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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

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

Emtricitabine (Emtriva, FTC)

(Last updated: August 6, 2015; last reviewed: August 6, 2015)

Emtricitabine is classified as Food and Drug Administration Pregnancy Category B.

Animal Studies

Carcinogenicity
Emtricitabine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. In long-term carcinogenicity studies of oral emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 26 times the human systemic exposure or in rats at doses up to 31 times the human systemic exposure at the therapeutic dose.1

Reproduction/Fertility
No effect of emtricitabine on reproduction or fertility was observed with doses that produced systemic drug exposures (as measured by area under the curve [AUC]) approximately 60-fold higher in female and male mice and 140-fold higher in male rats than human exposure at the recommended therapeutic dose.1

Teratogenicity/Developmental Toxicity
Incidence of fetal variations and malformations was not increased with emtricitabine dosing in mice that resulted in systemic drug exposure 60-fold higher than observed with human exposure at recommended doses or in rabbits with dosing resulting in drug exposure 120-fold higher than human exposure.1

Placental and Breast Milk Passage 
Emtricitabine has been shown to cross the placenta in mice and rabbits; the average fetal/maternal drug concentration was 0.4 in mice and 0.5 in rabbits.2

Human Studies in Pregnancy

Pharmacokinetics
Emtricitabine pharmacokinetic (PK) parameters have been evaluated in 18 HIV-infected pregnant women receiving antiretroviral therapy including emtricitabine (200 mg once daily) at 30 to 36 weeks’ gestation and 6 to 12 weeks postpartum.3 Emtricitabine exposure was modestly lower during the third trimester (8.6 mcg*h/mL [5.2–15.9]) compared with the postpartum period (9.8 mcg*h/mL [7.4–30.3]). Two-thirds (12 of 18) of pregnant women versus 100% (14 of 14) of postpartum women met the AUC target (10th percentile in non-pregnant adults). Trough emtricitabine levels were also lower during pregnancy (minimum plasma concentration 52 ng/mL [14–180]) compared with the postpartum period (86 ng/mL [<10 to 306]). In the IMPAACT P1026s study, 26 women had emtricitabine PKs assessed during the third trimester (median 35 weeks) and 22 postpartum (mean 8 weeks postpartum).4 The PK parameters during pregnancy were slightly altered in comparison to PK parameters during the postpartum period, with higher emtricitabine clearance (25.0 vs. 20.6 L/hour during pregnancy vs. postpartum, respectively) and lower 24-hour post-dose levels (0.058 vs. 0.085 mg/L), but the 24-hour, post-dose levels were well above the inhibitory concentration 50% (IC50) in all patients. Similar differences in PK parameters of emtricitabine among women during pregnancy or after delivery were found in the PACTG 394 study5 and in a European study.6 A population PK study of 83 pregnant women and 103 non-pregnant control women demonstrated that the 18% increase in emtricitabine clearance in pregnancy correlated with the normal pregnancy-related increase in glomerular filtration rate.7 Thus, these changes are not believed to be large enough to warrant dosage adjustment during pregnancy.

Placental and Breast Milk Passage 
Emtricitabine has been shown to have excellent placental transfer in pregnant women. In 18 women who received 200 mg emtricitabine once daily during pregnancy, mean cord blood concentration was 300 ± 268 ng/mL and the mean ratio of cord blood/maternal emtricitabine concentrations was 1.17 ± 0.6 (n = 9).3 In a study of 15 women enrolled in IMPAACT P1026s who received emtricitabine during pregnancy, the mean cord-to-maternal-blood ratio was 1.2 (90% confidence interval [CI], 1.0–1.5).4 In 8 women enrolled in PACTG 394 who were given a single dose of 600 mg emtricitabine with 900 mg tenofovir disoproxil fumarate, the median cord blood emtricitabine concentration was 717 ng/mL (range 21–1,072), and the median cord blood/maternal ratio was 0.85 (range 0.46–1.07).5 

Emtricitabine is excreted into human milk. In a study in the Ivory Coast, 5 HIV-infected women who chose to exclusively breastfeed their newborn infants were given 400 mg emtricitabine, 600 mg tenofovir, and 200 mg nevirapine at onset of labor, followed by 200 mg emtricitabine and 300 mg tenofovir once daily for 7 days postpartum. The median minimal and maximal concentrations of emtricitabine in breast milk were 177 and 679 ng/mL, respectively (interquartile ranges 105–254 and 658–743 ng/mL, respectively), well above the estimated emtricitabine IC50 for HIV-1.8
 
Teratogenicity/Developmental Toxicity
In a study of pregnancies occurring during an HIV pre-exposure prophylaxis (PrEP) trial in which HIV-uninfected participants were randomized to placebo, tenofovir, or tenofovir plus emtricitabine, there was no increase in congenital anomalies in the tenofovir-plus-emtricitabine arm.9 There was no overall difference in the rate of pregnancy loss in the tenofovir-plus-emtricitabine or tenofovir-alone arms of this PrEP study. In a large French cohort, emtricitabine exposure in the first trimester was associated with lower risk of birth defects.10 In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to emtricitabine in humans have been monitored to be able to detect at least a 1.5-fold increased risk of overall birth defects. No such increase in birth defects has been observed with emtricitabine. Among cases of first-trimester emtricitabine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.3% (35 of 1,543 births; 95% CI, 1.6% to 3.1%), compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.11

References

  1. Emtriva [package insert]. Gilead Sciences. 2012. Available at http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/emtriva/emtriva_pi.pdf. Accessed August 8, 2014.
  2. Szczech GM, Wang LH, Walsh JP, Rousseau FS. Reproductive toxicology profile of emtricitabine in mice and rabbits. Reprod Toxicol. 2003;17(1):95-108. Available at http://www.ncbi.nlm.nih.gov/pubmed/12507664.
  3. Hirt D, Urien S, Rey E, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother. 2009;53(3):1067-1073. Available at http://www.ncbi.nlm.nih.gov/pubmed/19104016.
  4. Stek AM, Best BM, Luo W, et al. Effect of pregnancy on emtricitabine pharmacokinetics. HIV Med. 2012;13(4):226-235. Available at http://www.ncbi.nlm.nih.gov/pubmed/22129166.
  5. Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants. Antimicrob Agents Chemother. 2011;55(12):5914-5922. Available at http://www.ncbi.nlm.nih.gov/pubmed/21896911.
  6. Colbers AP, Hawkins DA, Gingelmaier A, et al. The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnant women. AIDS. 2013;27(5):739-748. Available at http://www.ncbi.nlm.nih.gov/pubmed/23169329.
  7. Valade E, Treluyer JM, Dabis F, et al. Modified renal function in pregnancy: impact on emtricitabine pharmacokinetics. Br J Clin Pharmacol. 2014;78(6):1378-1386. Available at http://www.ncbi.nlm.nih.gov/pubmed/24995851.
  8. Benaboud S, Pruvost A, Coffie PA, et al. Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d'Ivoire, in the ANRS 12109 TEmAA Study, Step 2. Antimicrob Agents Chemother. 2011;55(3):1315-1317. Available at http://www.ncbi.nlm.nih.gov/pubmed/21173182.
  9. Mugo NR, Hong T, Celum C, et al. Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial. JAMA. 2014;312(4):362-371. Available at http://www.ncbi.nlm.nih.gov/pubmed/25038355.
  10. 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 http://www.ncbi.nlm.nih.gov/pubmed/24781315.
  11. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989 - 31 July 2014. Wilmington, NC: Registry Coordinating Center. 2014. Available at http://www.APRegistry.com.

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