Efavirenz Pregnancy and Breastfeeding Warnings

Brand names: Sustiva

Medically reviewed by Drugs.com. Last updated on Nov 12, 2024.

Efavirenz Pregnancy Warnings

Use is not recommended during the first trimester of pregnancy.
-According to some authorities: This drug should not be used during pregnancy unless there are no alternatives and the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned

Risk summary: This drug may cause fetal harm when administered to a pregnant woman during the first trimester.

Comments:
-A pregnancy exposure registry is available.
-Due to potential teratogenic effects, pregnancy should be avoided during use of this drug.
-If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
-Patients of childbearing potential should undergo pregnancy testing before starting this drug.
-Patients of childbearing potential should use effective contraception during therapy and for 12 weeks after the last dose; local protocol should be consulted regarding contraception timing.
---Barrier contraception should always be used in combination with other methods of contraception; hormonal methods that contain progesterone may have decreased efficacy.

Animal studies have revealed evidence of fetal harm. In cynomolgus monkeys, 3 of 20 fetuses/infants had at least 1 malformation (included anencephaly and unilateral anophthalmia in 1 fetus, microphthalmia in a second, and cleft palate in the third); in rats, embryofetal toxicity occurred at a dose 10 times less than the human exposure at the recommended clinical dose. This drug crosses the placenta in animals and produces fetal blood levels similar to maternal blood levels. There are no controlled data in human pregnancy.

Placental transfer to the fetus has been reported as moderate (mean/median cord blood-to-maternal plasma drug ratio: 0.3 to 0.6) with this drug.

There have been 7 retrospective reports of findings consistent with neural tube defects (including meningomyelocele), all in infants of mothers with first-trimester exposure to regimens containing this drug (not including fixed-dose combination tablets containing this drug); 2 additional cases (1 prospective, 1 retrospective) with findings consistent with neural tube defects were reported with efavirenz/emtricitabine/tenofovir disoproxil.

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

The APR has received prospective reports of over 1375 exposures to regimens containing this drug (over 1175 exposed in the first trimester; over 200 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 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. Detailed monitoring of first trimester exposures to this drug for anomalies (including central nervous system defects) did not reveal a pattern. The prevalence of birth defects/live births with first-trimester and second/third trimester exposures was 2.3% and 1.5%, respectively. One of these prospective reports with first-trimester exposure was a neural tube defect. Also, a single case of anophthalmia was prospectively reported with first-trimester exposure; this case included severe oblique facial clefts and amniotic banding, which have a known association with anophthalmia.

According to some experts, use of this drug in pregnant women or women planning to become pregnant is not restricted. These experts also recommend continuing this drug in pregnant women receiving a virally suppressive efavirenz-based regimen as antiretroviral drug changes during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission.

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

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.

See references

Efavirenz Breastfeeding Warnings

Breastfeeding is not recommended during use of this drug.
-According to some authorities: Use is not recommended.

Excreted into human milk: Yes

Comments:
-This drug has been used without apparent harmful effects in the nursing infant.
-According to the US CDC, American Academy of Pediatrics, and other experts, the complete avoidance of breastfeeding is the only method of infant feeding that eliminates the risk of postnatal HIV transmission to a child who may not yet be infected; replacement feeding (infant formula or banked pasteurized donor human milk) is recommended.
-Local guidelines should be consulted if replacement feeding is not an option.

Efavirenz is excreted in breast milk and small amounts are found in the serum of some infants. Treatment of HIV-positive mothers with this drug does not appear to affect growth and development of their HIV-negative breastfed infants.

Milk samples from 13 mothers and plasma samples from their breastfed infants were taken 3 to 4 hours after the last dose. The mothers, who averaged 15.8 weeks (range: 6 to 25 weeks) postpartum, used efavirenz 600 mg daily with lamivudine and (zidovudine [n=12] or stavudine [n=1]). Skimmed breast milk efavirenz levels averaged 3.5 mg/L (range: 1.3 to 7.4 mg/L) and infant plasma levels averaged 0.86 mg/L (range: 0.4 to 1.5 mg/L). Infant plasma levels averaged 13% of maternal plasma levels; correlation not statistically significant. Average plasma levels were slightly below the level effective for HIV suppression in adults. No adverse reactions were reported in the infants after 6 months of breastfeeding, none had developed HIV infection, and all were developing normally.

