Animal studies have failed to reveal evidence of teratogenicity with atazanavir at maternal doses producing systemic drug exposure levels 0.7 (rabbits) or 1.2 (rats) times those at the human clinical dose (atazanavir 300 mg/day boosted with ritonavir 100 mg/day); at an exposure level causing maternal toxicity, body weight loss or weight gain suppression was observed in rat offspring. Animal studies have failed to reveal evidence of teratogenicity, embryofetal toxicity, or an effect on reproductive function with cobicistat. There are no controlled data in human pregnancy with this combination drug.

Exposures of cobicistat were considerably lower during the second and third trimesters, compared to postpartum, and thus exposures were also lower for the coadministered antiretroviral agent, including atazanavir; ; pharmacokinetic data from evaluation of atazanavir and cobicistat in a limited number of pregnant patients showed a similar trend in lower exposures of atazanavir. This drug is not recommended for use during pregnancy and should not be started in pregnant patients; an alternative regimen is recommended for patients who become pregnant during therapy with this drug.

Placental transfer to the fetus has been reported as low (cord blood/maternal delivery plasma drug ratio less than 0.3) with atazanavir and cobicistat. In studies of patients using atazanavir plus ritonavir during therapy, cord blood atazanavir level averaged 13% to 21% of maternal serum levels at delivery.

Lactic acidosis syndrome (sometimes fatal) and symptomatic hyperlactatemia have been reported in pregnant patients using atazanavir in combination with nucleoside analogs, which are associated with greater risk of lactic acidosis syndrome. Hyperbilirubinemia has been reported frequently in patients using atazanavir, including pregnant patients; the manufacturer product information for atazanavir should be consulted regarding its use in pregnancy. Infants exposed to atazanavir in utero may develop severe hyperbilirubinemia during the first few days of life.

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 2150 exposures to atazanavir-containing regimens (over 1400 exposed in the first trimester; over 750 exposed in the second/third trimester) resulting in live births; there was no difference between atazanavir and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For atazanavir, enough first trimester exposures have been monitored to detect at least a 1.5-fold increased 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 atazanavir was 2.2% and 2.3%, respectively.

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.

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: No data available on use of this drug in pregnant women to inform a drug-related risk.

Comments:
-A pregnancy exposure registry is available.
-Both components of this drug interact with certain oral contraceptives; nonhormonal contraceptive measures should be considered for patients of childbearing potential.

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: Yes (atazanavir); Unknown (cobicistat)
Excreted into animal milk: Yes (cobicistat)

Comments:
-This drug has not been studied during breastfeeding.
-The effects in the nursing infant are unknown; potential for HIV-1-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.

Although this drug has not been studied during breastfeeding, similar or greater levels of atazanavir in milk would be expected.

On postpartum days 5 and 14, samples of breast milk and plasma were obtained at 0, 2, 5, 8, and 24 hours postdose from 3 women taking atazanavir (dose not stated; 300 mg/day likely) as part of highly active antiretroviral therapy. Breast milk levels over 24 hours averaged 212 mcg/L on day 5 and 265 mcg/L on day 14. Peak breast milk levels averaged 419 mcg/L at 5 hours after dosing.

See references