Animal studies have failed to reveal evidence of teratogenicity at maternal doses producing systemic drug exposure levels 0.7 (rabbits) or 1.2 (rats) times those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). This drug has been evaluated in a limited number of women during pregnancy. Available data suggest risk of major birth defects overall (compared to background rate) is not increased by this drug.

Hyperbilirubinemia has been reported frequently during drug therapy and it is not known whether maternal use would lead to neonatal kernicterus. Symptomatic hyperlactatemia and lactic acidosis syndrome (some cases fatal) have been reported in pregnant women using this drug in combination with nucleoside analogs. Patients should be apprised of the potential risks of lactic acidosis and hyperbilirubinemia.

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 1800 exposures to atazanavir-containing regimens (over 1200 exposed in the first trimester; over 600 exposed in the second/third trimester) resulting in live births; there was no difference between this drug and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. 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 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 was 2.2% and 2.4%, respectively.

In 1 clinical study, atazanavir plus ritonavir was given with lamivudine and zidovudine to 41 HIV-infected pregnant women during the second or third trimester. Less than 50 copies/mL HIV RNA was achieved at time of delivery by 38 of the 39 patients completing the study. Hyperbilirubinemia (total bilirubin at least 2.6 times the upper limit of normal) was reported in 6 of 20 women on atazanavir 300 mg plus ritonavir 100 mg and 13 of 21 women on atazanavir 400 mg plus ritonavir 100 mg. Lactic acidosis was not reported during this study.

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

Drug levels in fetal umbilical cord blood were about 12% to 19% of maternal levels. All 40 infants (83% Black/African American) born to 40 HIV-infected pregnant women were negative for HIV-1 DNA at delivery and/or during the first 6 months postpartum. Antiretroviral prophylactic therapy containing zidovudine was administered to all 40 infants. During this study, the neonates did not develop severe hyperbilirubinemia (total bilirubin greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy. Bilirubin levels of at least 4 mg/dL were reported within the first day of life in 10 of 36 infants (6 were at least 38 weeks gestation and 4 were less than 38 weeks gestation). Of the 38 infants who had glucose samples collected the first day of life, 3 had values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.

All infants (including newborns exposed to this drug in utero) should be monitored for the development of severe hyperbilirubinemia during the first few days of life.

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.

This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk.

AU TGA pregnancy category: B2
US FDA pregnancy category: Not assigned.

Risk summary: Malformative risk with use of this drug in pregnant women is unlikely.

Comments:
-A pregnancy exposure registry is available.
-This drug must be administered with ritonavir during pregnancy.
-No dose adjustment required during pregnancy with 1 exception: therapy-experienced patients during the second/third trimester coadministered either an H2-receptor antagonist or tenofovir disoproxil fumarate should receive atazanavir 400 mg plus ritonavir 100 mg once a day.
-No dose adjustment required postpartum; should closely monitor for side effects as drug exposures may be higher during the first 2 months after delivery

See references

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, a different drug may be preferred.

Excreted into human milk: Yes

Comments:
-The effects in the nursing infant are unknown.
-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.

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 this drug (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 postdose. The breast milk to plasma ratio averaged 13% for this drug.

See references