About 146 days after delivery, mid-feed milk samples were collected from 5 mothers at 0.5, 1, 2, 4, 8, 12, and 24 hours after an evening dose; they were using efavirenz 600 mg orally daily (as part of antiretroviral regimen). The peak level averaged 4.5 mg/L at about 4 hours postdose; the trough milk value averaged 2.5 mg/L.

Mothers (n=134) using efavirenz 600 mg at bedtime (as part of antiretroviral regimen) and their infants were studied; during the first part of the trial, women were separated into noncarriers, heterozygotes, and homozygotes for the CYP450 2B6 516TT gene. Random breast milk levels had median values of 1610, 2370, and 4070 mcg/L and random infant serum levels had median values of 124, 164, and 333 mcg/L in the 3 groups, respectively. A subset of mothers and infants underwent extensive plasma and breast milk sampling; in these mothers, peak breast milk levels were 4020, 4540, and 8920 mcg/L, respectively, with corresponding trough milk levels of 1120, 1500, and 2480 mcg/L while in these infants, median plasma levels were 166, 89, and 293 mcg/L at 2 hours after maternal dosing and 134, 86, and 342 mcg/L at 8 hours after maternal dosing, respectively. According to author estimation, average infant dose would be 344, 379, and 1340 mcg/kg/day in the maternal noncarrier, heterozygous, and homozygous groups, respectively.

Efavirenz (dose not proved; presumed 600 mg/day), lamivudine, and tenofovir were administered daily (between 6 and 8 p.m.) for prevention of mother-to-child HIV transmission. At 1 month postpartum, milk samples collected in the morning from 33 women had a median efavirenz level of 1.6 mg/L (interquartile range [IQR]: 0.86 to 2.3 mg/L); at 12 months postpartum, milk samples collected in the morning from 47 women had a median efavirenz level of 1.8 mg/L (IQR: 1 to 4.3 mg/L). Blood samples were obtained from 25 of their breastfed infants; the median morning infant plasma level of efavirenz at 6 months of age was 86.4 mcg/L (IQR: 0 to 329 mcg/L) and was 0 mcg/L at 12 months of age.

Mother-infant pairs were studied among mothers taking efavirenz 600 mg daily (as part of multidrug HIV regimen). Mothers hand-express milk samples 12 to 14 hours after a morning dose at 1, 3, and 6 months postpartum; infants were breastfed (extent not provided) and plasma levels were measured postpartum. At 1, 3, and 6 months, breast milk efavirenz levels averaged 4.66 mg/L (n=22), 4.16 mg/L (n=31), and 3.92 mg/L (n=30), respectively, and infant plasma efavirenz levels averaged 347 mcg/L (n=22), 268 mcg/L (n=30), and 175 mcg/L (n=17), respectively. The weight-adjusted infant dose was calculated as 2.46% at 6 months; the plasma levels ranged from 4.8% to 7.2% of simultaneous maternal plasma levels. Among 32 of their breastfed infants, no adverse reactions were observed by investigators or reported by mothers at 1, 3, and 6 months of age.

This drug was measured in 117 breastfed (90% exclusive) infants whose mothers used efavirenz for HIV infection during pregnancy and postpartum. The drug was detectable in all plasma samples at 0 (mean 1.7 mg/L), 8 (mean 0.3 mg/L), and 12 (mean 0.3 mg/L) weeks postpartum. It was also detectable in all hair samples at 12 weeks postpartum (mean 1.9 ng/mg of hair; range: 0.34 to 11 ng/mg). The results suggest infants have substantial exposure to this drug during breastfeeding.

A prospective cohort study compared growth and development of infants of non-HIV-infected mothers and infants of HIV-infected mothers using efavirenz and tenofovir for prevention of mother-to-child HIV transmission; infants were followed up to 12 months of age. No differences in the groups were found in any growth parameters.

See references

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