This drug should be used during pregnancy only if clinically needed and the benefit outweighs the risk to the fetus.
-According to some authorities: Use of products for chronic hepatitis B virus (HBV) infection is not recommended during the first 3 months of pregnancy.

AU TGA pregnancy category: B3
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.

Animal studies have failed to reveal evidence of teratogenicity at doses producing Cmax about 35 times higher (rats and rabbits) than human exposure at the recommended daily dose; 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. Data in pregnant women treated with this drug (more than 1000 outcomes from first trimester exposure and more than 1000 outcomes from second/third trimester exposure) indicate no malformative and fetal/neonatal effect, There are no controlled data in human pregnancy; however, the malformative risk is unlikely in humans.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with this drug.

The pharmacokinetics of this drug in patients with HIV-1 or HBV infection and in healthy subjects were similar at similar doses. 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 3.9-fold (1.2- to 12.8-fold) greater than corresponding maternal serum levels, based on limited data at delivery.

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 12,950 exposures to lamivudine-containing regimens (over 5450 exposed in the first trimester; over 7500 exposed in the second/third trimester) resulting in live births; there was no difference between the overall risk of birth defects for lamivudine 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. The prevalence of birth defects/live births with first trimester and second/third trimester exposures was 3.1% and 2.9%, respectively.

Of over 12,900 women exposed to lamivudine in the APR, less than 2% were HBV monoinfected. Most women exposed to this drug in the APR were treated for HIV at higher doses (compared with HBV monoinfected women) and with other antiretroviral agents.

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 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

This drug has been well studied in HIV-infected breastfeeding patients; it appears to be well tolerated by their nursing infants. This drug has not been studied in HIV-negative nursing mothers receiving treatment for HBV infection, but serious side effects in nursing infants would not be expected from the low doses used.

No information is available regarding drug levels in milk from lactating women using this drug to treat HBV infection; however, in lactating women with HIV-1 infection receiving treatment with this drug at 3 or 6 times the recommended daily dose for HBV, drug levels in milk were similar to those seen in serum. The dose of this drug received by a breastfed infant of a mother receiving treatment for HIV-1 infection was about 6% (estimated) of the recommended daily dose for HBV in children over 2 years of age. In breastfed infants of mothers with HIV-1 infection using this drug, the blood levels of lamivudine decreased after delivery and were undetectable at 6 months despite constant milk levels; this is consistent with increased drug renal clearance in the first 6 months of life.

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.

Milk samples were collected daily before breastfeeding from 2 groups of women using lamivudine, 1 group on monotherapy and the other on combination therapy. In the group using lamivudine 300 mg twice a day (n=10), milk level averaged 1.2 mg/L (range: less than 0.5 to 6.1 mg/L); in the group using lamivudine 150 mg twice a day plus zidovudine (n=10), milk lamivudine averaged 0.9 mg/L (range: less than 0.5 to 8.2 mg/L).

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=9) 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 [IQR]: 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.

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. According to author estimation, a fully breastfed infant would receive 182 mcg/kg/day of this drug.

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. 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.

Lamivudine (dose not provided but presumed 300 mg/day), tenofovir, and efavirenz were administered daily (between 6 and 8 p.m.) for prevention of mother-to-child HIV transmission. At 1 month postpartum, milk samples were collected in the morning from 33 women; lamivudine level was 537 mcg/L (IQR: 369 to 768 mcg/L). At 12 months postpartum, milk samples were collected in the morning from 47 women; lamivudine level was 430 mcg/L (IQR: 266 to 531 mcg/L). Blood samples were obtained from 25 of their breastfed infants; the morning infant plasma levels of lamivudine at 6 and 12 months of age were 2.5 mcg/L (IQR: 2.5 to 7.6 mcg/L) and 0 mcg/L, respectively.

In 6 HIV-infected breastfeeding mothers using 150 mg twice a day, a peak breast milk level of 994 mcg/L (range: 958 to 1274 mcg/L) was reached at 2 to 4 hours after dosing; 2 of their breastfed infants had detectable serum levels (13.2 and 15.6 mcg/L).

Nigerian and Ugandan women (n=39) used 150 mg twice a day (n=11) or 300 mg once a day (n=10 [morning]; n=18 [prior evening]) as part of combination HIV therapy. Expressed milk samples were collected before dosing and at 0.5, 1, 2, 4, and 8 hours after the morning dose (150 or 300 mg) or between 12 to 20 hours after the evening dose (300 mg). Using dried breast milk spots, peak breast milk level averaged 908 mcg/L (IQR: 772 to 1015 mcg/L) at about 6 hours (IQR: 4 to 6 hours) after dosing and 663 mcg/L (IQR: 445 to 890 mcg/L) at about 6 hours (IQR: 4 to 8 hours) after dosing in mothers using 150 mg twice a day and 300 mg once a day, respectively. Their exclusively breastfed infants were fed on demand and had blood samples collected at 2 and 8 hours after maternal dosing. This drug was detectable (greater than 16.6 mcg/L) in dried blood spots of 14 of 39 infants (averaged 17.7 mcg/L [IQR: 16.3 to 22.7 mcg/L]); of these, levels were detectable in 7 of 10 infants whose mothers used 300 mg once a day in the morning, in 4 of 18 infants whose mothers had used their dose the prior evening, and in 3 of 11 infants whose mothers used 150 mg twice a day.

At 3-hour intervals before cesarean section, 9 HIV-infected women received 3 doses of lamivudine 50 mg, lopinavir 200 mg, ritonavir 150 mg, zidovudine 300 mg. Breast milk samples were obtained at 25 hours postpartum (mean); milk level of lamivudine averaged 449 mcg/L (range: 143 to 1148 mcg/L) in the 8 women it was quantified.

Of 24 infants breastfed by HIV-infected mothers who developed HIV infection by 6 months of age, 6 infants had a mutation that may have been selected for by subtherapeutic levels of this drug in breast milk.

An HIV-infected mother took a combination tablet (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg) once a day. She exclusively breastfed her infant for about 30 weeks and then partially breastfed for about 20 weeks; the infant showed no obvious side effects.

A mother took this drug for 33 days (25 before birth and 8 days postpartum) for chronic HBV infection; her infant was breastfed (extent not provided). At 3 months of age, the infant died with the death attributed to sudden infant death syndrome; the death was unlikely to be related to this drug.

Hepatitis B Virus (HBV) Infection: According to some experts, there is currently no justification for contraindicating the use of this drug for HBV therapy during breastfeeding.
-According to some authorities: 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.
-According to some authorities: 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.

HIV Infection: Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Yes

Comments:
-HBV Infection:
---Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug.
---The effects in the nursing infant are unknown; potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered.
---According to some authorities: 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.
-HIV Infection:
---The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects
---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