Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Protease Inhibitors (PIs)

Indinavir

Last Updated: May 22, 2018; Last Reviewed: May 22, 2018

Indinavir (IDV, Crixivan)
Indinavir (IDV, Crixivan)
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
Formulations
Capsules: 100 mg, 200 mg, and 400 mg
Dosing Recommendations Selected Adverse Events
Neonate and Infant Dose:
  • Not approved for use in neonates/infants
  • Should not be administered to neonates because of the risks associated with hyperbilirubinemia (kernicterus)
Pediatric Dose:
  • Not approved for use in children
  • A range of indinavir doses (234–500 mg/m2 body surface area) boosted with low-dose ritonavir has been studied in children (see text below).
Adolescent and Adult Dose:
  • 800 mg indinavir plus 100 or 200 mg ritonavir every 12 hours
  • The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV does not recommend the use of indinavir in adolescents.
  • Nephrolithiasis
  • Gastrointestinal intolerance, nausea
  • Hepatitis
  • Indirect hyperbilirubinemia
  • Hyperlipidemia
  • Hyperglycemia
  • Fat maldistribution
  • Possible increased bleeding episodes in patients with hemophilia
Special Instructions
  • When indinavir is given in combination with ritonavir, meal restrictions are not necessary.
  • Adequate hydration is required to minimize risk of nephrolithiasis (≥48 oz of fluid daily in adult patients).
  • Indinavir capsules are sensitive to moisture; store at room temperature (59–86ºF) in original container with desiccant.
Metabolism/Elimination
  • Cytochrome P450 3A4 (CYP3A4) inhibitor and substrate
Indinavir Dosing in Patients with Hepatic Impairment:
  • Dose should be decreased in patients with mild-to-moderate hepatic impairment (recommended dose for adults is 600 mg indinavir every 8 hours). No dosing information is available for children with any degree of hepatic impairment or for adults with severe hepatic impairment.

Drug Interactions (see also the Adult and Adolescent Guidelines and HIV Drug Interaction Checker)

  • Metabolism: Cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for metabolism. There is potential for multiple drug interactions with indinavir.
  • 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.

Major Toxicities

  • More common: Nephrolithiasis/urolithiasis with indinavir crystal deposit (higher in children [29%] than in adults [12.4%]).1 Interstitial nephritis and urothelial inflammation has been commonly reported in adults.2 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).

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval
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.3 Indinavir is not recommended by the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV for use in children and adolescents 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. In children, 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 that are slightly higher than those in adults, but trough concentrations are considerably lower. A significant proportion of children have trough indinavir concentrations less than the 0.1 mg/L value associated with virologic efficacy in adults.4-7 Studies that investigated a range of indinavir/ritonavir doses in small groups of children have shown that indinavir 500 mg/m2 body surface area plus ritonavir 100 mg/m2 body surface area twice daily is probably too high,8 that indinavir 234 to 250 mg/m2 body surface area plus low-dose ritonavir twice daily is too low,9,10 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 indinavir 800 mg plus ritonavir 100 mg twice daily in adults, albeit with considerable inter-individual variability and high rates of toxicity.10-12

References

  1. Indinavir [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020685s077lbl.pdf.
  2. Kopp JB, Falloon J, Filie A, et al. Indinavir-associated interstitial nephritis and urothelial inflammation: clinical and cytologic findings. Clin Infect Dis. 2002;34(8):1122-1128. Available at https://www.ncbi.nlm.nih.gov/pubmed/11915002.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.

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