This drug should be used during pregnancy only if the benefit outweighs the risk.
-According to some authorities: Use is not recommended unless clearly needed.

AU TGA pregnancy category: B3
US FDA pregnancy category: C

Comments:
-A pregnancy exposure registry is available.
-WHO has recommended a maximum dose of 30 mg twice a day, regardless of weight.
-According to some experts, this drug is not recommended for use during pregnancy due to its toxicity; current guidelines should be consulted for additional information.

Animal studies have failed to reveal evidence of teratogenicity using drug exposures of 183 and 399 times the normal human exposure in rabbits and rats, respectively; the fetal incidence of a common skeletal variation, unossified or incomplete ossification of sternebra, and early neonatal mortality were increased in rats using drug exposure of 399 times the normal human exposure. This drug crosses the human placenta, resulting in cord/maternal blood level of 1 to 1.3 (considered high placental transfer [cord blood/maternal delivery plasma drug ratio over 0.6]). There are no controlled data in human pregnancy; although clinical experience in pregnant women is limited, congenital anomalies and abortions have been reported.

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

In the APR, enough first trimester exposures have been monitored to detect at least a 2-fold increased risk of overall birth defects; no such increase detected. The prevalence of birth defects with first trimester and second/third trimester exposures was 2.6% and 3.1%, respectively, compared with the background rate of 2.7% in the reference population.

Fatal lactic acidosis has been reported in pregnant women who received this drug plus didanosine with other antiretroviral agents; coadministration of this drug with didanosine is contraindicated. According to some authorities, this drug in combination with didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome in HIV-infected pregnant women using this drug.

AU TGA pregnancy category B3: 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 shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

See references

This drug crosses into human breast milk, resulting in breast milk/maternal plasma levels of 1 to 1.76; levels in nursing infants were negligible.

In 1 study, breast milk samples were collected from nursing mothers using this drug as part of a clinical trial to evaluate maternal-to-child transmission of HIV infection. Doses, dose regimens, and breast milk collection times were not provided. The milk to plasma ratio of this drug was 1.73 in 2 patients.

Milk and blood samples from 52 mothers using this drug (30 or 40 mg twice a day, depending on weight) and their 52 infants, respectively, were analyzed for this drug; precise timing of the previous maternal dose was not reported. This drug was detectable in 44 samples of whole milk and 45 samples of skim milk with median drug levels of 151 and 190 mcg/L, respectively. Estimated infant intake of this drug via breast milk averaged 22.7 mcg/kg/day. With this estimated intake from milk, drug was undetectable (less than 5 mcg/L) in all except 7 infants; in the 7 infants with detectable serum levels, all serum levels were less than 10 mcg/L and their median serum level was 5% (range: 1% to 15%) of their mothers' serum levels.

A total of 93 milk samples were obtained (at birth, 1 month, 3 months, and/or 6 months postpartum) from 28 mothers using 30 mg twice a day as part of combination antiretroviral therapy. Their breastfed infants had a total of 30 blood samples analyzed at 1 month, 3 months, and/or 6 months postpartum. Milk samples and infant blood samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the previous maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. The drug level in breast milk averaged 105 mcg/L (range: 34 to 117 mcg/L); the drug plasma level in infants ranged from 0 to 2.5 mcg/L, which was about 4% (range: 0 to 8%) of the maternal serum level.

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:
-This drug should not be used in first-line regimens due to metabolic toxicities.
-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.

See references