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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

Non-Nucleoside Reverse Transcriptase Inhibitors

Rilpivirine (Edurant, RPV)

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

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

Animal Studies

Carcinogenicity
Rilpivirine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Rilpivirine was not carcinogenic in rats when administered at doses 3 times higher than exposure in humans at the recommended dose of 25 mg once daily. Hepatocellular neoplasms were observed in both male and female mice at doses 21 times that of human therapeutic exposure; the observed hepatocellular findings in mice may be rodent-specific.1

Reproduction/Fertility
No effect on fertility was observed when rilpivirine was tested in rats at maternal doses up to 400 mg/kg/day, resulting in systemic drug exposure equivalent to 40 times the recommended human dose.1

Teratogenicity/Developmental Toxicity
No evidence of embryonic or fetal toxicity or an effect on reproductive function was observed in rat and rabbit dams treated with rilpivirine during pregnancy and lactation at doses 15 and 70 times higher, respectively, than exposure in humans at the recommended dose of 25 mg once daily.1

Placental and Breast Milk Passage
Studies in lactating rats and their offspring indicate that rilpivirine is present in rat milk.1

Human Studies in Pregnancy

Pharmacokinetics
A case report describing rilpivirine pharmacokinetic (PK) evaluations at 32 weeks’ gestation and again postpartum in 2 HIV-infected pregnant women showed that rilpivirine area under the curve [AUC] was decreased by 30% to 43% during pregnancy, while postpartum AUC was similar to that seen in non-pregnant adults.2 A similar finding was reported in a study presenting PK and safety data from 32 HIV-infected pregnant women receiving rilpivirine. Median rilpivirine AUC and trough concentrations were reduced by about 20% to 30% in the second and third trimesters, compared with postpartum. Median trough rilpivirine concentrations were significantly lower at 14 visits where the women had detectable HIV-1 RNA (30 ng/mL) compared to 62 visits with undetectable HIV-1 RNA (63 ng/mL). Ninety percent of women had trough concentrations above the protein-adjusted EC90 for rilpivirine. PK exposure was highly variable in this study.3

Placental and Breast Milk Passage
In the case report described above, cord blood and maternal plasma rilpivirine concentrations obtained from one mother-infant pair were 0.016 and 0.021 mg/L, for a cord blood/maternal concentration ratio of 0.74.2 The PK and safety study described above included rilpivirine delivery concentration data from 9 mother-infant pairs, with median (range) cord blood rilpivirine plasma concentration of 53.8 ng/mL (<10.0 to 219.7 ng/mL), maternal delivery plasma rilpivirine concentration of 103.3 ng/mL (<10.0 to 273.4 ng/mL) and cord blood/maternal plasma ratio of 0.55 (0.38 to 0.83).4 An ex vivo human cotyledon perfusion model also showed that rilpivirine crosses the placenta with fetal transfer rates ranging from 17% to 37%.5,6 No data exist on whether rilpivirine is excreted in breast milk in humans.

Teratogenicity/Developmental Toxicity
The number of first-trimester exposures to rilpivirine that have been monitored to date in the Antiretroviral Pregnancy Registry is insufficient to allow conclusions to be drawn regarding risk of birth defects.7

Excerpt from Table 8a
Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy
Rilpivirine
(RPV)
Edurant

(RPV/TDF/FTC)
Complera
RPV (Edurant)
Tablets: 
  • 25 mg
Complera:
  • RPV 25 mg plus TDF 300 mg plus FTC 200 mg tablet
Standard Adult Dose
RPV (Edurant):
  • 25 mg once daily with food
Complera:
  • 1 tablet once daily with food
PK in Pregnancy
  • RPV PK highly variable during pregnancy. RPV AUC and trough concentration reduced 20% to 30% in pregnancy compared with postpartum, but most pregnant women exceeded target exposure.
Dosing in Pregnancy:
  • Routine dosing adjustment in all women is not recommended for RPV during pregnancy. Individual patients should be closely monitored.
Moderate to high placental transfer to fetus.b

No evidence of teratogenicity in rats or rabbits. Insufficient data to assess for teratogenicity in humans.
a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see Adult Guidelines, 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: AUC = area under the curve; FTC = emtricitabine; PK = pharmacokinetic; RPV = rilpivirine; TDF = tenofovir disoproxil fumarate

References

  1. Rilpivirine (Edurant) [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf. Accessed April 15, 2016.
  2. Colbers A, Gingelmaier A, van der Ende M, Rijnders B, Burger D. Pharmacokinetics, safety and transplacental passage of rilpivirine in pregnancy: two cases. AIDS. 2014;28(2):288-290. Available at http://www.ncbi.nlm.nih.gov/pubmed/24413315.
  3. Tran AH, Best BM, Stek A, et al. Pharmacokinetics of rilpivirine in HIV-infected pregnant women. J Acquir Immune Defic Syndr. 2016. Available at http://www.ncbi.nlm.nih.gov/pubmed/26918544.
  4. Mirochnick M, Stek A, Kreitchman R, et al. Pharmacokinetics of Rilpivirine in HIV-Infected Women during Pregnancy and Postpartum. 22nd Conference on Retroviruses and Opportunistic Infections; 2015; Seattle, WA.
  5. Mandelbrot L, Duro D, Belissa E, Peytavin G. Erratum for Mandelbrot et al., placental transfer of rilpivirine in an ex vivo human cotyledon perfusion model. Antimicrob Agents Chemother. 2015;59(9):5869. Available at http://www.ncbi.nlm.nih.gov/pubmed/26276897.
  6. Mandelbrot L, Duro D, Belissa E, Peytavin G. Placental transfer of rilpivirine in an ex vivo human cotyledon perfusion model. Antimicrob Agents Chemother. 2015;59(5):2901-2903. Available at http://www.ncbi.nlm.nih.gov/pubmed/25691637.
  7. 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 http://www.apregistry.com/.

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