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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Protease Inhibitors

Indinavir (Crixivan, IDV)

(Last updated: June 7, 2016; last reviewed: June 7, 2016)

Indinavir is classified as Food and Drug Administration Pregnancy Category C.

Animal Studies

Indinavir is neither mutagenic nor clastogenic in both in vitro and in vivo assays. No increased incidence of any tumor types occurred in long-term studies in mice. At the highest dose studied in rats (640 mg/kg/day or 1.3-fold higher than systemic exposure at human therapeutic doses), thyroid adenomas were seen in male rats.1

No effect of indinavir has been seen on reproductive performance, fertility, or embryo survival in rats.1

Teratogenicity/Developmental Toxicity
There has been no evidence of teratogenicity or treatment-related effects on embryonic/fetal survival or fetal weights of indinavir in rats, rabbits, or dogs at exposures comparable to, or slightly greater than, therapeutic human exposure. In rats, developmental toxicity manifested by an increase in supernumerary and cervical ribs was observed at doses comparable to those administered to humans. No treatment-related external or visceral changes were observed in rats. No treatment-related external, visceral, or skeletal changes were seen in rabbits (fetal exposure limited, approximately 3% of maternal levels) or dogs (fetal exposure approximately 50% of maternal levels). Indinavir was administered to Rhesus monkeys during the third trimester (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 4-fold greater than controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester. 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.1

Placental and Breast Milk Passage
Significant placental passage of indinavir occurs in rats and dogs, but only limited placental transfer occurs in rabbits. Indinavir is excreted in the milk of lactating rats at concentrations slightly greater than maternal levels.1

Human Studies in Pregnancy

The optimal dosing regimen for use of indinavir in pregnant patients has not been established. Two studies of the pharmacokinetics (PKs) of unboosted indinavir (800 mg 3 times/day) during pregnancy demonstrated significantly lower indinavir plasma concentrations during pregnancy than postpartum.2,3 Use of unboosted indinavir is not recommended in HIV-infected pregnant patients because of the substantially lower antepartum exposures observed in these studies and the limited experience in this patient population.

Several reports have investigated use of indinavir/ritonavir during pregnancy. In an intensive PK study of 26 Thai pregnant women receiving 400 mg indinavir/100 mg ritonavir twice a day, indinavir plasma concentrations were significantly lower during pregnancy than postpartum. The median trough indinavir concentration was 0.13 µg/mL; 24% of subjects had trough concentrations below 0.10 µg/mL, the target trough concentration used in therapeutic drug monitoring programs; and 81% had RNA viral loads <50 copies/mL at delivery.4 In a study of pregnant French women receiving 400 mg indinavir/100 mg ritonavir twice a day, the median indinavir trough concentration was 0.16 µg/mL, 18% of subjects had trough concentrations below 0.12 µg/mL, and 93% had HIV RNA level <200 copies/mL at delivery.5 In a small study of two patients who received indinavir 800 mg and ritonavir 200 mg twice daily, third-trimester indinavir area under the curve exceeded that for historical non-pregnant controls.6 The available data are insufficient to allow for definitive dosing recommendations for use of indinavir/ritonavir during pregnancy.

Placental and Breast Milk Passage
In studies of pregnant women receiving unboosted indinavir and their infants, transplacental passage of indinavir was minimal.2,7 In a study of Thai pregnant women receiving indinavir/ritonavir, median cord blood indinavir concentration was 0.12 µg/mL, median maternal plasma delivery concentration was 0.96 µg/mL, and the median ratio between indinavir concentrations in cord blood and maternal plasma at delivery was 0.12.4 In 1 woman taking indinavir 600 mg and ritonavir 200 mg twice daily, indinavir concentrations in breast milk were 90% to 540% of plasma concentrations over the first 5 days after delivery.8

Teratogenicity/Developmental Toxicity
Although the French Perinatal Cohort reported an association of head and neck birth defects with first trimester exposure to indinavir (3 defects in 350 first-trimester exposures, 0.9%), the Antiretroviral Pregnancy Registry (APR) has not observed an increase in birth defects with indinavir.9,10 Among cases of first-trimester indinavir exposure reported to the APR, defects have been seen in 2.4% (7/289; 95% CI, 1.0% to 4.9%) compared to total prevalence of birth defects in the U.S. population based on Centers for Disease Control and Prevention surveillance of 2.7%.10

Excerpt from Table 8a
Generic Name
Trade Name
Formulation  Dosing Recommendations Use in Pregnancy

Note: Must be combined with low-dose RTV boosting in pregnancy
  • 200 mg
  • 400 mg
Standard Adult Dose
Without RTV Boosting:
  • IDV 800 mg every 8 hours, taken 1 hour before or 2 hours after meals; may take with skim milk or low-fat meal.
With RTV Boosting:
  • IDV 800 mg plus RTV 100 mg twice daily without regard to meals
PK in Pregnancy:
  • IDV exposure markedly reduced when administered without RTV boosting during pregnancy. IDV exposure low with IDV 400 mg/RTV 100 mg dosing during pregnancy; no PK data available on alternative boosted dosing regimens in pregnancy.
Dosing in Pregnancy:
  • Use of unboosted IDV is not recommended during pregnancy.
Minimal placental transfer to fetus.b

No evidence of human teratogenicity in cases reported to the APR (can rule out 2-fold increase in overall birth defects).

Must be given as low-dose, RTV-boosted regimen in pregnancy.

Theoretical concern regarding increased indirect bilirubin levels, which may exacerbate physiologic hyperbilirubinemia in neonates. Minimal placental passage mitigates this concern.

a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, Appendix B, Table 7).
b Placental transfer categories—Mean or median cord blood/maternal delivery plasma drug ratio:
   High: >0.6
   Moderate: 0.3–0.6
   Low: <0.3

Key to Abbreviations: IDV = indinavir; PK = pharmacokinetic; RTV = ritonavir


  1. Indinavir sulfate (Crixivan) [package insert]. Food and Drug Administration. 2015. Available at Accessed April 15, 2016.
  2. Unadkat JD, Wara DW, Hughes MD, et al. Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother. 2007;51(2):783-786. Available at
  3. Hayashi S, Beckerman K, Homma M, Kosel BW, Aweeka FT. Pharmacokinetics of indinavir in HIV-positive pregnant women. AIDS. 2000;14(8):1061-1062. Available at
  4. Cressey TR, Best BM, Achalapong J, et al. Reduced indinavir exposure during pregnancy. Br J Clin Pharmacol. 2013;76(3):475-483. Available at
  5. Ghosn J, De Montgolfier I, Cornelie C, et al. Antiretroviral therapy with a twice-daily regimen containing 400 milligrams of indinavir and 100 milligrams of ritonavir in human immunodeficiency virus type 1-infected women during pregnancy. Antimicrob Agents Chemother. 2008;52(4):1542-1544. Available at
  6. Kosel BW, Beckerman KP, Hayashi S, Homma M, Aweeka FT. Pharmacokinetics of nelfinavir and indinavir in HIV-1-infected pregnant women. AIDS. 2003;17(8):1195-1199. Available at
  7. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in utero exposure. Pediatr Infect Dis J. 2002;21(9):835-838. Available at
  8. Colebunders R, Hodossy B, Burger D, et al. The effect of highly active antiretroviral treatment on viral load and antiretroviral drug levels in breast milk. AIDS. 2005;19(16):1912-1915. Available at
  9. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at
  10. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 July 2015. Wilmington, NC: Registry Coordinating Center. 2015. Available at

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