Lamivudine Pregnancy and Breastfeeding Warnings
Lamivudine Pregnancy Warnings
This drug should be used during pregnancy only if clinically needed and the benefit outweighs the risk to the fetus. -AU products for chronic hepatitis B: Use is not recommended during the first trimester of pregnancy. AU TGA pregnancy category: B3 US FDA pregnancy category: -Epivir-HBV(R): C -Epivir(R): Not assigned.
Animal studies have failed to reveal evidence of teratogenicity. While early embryolethality was observed in rabbit studies (exposure levels similar to human levels), this effect was not seen in high-dose studies in rats. Placental transfer has been observed in humans. There are no controlled data in human pregnancy; however, based on observed outcomes (more than 1000 after first-trimester exposure and more than 1000 after second-/third-trimester exposure), the malformative risk is unlikely in humans. 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 11,000 exposures to this drug resulting in live births (over 4300 exposed in the first trimester); there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program. The prevalence of defects in the first trimester was 3.1%. In 2 clinical trials, maternal, neonatal, and umbilical cord serum drug levels were generally comparable. Amniotic fluid samples collected after natural rupture of membranes from a subset of patients confirmed placental transfer in humans. Amniotic fluid levels of this drug were usually 2 times greater than maternal serum levels, ranging from 1.2 to 2.5 mcg/mL (150 mg twice a day) and 2.1 to 5.2 mcg/mL (300 mg twice a day). 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. 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.
Lamivudine Breastfeeding Warnings
After oral dosing of this drug, breast milk levels were similar to maternal serum levels. Based on more than 200 mother/child pairs treated for HIV, serum drug levels in breastfed infants of mothers treated for HIV are very low (less than 4% of maternal serum levels) and gradually decrease to undetectable levels by 24 weeks of age. The total amount of drug ingested by a breastfed infant is very low; likely to have exposures resulting in suboptimal antiviral effect. Breastfeeding is not contraindicated due to maternal HBV if the neonate is adequately managed at birth for prevention of HBV. There is no sign that the low drug level in human milk causes harmful effects in the nursing infant. In a trial after 150 mg orally twice a day (with zidovudine) or 300 mg orally twice a day, lamivudine levels in breast milk were 0.5 to 8.2 mcg/mL (similar to levels in maternal serum). In other trials after 150 mg orally twice a day (with zidovudine; with or without abacavir), the breast milk-to-maternal plasma ratio was between 0.6 and 3.3. Infant serum drug levels were between 18 and 28 ng/mL and not detectable (less than 7 ng/mL) in 1 trial. In 1 study, this drug was measured in the milk of 20 HIV-infected women given 150 mg every 12 hours since week 38 of pregnancy. Mean drug levels in milk ranged from undetectable (less than 500 mcg/L) to 8200 mcg/L and was measured at any time relative to the dose. The breast milk-to-maternal serum ratio was about 1 to 1. Serum and breast milk from 58 mothers using 150 mg twice a day (with nevirapine and zidovudine) and serum levels from their 58 infants were analyzed. Mothers started this drug at 34 to 36 weeks gestation and continued until 6 months postpartum; they were instructed to exclusively breastfeed for 5.5 months. Breast milk and serum samples were collected within 24 hours after delivery and at 2, 6, 14, and 24 weeks postpartum; breast milk was collected at various times after the prior dose. The breast milk lamivudine level averaged 1214 mcg/L (all visits). The infant dried blood spot lamivudine levels averaged 67 mcg/L at delivery, 32 mcg/L at week 2, 24 mcg/L at week 6, 20 mcg/L at week 14, and were not measurable (less than 16 mcg/L) at week 24 postpartum. A fully breastfed infant would receive 182 mcg/kg/day of this drug (estimated). Milk samples were obtained daily before breastfeeding. The milk lamivudine level averaged 1.2 mg/L (range: less than 0.5 to 6.1 mg/L) with 300 mg twice a day (n=10) and 0.9 mg/L (range: less than 0.5 to 8.2 mg/L) with 150 mg twice a day plus zidovudine (n=10). Milk samples from 20 women taking 150 mg orally twice a day as part of combination antiretroviral therapy (cART) and serum levels from their infants were obtained at 2 or 5 months postpartum, about 4 hours (range: 1 to 8.5 hours) after the last dose. The drug level in breast milk averaged 1.8 mg/L and the infant serum drug level averaged 28 mcg/L (range: less than 14 to 53 mcg/L). Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with lamivudine, nevirapine, and zidovudine or stavudine; doses not provided) once during the first 3 days postpartum and once at 7 days postpartum. Samples were collected after a dose at 5.3 hours (range: 0 to 99 hours) for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk lamivudine levels averaged 0.4 mg/L (n=20) for the first sample and 0.4 mg/L (n=30) for the second sample; these levels were 2.9 to 3.3 times the coinciding maternal serum levels. Mothers using this drug (dose not provided) as part of cART provided 47 breast milk and serum samples at 6, 12, and 24 weeks postpartum. The breast milk drug levels at about 14 hours after the last dose averaged 510 (17 samples), 387 (17 samples), and 310 mcg/L (13 samples). Milk levels were about 2.6 times (interquartile range: 1.1 to 3.5 times) the maternal plasma levels; milk to plasma ratio was 2.96 in 49 patients in a related study (same authors). Infant serum levels measured about 14 hours after the last maternal dose averaged 13, 10, and 5 mcg/L at 6 (17 samples), 12 (17 samples), and 24 (13 samples) weeks of age, respectively, which was 6% of the maternal serum level. A total of 206 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 66 mothers using 150 mg twice a day as part of cART and 64 blood samples from their breastfed infants were analyzed at 1, 3, and/or 6 months postpartum; samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the prior maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. The breast milk drug level averaged 446 mcg/L (range: 269 to 683 mcg/L). The infant plasma drug level averaged 18 mcg/L (range: 7 to 35 mcg/L), which averaged 2% (range: 0 to 4%) of the maternal serum level. In a continuation of this study, 65 breast milk samples (after the same dose at 1, 3, and 6 months postpartum) and 22 blood samples (from 17 breastfed infants [extent not provided] between 1 and 6 months) were collected for drug analysis; drug levels averaged 684 mcg/L in breast milk and 29.2 mcg/L in infant blood. Not clear if some of the same patients from the first study were in the latter study. Samples of breast milk were obtained right before a dose at about 1 month postpartum from 15 women using 150 mg twice a day for 53 to 182 days as part of cART. Whole breast milk levels contained about 0.14 mg/L of this drug (about 74% of maternal blood levels). Infant blood was obtained from 24 infants partially or exclusively breastfed by their mothers at about 1 month postpartum, 11 to 18 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding. Plasma drug levels were undetectable (less than 7 mcg/L) in all infant samples. Mothers (n=30) starting 150 mg orally twice a day (with zidovudine and lopinavir-ritonavir) at delivery provided plasma and breast milk samples at 6, 12, or 24 weeks postpartum (n=10 each time). Maternal plasma and breast milk samples were collected about 14.9 hours after the prior evening dose, before the morning dose, and 2, 4, and 6 hours after the dose. Infant plasma samples were collected before the first maternal dose and at 2, 4, and 6 hours after the maternal dose. Breastfeeding was not restricted during the study. Detectable lamivudine levels (at least 10 mcg/L) were found in 107 of 121 breast milk samples and 107 of 115 infant plasma samples; breast milk level averaged 0.94 mg/L over the 6 hours and infant plasma level averaged 180 mcg/L.
Hepatitis B Virus (HBV) Infection: -AU: Use is recommended only if the benefit outweighs the risk to the infant; a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother and known benefits of breastfeeding. -UK: Breastfeeding may be considered during use of this drug, taking into account the importance of the drug to the mother and known benefits of breastfeeding. -US: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother and known benefits of breastfeeding. HIV Infection: 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; this drug is included in the first-choice regimen. Excreted into human milk: Yes Comments: -The effects in the nursing infant are unknown. -UK: If maternal transmission of HBV occurs despite adequate prophylaxis, discontinuation of breastfeeding should be considered to reduce the risk of lamivudine-resistant mutants developing in the infant. -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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