Efavirenz / lamivudine / tenofovir Pregnancy and Breastfeeding Warnings

Brand names: Symfi, Symfi Lo

Medically reviewed by Drugs.com. Last updated on Nov 23, 2023.

Efavirenz / lamivudine / tenofovir Pregnancy Warnings

This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus.

US FDA pregnancy category: Not assigned.

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

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.
-A pregnancy exposure registry is available.

Animal studies with efavirenz 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). Animal studies with lamivudine 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. Animal studies with tenofovir disoproxil fumarate (DF) have failed to reveal evidence of fetal harm. Placental transfer of each drug has been observed in humans. There are no controlled data in human pregnancy with this combination drug.

Placental transfer to the fetus has been reported as moderate (cord blood/maternal delivery plasma drug ratio 0.3 to 0.6) with efavirenz and high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with lamivudine and tenofovir DF.

In 2 clinical trials, maternal, neonatal, and umbilical cord serum lamivudine 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 lamivudine 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).

There are retrospective postmarketing reports of findings consistent with neural tube defects (including meningomyelocele), all in infants of mothers with first-trimester exposure to efavirenz-containing regimens.

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 1000 exposures to efavirenz-containing regimens (over 900 exposed in the first trimester; over 100 exposed in the second/third trimester) resulting in live births; there was no difference between efavirenz 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 2-fold increased risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures was 2.2% and 1.6%, respectively. Defects reported with first-trimester exposure to efavirenz included a neural tube defect and a single case of anophthalmia with severe oblique facial clefts and amniotic banding.

The APR has received prospective reports of over 12,000 exposures to lamivudine-containing regimens (over 4800 exposed in the first trimester; over 7300 exposed in the second/third trimester) resulting in live births; 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. Enough first trimester exposures have been monitored to detect at least a 1.5-fold increased 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 with first trimester and second/third trimester exposures was 3.1% and 2.9%, respectively.

The APR has received prospective reports of over 4000 exposures to tenofovir DF-containing regimens (over 3000 exposed in the first trimester; over 1000 exposed in the second/third trimester) resulting in live births; there was no difference between tenofovir DF 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 increased 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 with first trimester and second/third trimester exposures was 2.3% and 2.1%, respectively.

Pregnancy should be avoided during use of this drug and for 12 weeks after discontinuation. Females of reproductive potential should use effective contraception during therapy and for 12 weeks after stopping this drug. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods containing progesterone may have decreased efficacy. Females of reproductive potential should undergo pregnancy testing before starting this drug.

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

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 / lamivudine / tenofovir Breastfeeding Warnings

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; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects similar to those in adults
-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.

Efavirenz, lamivudine, and tenofovir (doses not provided; presumed 600, 300, and 300 mg/day, respectively) 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; efavirenz level was 1.6 mg/L (interquartile range [IQR]: 0.86 to 2.3 mg/L), lamivudine level was 537 mcg/L (IQR: 369 to 768 mcg/L), and tenofovir level was 5 mcg/L (IQR: 0 to 6.1 mcg/L). At 12 months postpartum, milk samples were collected in the morning from 47 women; efavirenz level was 1.8 mg/L (IQR: 1 to 4.3 mg/L), lamivudine level was 430 mcg/L (IQR: 266 to 531 mcg/L), and tenofovir level was 2.5 mcg/L (IQR: 0 to 5.5 mcg/L). Blood samples were obtained from 25 of their breastfed infants; the morning infant plasma level of efavirenz, lamivudine, and tenofovir at 6 months of age was 86.4 mcg/L (IQR: 0 to 329 mcg/L), 2.5 mcg/L (IQR: 2.5 to 7.6 mcg/L), and 24 mcg/L (IQR: 0 to 51.6 mcg/L), respectively, and was 0 mcg/L (for each component) at 12 months of age.

A study of 136 breastfed infants of mothers who used efavirenz, lamivudine, and tenofovir during pregnancy and postpartum measured bone markers at 1, 6, and 12 months of age; markers included bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen. Although tenofovir is known to affect bone density and bone mineral density in adults, no effects were seen on infants' bone markers in the study.

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 as part of combination HIV therapy; infants were followed up to 12 months of age. No differences in the groups were found in any growth parameters.

EFAVIRENZ:
Milk samples from 13 mothers and plasma samples from their breastfed infants were taken 3 to 4 hours after the last maternal 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.

