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Efavirenz / emtricitabine / tenofovir Pregnancy and Breastfeeding Warnings

Efavirenz / emtricitabine / tenofovir is also known as: Atripla

Efavirenz / emtricitabine / tenofovir Pregnancy Warnings

Animal studies have revealed evidence of fetal harm with efavirenz. Efavirenz crosses the placenta in animals and produces fetal blood levels similar to maternal blood levels. Efavirenz may cause fetal harm when used during the first trimester. There are no controlled data in human pregnancy. 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: As of July 2014, the APR received prospective reports of about 1000 live births after exposure to efavirenz-containing regimens, over 800 of which were first-trimester exposures. Birth defects were observed in 19 of 825 live births with first-trimester exposure and 3 of 171 live births with second or third trimester exposure. 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 efavirenz exposure; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. 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 efavirenz-containing regimens (not including this drug). Two cases (1 prospective, 1 retrospective) with findings consistent with neural tube defects were reported with this drug. Multiple defects (Dandy-Walker syndrome) in a fetus from a spontaneous abortion and neural tube defects in a fetus from a pregnancy terminated during the second trimester have also been reported. Both mothers had first-trimester exposure to efavirenz-containing regimens. Causality could not be clearly established in any of these cases. Pregnancy should be avoided during use of this drug. Barrier contraception should always be used in combination with other methods of contraception (e.g., hormonal). Use of adequate contraception for 12 weeks after drug discontinuation is recommended. Women of childbearing potential should undergo pregnancy testing before starting therapy and should be advised to notify their physician if they become pregnant during therapy. 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 D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

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: D Comments: -Effective contraception is recommended during therapy and for 12 weeks after the last dose; local protocol should be consulted regarding contraception timing. -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.

Efavirenz / emtricitabine / tenofovir Breastfeeding Warnings

EFAVIRENZ: 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 side effects were reported in the infants after 6 months of breastfeeding, none had developed HIV infection, and all were developing normally. Breast milk from 51 HIV-infected nursing mothers and blood samples from their exclusively breastfed infants were obtained 12 to 14 hours after a dose and dried; the mothers were using efavirenz 600 mg once a day (as part of antiretroviral regimens). Breast milk level averaged 2280 mcg/L (interquartile range: 1180 to 3270 mcg/L) and infant plasma level averaged 178 mcg/L (interquartile range: 88 to 340 mcg/L). The maternal CYP450 2B6 rs3745274 genotype affected breast milk levels and infant plasma levels; the TT genotype had statistically significant higher milk levels than the GG or GT genotypes and the TT and GT genotypes had statistically significant higher infant plasma levels than the GG genotype. An infant dose of 340 mcg/kg/day (median) was estimated. 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. Efavirenz 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). According to author interpretation, the results suggest infants have substantial exposure to efavirenz during breastfeeding. EMTRICITABINE: Breast milk samples from 5 HIV-1-infected women show emtricitabine is secreted in human milk. Average peak and trough drug levels in breast milk were 679 and 177 mcg/L, respectively. An exclusively breastfed infant would receive about 2% of the proposed emtricitabine dose for infants (estimated). Infants breastfed by mothers treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in such infants are unknown. TENOFOVIR: Breast milk samples from 5 HIV-1-infected mothers show tenofovir is secreted in human milk. Average peak and trough drug levels in breast milk were 14.1 and 6.8 mcg/L, respectively. An exclusively breastfed infant would receive about 0.03% of the proposed tenofovir dose for infants (estimated) and attain trivial infant serum levels. The impact of this exposure in infants breastfed by mothers treated with tenofovir is unknown. Breast milk samples were obtained at various times postpartum from mothers who received a single 600 or 900 mg tenofovir dose during labor. Tenofovir was detected (greater than 2.5 mcg/L) in 75% of samples collected from 25 mothers during the first 2 days postpartum; levels ranged from 6.3 to 17.8 mcg/L. At 4 to 6 days postpartum, only 1 of 21 milk samples had detectable drug level (15.7 mcg/L). Serum tenofovir levels were measured in 5 exclusively breastfed infants whose mothers were treated with tenofovir 245 mg daily; infant age averaged 1.8 months. The drug was undetectable (less than 0.005 mg/L) in the serum of 4 infants; serum level was 0.0055 mg/L in 1 infant. No adverse outcomes on standard developmental parameters were observed in two 4-month-old infants whose mothers were treated with tenofovir 245 mg daily; the infants were exclusively breastfed for 3 months.

Breastfeeding is not recommended during use of this drug. If replacement feeding is not an option, the WHO recommends a triple-drug regimen for HIV-infected women who are nursing; the 3 components are included as a first-choice regimen. 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.

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