Animal studies have failed to reveal evidence of teratogenicity, embryofetal toxicity, or an effect on reproductive function and fertility; no adverse developmental effects observed at cobicistat exposures 1.6-times (rats) and 3.8-times (rabbits), and at darunavir exposures lower than (mice and rabbits) and 3-times (rats) human exposures at the recommended daily dose of these components in this combination drug. There are no controlled data in human pregnancy; however, available data showed no difference in rate of overall birth defects for cobicistat and darunavir compared with the background rate in the US reference population.

Exposures of darunavir and cobicistat are considerably lower during the second and third trimesters of pregnancy compared to postpartum. Low darunavir exposure may be associated with increased risk of treatment failure and increased risk of HIV-1 transmission to the child. This drug should not be started in pregnant patients and patients who become pregnant during therapy with this drug should be switched to an alternative regimen. According to some authorities, darunavir plus ritonavir may be considered as an alternative.

In 1 study, 6 pregnant subjects were using this combination drug with a background regimen before enrollment; study period included the second and third trimesters, and through 12 weeks postpartum. Of the 6 subjects, 1 had virologic failure with HIV-1 RNA greater than 1000 copies/mL from the third trimester visit through the postpartum period; 5 subjects had sustained virologic response (HIV-1 RNA less than 50 copies/mL) throughout the study period. No clinical data available on the virologic response when this drug was started during pregnancy.

Placental transfer to the fetus has been reported as low (cord blood/maternal delivery plasma drug ratio less than 0.3) with cobicistat and darunavir.

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

The APR has received prospective reports of over 475 exposures to cobicistat-containing regimens (over 400 exposed in the first trimester; over 75 exposed in the second/third trimester) resulting in live births; there was no difference between cobicistat and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For cobicistat, 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 with first trimester and second/third trimester exposures to cobicistat was 3.9% and 1.2%, respectively.

The APR has received prospective reports of over 900 exposures to darunavir-containing regimens (over 600 exposed in the first trimester; over 300 exposed in the second/third trimester) resulting in live births; there was no difference between darunavir and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For darunavir, 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 with first trimester and second/third trimester exposures to darunavir was 3.6% and 2.6%, respectively.

AU TGA pregnancy category B2: 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 are inadequate or may be lacking, but available data show no 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.

Use is not recommended.

AU TGA pregnancy category: B2
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.

Comments:
-A pregnancy exposure registry is available.
-Additional or alternative (nonhormonal) contraceptive measures should be considered for patients of childbearing potential using estrogen-containing contraceptives with this drug; due to potential for hyperkalemia, clinical monitoring is recommended if coadministered with drospirenone; no data available to make recommendations on use with other hormonal contraceptives.

See references

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, alternative therapy is recommended.

Excreted into human milk: Unknown (cobicistat, darunavir)
Excreted into animal milk: Yes (cobicistat, darunavir)

Comments:
-The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects
-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