FDA approved revisions to the ODEFSEY (emtricitabine, rilpivirine, and tenofovir alafenamide) and COMPLERA (emtricitabine, rilpivirine, and tenofovir disoproxil fumarate) labels to add safety and pharmacokinetic data in HIV-1 infected pregnant women, to align with the recently approved
EDURANT (rilpivirine) USPI. Listed below are the specific changes to the labels.
Section 2: DOSING AND ADMINISTRATION
2.3 Recommended Dosage During Pregnancy
For pregnant patients who are already on ODEFSEY prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of ODEFSEY taken once daily may be continued. Lower exposures of rilpivirine, a component of ODEFSEY, were observed during pregnancy, therefore viral load should be monitored closely.
The same recommendations were added to the COMPLERA label.
Section 8: USE IN SPECIFIC POPULATIONS
Updates were made with respect to APR data. In general, available data from the APR show no increase in the risk of overall major birth defects with first trimester exposure for rilpivirine (RPV). In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period.
8.1 Pregnancy
Data
Human Data
Rilpivirine: RPV in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant subjects during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6-12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C0h and AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period. One subject discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant subjects, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in HIV–1-infected adults.
Section 12: Clinical Pharmacology
12.3 Pharmacokinetics
Pregnancy and Postpartum was updated to provide the pharmacokinetic results of total rilpivirine exposures during the second and third trimester of pregnancy and postpartum.
In summary, the exposure (C0h and AUC24h) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum. However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum.
EDURANT (rilpivirine) USPI. Listed below are the specific changes to the labels.
Section 2: DOSING AND ADMINISTRATION
2.3 Recommended Dosage During Pregnancy
For pregnant patients who are already on ODEFSEY prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of ODEFSEY taken once daily may be continued. Lower exposures of rilpivirine, a component of ODEFSEY, were observed during pregnancy, therefore viral load should be monitored closely.
The same recommendations were added to the COMPLERA label.
Section 8: USE IN SPECIFIC POPULATIONS
Updates were made with respect to APR data. In general, available data from the APR show no increase in the risk of overall major birth defects with first trimester exposure for rilpivirine (RPV). In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period.
8.1 Pregnancy
Data
Human Data
Rilpivirine: RPV in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant subjects during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6-12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C0h and AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period. One subject discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant subjects, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in HIV–1-infected adults.
Section 12: Clinical Pharmacology
12.3 Pharmacokinetics
Pregnancy and Postpartum was updated to provide the pharmacokinetic results of total rilpivirine exposures during the second and third trimester of pregnancy and postpartum.
In summary, the exposure (C0h and AUC24h) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum. However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum.
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Elizabeth Thompson
Division of Antiviral Products
Food and Drug Administration
Michael Stanfield Jr.
Division of Antiviral Products
Food and Drug Administration
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