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 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.

LAMIVUDINE:
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 lamivudine 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 lamivudine level in breast milk averaged 1.8 mg/L and the infant serum lamivudine 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 lamivudine (dose not provided) as part of cART provided 47 breast milk and serum samples at 6, 12, and 24 weeks postpartum. The breast milk lamivudine 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 (IQR: 1.1 to 3.5 times) the maternal plasma levels; lamivudine milk to plasma ratio was 2.96 in 49 patients in a related study (same authors). Infant serum lamivudine 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 lamivudine 150 mg twice a day (with nevirapine and zidovudine) and serum levels from their 58 infants were analyzed. Mothers started lamivudine 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 lamivudine.

A total of 206 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 66 mothers using lamivudine 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 lamivudine level averaged 446 mcg/L (range: 269 to 683 mcg/L). The infant plasma lamivudine 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 lamivudine analysis; lamivudine 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 lamivudine 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 lamivudine (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 lamivudine levels were undetectable (less than 7 mcg/L) in all infant samples.

Mothers (n=30) starting lamivudine 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.

In 6 HIV-infected breastfeeding mothers using lamivudine 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 lamivudine serum levels (13.2 and 15.6 mcg/L).

Nigerian and Ugandan women (n=39) used lamivudine 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. Lamivudine 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 lamivudine in breast milk.

An HIV-infected mother used a combination tablet (containing 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; no obvious side effects were observed.

TENOFOVIR DISOPROXIL FUMARATE (DF):
Bioavailability of tenofovir is very poor; it is available as tenofovir DF (more bioavailable), which is metabolized intracellularly to tenofovir diphosphate (active metabolite). Although unknown, the bioavailabilities of tenofovir and tenofovir diphosphate from breast milk are believed to be very low.

Limited data on use of this drug during breastfeeding in HIV-infected mothers and mothers without HIV infection treated for hepatitis B infection shows infant exposure to the drug is trivial. A few infants have been breastfed during maternal use of this drug and no side effects have been observed.

Samples of breast milk obtained from 5 HIV-1-infected mothers show that tenofovir is secreted in human milk. Average peak and trough drug levels in breast milk were 14.1 and 6.8 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 0.03% of the proposed dose for infants and attain trivial infant serum levels. The impact of this exposure in infants breastfed by mothers treated with tenofovir DF is unknown.

In a multicenter study, a single 600 or 900 mg dose of tenofovir was administered to mothers during labor; samples of breast milk were collected at various times postpartum. In 75% of samples obtained from 25 mothers during the first 2 days postpartum, tenofovir was detected (greater than 2.5 mcg/L); levels ranged from 6.3 to 17.8 mcg/L. Only 1 of 21 milk samples had detectable tenofovir level (15.7 mcg/L) at 4 to 6 days postpartum.

Tenofovir 300 mg/day was administered to 6 HIV-infected breastfeeding mothers; it was measured after dosing during ongoing therapy. Peak breast milk tenofovir level of 5.9 mcg/L (range: 5.5 to 8 mcg/L) was reached at about 3 hours (range: 1 to 7 hours) after dosing; none of the breastfed infants had detectable tenofovir serum levels.

Nigerian and Ugandan women (n=48) used tenofovir DF 300 mg once a day (either in the morning or evening) as part of combination HIV therapy. Expressed milk samples were collected before dosing and several times during the 12 hours after the morning dose (n=30) or at 12, 16, and 20 hours after the prior evening dose (n=18). Using dried breast milk spots, peak breast milk level averaged 5.98 mcg/L (IQR: 0 to 8.05 mcg/L) at about 4 hours (IQR: 1 to 6 hours) after dosing. Their exclusively breastfed infants were fed on demand and had blood samples collected at 2 and 8 hours after maternal dosing; no infants had measurable (greater than 4.2 mcg/L) tenofovir blood level in dried blood spots.

Serum tenofovir levels were measured in 5 infants exclusively breastfed by 4 mothers using tenofovir 245 mg (presumably tenofovir DF 300 mg) daily; infant age averaged 1.8 months. In 4 infants, serum tenofovir was undetectable (less than 0.005 mg/L); in 1 infant, serum tenofovir was 0.0055 mg/L. At 4 months of age, no adverse outcomes (on standard developmental parameters) were observed in 2 of the infants exclusively breastfed for 3 months.

See references

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