This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: B1
US FDA pregnancy category: Not assigned

Risk summary: Insufficient data available on use of this drug in pregnant women to inform a drug-related risk of birth defects and miscarriage.

Comments:
-A pregnancy exposure registry is available.
-Cabotegravir has not been studied in pregnant patients.
-While insufficient human data are available to assess the risk of neural tube defects with exposure to this drug during pregnancy, neural tube defects were reported with dolutegravir (another integrase inhibitor).
-The benefit-risk of using this drug should be discussed with patients of childbearing potential or during pregnancy.
-Lower exposures with oral rilpivirine were observed during pregnancy; viral load should be monitored closely if the patient continues this drug during pregnancy.
-Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after administration of the last injections; the potential for fetal exposure during pregnancy should be considered.

Animal studies with cabotegravir have failed to reveal evidence of teratogenicity, but have revealed evidence of fetal harm at exposures higher than for therapeutic doses. After oral dosing to pregnant rabbits, at doses with exposures up to 0.66 times the exposure at the maximum recommended human dose (MRHD) of 30 mg (about 0.7 times the exposure in humans at the recommended human dose [RHD]), no adverse developmental outcomes or drug-related fetal toxicities were observed. In rats, at exposures 28 times the exposures at the MRHD of 30 mg oral or 400 mg IM (greater than 28 times the exposure in humans at the RHD), cabotegravir was associated with decreased fetal weight, delayed onset of parturition, and increased number of stillbirths and neonatal mortalities immediately after birth, but there were no effects on fetal viability when fetuses were delivered by caesarean; a lower dose of cabotegravir, at exposures greater than 10 times the exposure at the MRHD of 30 mg oral or 400 mg IM (13 times the exposure at the RHD), was not associated with delayed parturition or neonatal mortality in rats. In rats, cabotegravir crossed the placental barrier and was detected in fetal tissue. Animal studies with rilpivirine have failed to reveal evidence of adverse developmental outcomes; no evidence of significant embryofetal toxicity was observed at exposures at least 12 (rats) and at least 57 (rabbits) times the exposure at the MRHD of 25 mg orally once daily or 600 mg IM monthly in HIV-1-infected patients; after oral administration, no evidence of significant embryofetal toxicity was observed at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD. There are no controlled data in human pregnancy.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Health care providers are encouraged to prospectively register patients. For additional information: apregistry.com

The APR has received prospective reports of over 800 exposures to rilpivirine-containing regimens (over 600 exposed in the first trimester; over 200 exposed in the second/third trimester) resulting in live births; there was no significant difference in the overall risk of birth defects for rilpivirine compared with the background birth defect rate of 2.7% in the US reference population. For rilpivirine, enough first-trimester exposures have been monitored to detect at least a 2-fold increased risk of overall birth defects; no such increases detected. The prevalence of birth defects/live births with first trimester and second/third trimester exposures to rilpivirine was 1.6% and 1.4%, respectively.

Data from a birth outcome surveillance study in Botswana showed that dolutegravir (another integrase inhibitor) was associated with increased risk of neural tube defects when administered at time of conception and in early pregnancy. Data from clinical trials are insufficient to address this risk with cabotegravir.

In a clinical trial, rilpivirine (in combination with background regimen) was evaluated in 19 HIV-1-infected pregnant patients (who were using a rilpivirine-based regimen at time of enrollment) during the second and third trimesters and postpartum; 12 patients completed the trial through postpartum period (6 to 12 weeks after delivery) and 6 pregnancy outcomes were missing. Total rilpivirine exposure was about 30% to 40% lower during pregnancy compared with postpartum (6 to 12 weeks); protein binding was similar (greater than 99%) during the second and third trimester and postpartum. One patient discontinued the trial after spontaneous termination of pregnancy at 25 weeks gestation due to suspected premature rupture of membranes. Of the 12 patients who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was sustained in 10 patients (83.3%) through the third trimester visit and in 9 patients (75%) through the 6- to 12-week postpartum visit; virologic outcomes during the third trimester visit were missing for 2 patients who were withdrawn (1 was nonadherent to study drug; 1 withdrew consent). Of the 10 infants with HIV test results available (born to 10 HIV-1-infected pregnant patients), all had negative HIV-1 test results at time of delivery and up to 16 weeks postpartum; all 10 infants received antiretroviral prophylaxis with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum (no new safety findings compared with its known safety profile in HIV-1-infected adults).

AU TGA pregnancy category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

See references

Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Unknown
Excreted into animal milk: Yes

Comments:
-No published data available regarding use of cabotegravir or rilpivirine during breastfeeding; an alternate agent may be preferred.
-If cabotegravir and/or rilpivirine are present in human milk, residual exposures may remain for up to 12 months or longer after administration of the last injection.
-The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects similar to those in adults
-The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.
-Local guidelines should be consulted if replacement feeding is not an option.

See references