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Abacavir / dolutegravir / lamivudine Pregnancy and Breastfeeding Warnings

Abacavir / dolutegravir / lamivudine is also known as: Triumeq

Medically reviewed on Jul 20, 2018

Abacavir / dolutegravir / lamivudine Pregnancy Warnings

Animal studies with abacavir (high-dose) have revealed evidence of embryonic and fetal toxicity, including developmental toxicity, fetal anasarca, skeletal malformations, and increased incidence of stillbirth. Animal studies with dolutegravir have failed to reveal evidence of developmental toxicity or teratogenicity; systemic exposures to this component were less than (rabbits) and about 50 times (rats) the exposure in humans at the recommended human dose. 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. Data on pregnant women using abacavir with lamivudine (as the individual components), abacavir, and lamivudine (more than 400, 600, and 3000 outcomes from first trimester exposures, respectively) showed no malformative toxicity. There are no controlled data in human pregnancy with this combination drug.

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

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 3.9 (1.2 to 12.8)-fold greater than corresponding maternal serum levels, based on limited data at delivery.

In an ongoing observational study in Botswana, neural tube defects were detected in 4 infants born to 426 women who started a dolutegravir-containing regimen before pregnancy and who were still using it at time of conception; more data expected from about 600 additional births among pregnant women using a dolutegravir-containing regimen from conception. This study showed no neural tube defects in infants born to 116 women who started a dolutegravir-containing regimen in the first trimester.

The Department of Health and Human Services Antiretroviral Guidelines Panels provide the following interim recommendations regarding use of dolutegravir in adults and adolescents with HIV who are pregnant or of reproductive potential:
-Females not known to be pregnant should have a negative pregnancy test before starting dolutegravir.
-Females currently using a dolutegravir-containing regimen or who wish to be started on dolutegravir should be apprised of the potential risk of neural tube defects when dolutegravir is used near time of conception; neural tube defects occur within the first 28 days after conception or 6 weeks from the last menstrual period.
-Within 8 weeks from last menstrual period, pregnant patients using dolutegravir should consult healthcare providers regarding the risks and benefits of their current regimens; if good alternative options are available, then patients should be switched to a regimen without dolutegravir.
-Pregnant patients at least 8 weeks from last menstrual period may start or continue dolutegravir-containing regimens; stopping such regimens is unlikely to provide any benefits after neural tube formation, and drug changes during pregnancy could increase the risk of viremia and transmission of HIV to the infant.
Current guidelines should be consulted for additional information.

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 2350 exposures to abacavir-containing regimens (over 1100 exposed in the first trimester; over 1250 exposed in the second/third trimester) resulting in live births; there was no difference between abacavir 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 2.8% and 2.8%, respectively.

Insufficient prospective pregnancy data from the APR to adequately assess risk of birth defects with dolutegravir. Neural tube defects have not been seen with preconception dolutegravir exposure in prospective reports to the APR; only a small number of preconception exposures reported thus far. Due to limited number of pregnancies exposed to dolutegravir-containing regimens, no final decisions regarding safety of dolutegravir in pregnancy can be made.

The APR has received prospective reports of over 12,300 exposures to lamivudine-containing regimens (over 5000 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% and 2.9%, respectively.

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.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.
-According to some experts: Use of dolutegravir is not recommended within the first 28 days after conception or 6 weeks from the last menstrual period.

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned.

Risk summary: Insufficient data available on use of this drug in pregnant women to inform a drug-related risk.

Comments:
-A pregnancy exposure registry is available.
-According to some authorities: Females of reproductive potential should use effective contraception while using dolutegravir.
-According to some experts: If the patient becomes pregnant while taking dolutegravir, the patient should be apprised of the potential harm to the fetus.

See references

Abacavir / dolutegravir / lamivudine Breastfeeding Warnings

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, a different drug may be preferred, particularly while breastfeeding newborn or preterm infants.

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
-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.

An HIV-infected mother used this combination drug (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; the infant showed no obvious side effects.

ABACAVIR:
In a study after abacavir 300 mg orally twice a day (as abacavir/lamivudine/zidovudine), the breast milk to maternal plasma ratio was 0.9.

Breast milk from 15 women and blood samples from 9 of their partially or exclusively breastfed infants were collected about 1 month postpartum; the mothers were using abacavir 300 mg twice a day for 53 to 182 days (with lamivudine and zidovudine). Breast milk was obtained right before a dose; whole breast milk abacavir levels averaged 0.057 mg/L (about 85% of maternal blood levels). Infant blood was obtained 11 to 17 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding; plasma abacavir levels were undetectable (less than 16 mcg/L) in 8 of 9 infants.

DOLUTEGRAVIR:
Limited published data available regarding use during breastfeeding.

An HIV-infected mother used this combination drug once a day. Her breast milk dolutegravir levels over 10 months averaged about 10 mg/L at 11 hours after dosing; authors estimated an infant dose of 15 mcg/kg/day. During the period of exclusive nursing (up to about 30 weeks postpartum), her infant had a plasma dolutegravir level of 10 mg/L; as supplemental food was introduced, plasma levels declined to about 0.3 mg/L at 35 weeks and to zero with no nursing after about 50 weeks postpartum.

LAMIVUDINE:
Based on more than 200 mother/child pairs treated for HIV, serum lamivudine 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.

In studies after lamivudine 150 mg orally twice a day (with zidovudine or as lamivudine-zidovudine or abacavir/lamivudine/zidovudine), the breast milk to maternal plasma ratio ranged between 0.6 and 3.3. Lamivudine infant serum levels ranged between 18 and 28 ng/mL and were undetectable (less than 7 ng/mL) in 1 study.

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 (interquartile range [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 taking 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.

See references

References for pregnancy information

  1. "Product Information. Triumeq (abacavir/dolutegravir/lamiVUDine)." ViiV Healthcare, Research Triangle Park, NC.
  2. Cerner Multum, Inc. "Australian Product Information." O 0
  3. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission "Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Available from: URL: https://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf." ([2018, May 30]):
  4. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  5. DHHS AIDSinfo "Recommendations regarding the use of dolutegravir in adults and adolescents with HIV who are pregnant or of child-bearing potential. Available from: URL: https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-and-ad" ([2018, May 30]):
  6. "Product Information. Epzicom (abacavir-lamivudine)." GlaxoSmithKline, Research Triangle Park, NC.

References for breastfeeding information

  1. "Product Information. Triumeq (abacavir/dolutegravir/lamiVUDine)." ViiV Healthcare, Research Triangle Park, NC.
  2. Cerner Multum, Inc. "Australian Product Information." O 0
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  4. United States National Library of Medicine "Toxnet. Toxicology Data Network. Available from: URL: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT." ([cited 2013 -]):
  5. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission "Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Available from: URL: https://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf." ([2018, May 30]):
  6. Mirochnick M, Thomas T, Capparelli E, et al. "Antiretroviral Concentrations in Breast-feeding Infants of Mothers Receiving HAART." Antimicrob Agents Chemother (2008):
  7. "Infant feeding and transmission of human immunodeficiency virus in the United States." Pediatrics 131 (2013): 391-6

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