar N, Chokephaibulkit K. Efficacy and plasma concentrations of indinavir when boosted with ritonavir in human immunodeficiency virus-infected Thai children. Pediatr Infect Dis J. 2007;26(1):86-88. Available at http://www.ncbi.nlm.nih.gov/pubmed/17195716.
- Curras V, Hocht C, Mangano A, et al. Pharmacokinetic study of the variability of indinavir drug levels when boosted with ritonavir in HIV-infected children. Pharmacology. 2009;83(1):59-66. Available at http://www.ncbi.nlm.nih.gov/pubmed/19052483.
- Bergshoeff AS, Fraaij PL, van Rossum AM, et al. Pharmacokinetics of indinavir combined with low-dose ritonavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. 2004;48(5):1904-1907. Available at http://www.ncbi.nlm.nih.gov/pubmed/15105157.
- Fraaij PL, Bergshoeff AS, van Rossum AM, Hartwig NG, Burger DM, de Groot R. Changes in indinavir exposure over time: a case study in six HIV-1-infected children. J Antimicrob Chemother. 2003;52(4):727-730. Available at http://www.ncbi.nlm.nih.gov/pubmed/12917234.