Animal studies of the components of this drug have failed to reveal evidence of embryofetal toxicity or teratogenicity; no adverse developmental effects observed at cobicistat exposures 1.7-times (rats) and 4.1-times (rabbits) higher than, at darunavir exposures lower than (mice and rabbits) and 2.6-times (rats) higher than, at emtricitabine exposures 88-times (mice) and 7.3-times (rabbits) higher than, and tenofovir alafenamide exposures equal to (rats) and 85-times (rabbits) higher than 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, darunavir, and emtricitabine 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 women and patients who become pregnant during therapy with this drug should be switched to an alternative regimen. According to some authorities, darunavir/ritonavir plus emtricitabine-tenofovir alafenamide may be considered as an alternative.

Placental transfer to the fetus has been reported as low (cord blood/maternal delivery plasma drug ratio less than 0.3) with cobicistat, darunavir, and tenofovir alafenamide and as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with emtricitabine.

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 over 400 exposures to cobicistat-containing regimens (over 325 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 increase in 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 3.7% and 1.3%, respectively.

The APR has received prospective reports of over 850 exposures to darunavir-containing regimens (over 550 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 increase in 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 3.4% and 2.6%, respectively.

The APR has received prospective reports of over 4700 exposures to emtricitabine-containing regimens (over 3325 exposed in the first trimester; over 1375 exposed in the second/third trimester) resulting in live births; there was no difference between emtricitabine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For emtricitabine, enough first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of cardiovascular and genitourinary defects (the more common classes); no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to emtricitabine was 2.6% and 2.3%, respectively.

The APR has received prospective reports of over 300 exposures to tenofovir alafenamide-containing regimens (over 225 exposed in the first trimester; over 75 exposed in the second/third trimester) resulting in live births; available data showed 12 birth defects in the first trimester compared with 1 birth defect in the second/third trimester. For tenofovir alafenamide, enough first-trimester exposures have been monitored to detect at least a 2-fold increase in risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to tenofovir alafenamide was 5.2% and 1.2%, 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.

See references

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, a different drug may be preferred.
-According to some authorities: Use is not recommended.

Excreted into human milk: Yes (emtricitabine); Unknown (cobicistat, darunavir, tenofovir alafenamide)
Excreted into animal milk: Yes (cobicistat, darunavir, tenofovir)

Comments:
-Tenofovir is present in human breast milk after administration of tenofovir disoproxil fumarate.
-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.

EMTRICITABINE:
Samples of breast milk obtained from 5 HIV-1-infected women show that emtricitabine is secreted in human milk. Average peak and trough drug levels in breast milk were 679 and 177 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 2% of the proposed emtricitabine dose for infants and achieve serum levels that may lead to emergence of viral resistance to emtricitabine. Breastfeeding infants whose mothers are treated with emtricitabine may be at risk for developing viral resistance to emtricitabine; other emtricitabine-related risks in such infants are unknown.

Preexposure prophylaxis, using emtricitabine (200 mg/day) and tenofovir disoproxil fumarate, was administered by directly observed therapy for 10 days to 50 women without HIV infection who were breastfeeding their infants. On days 7 and 10 of therapy, peak and trough milk samples were collected 1 to 2 hours after dosing and 23 to 24 hours after the previous dose, respectively; a single infant blood sample was collected after the mother's 7th dose. Median peak and trough milk emtricitabine levels were 212.5 and 183 mcg/L, respectively; these levels correspond to a daily dose of 27.5 to 31.5 mcg/kg (estimated), which is about 0.5% of the proposed therapeutic dose for infants. Of 49 infant blood samples collected, 47 had detectable emtricitabine levels (median plasma level: 13.2 mcg/L); plasma levels were 16.6 mcg/L in infants younger than 13 weeks and 10.5 mcg/L in infants at least 13 weeks of age. Diarrhea lasting 2 to 3 days was reported in 2 of the 50 breastfed infants; no other side effects were reported.

During ongoing therapy, emtricitabine was measured after a 300-mg dose to 6 nursing mothers with HIV infection. Peak breast milk level was 872 mcg/L (range: 696 to 1063 mcg/L) at about 3 hours; 1 breastfed infant had detectable emtricitabine serum level of 17.5 mcg/L.

Emtricitabine (200 mg once a day) was part of a combination regimen for HIV in 16 Nigerian women exclusively breastfeeding their infants (on demand). Expressed milk samples were collected before dosing and at 0.5, 1, 2, 4, 8, and 12 hours after dosing; peak breast milk level from dried breast milk spots was 843 mcg/L (interquartile range [IQR]: 702 to 1132 mcg/L) at 4 hours (IQR: 2 to 8 hours) after dosing. Infant blood samples were collected at 2 and 8 hours after maternal dosing; analysis of the dried blood spots showed only 3 samples with quantifiable (greater than 16.6 mcg/L) emtricitabine blood levels of 17.5, 18.8, and 19.4 mcg/L.

See references