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Dolutegravir Pregnancy and Breastfeeding Warnings

Dolutegravir is also known as: Tivicay

Medically reviewed on Aug 6, 2018

Dolutegravir Pregnancy Warnings

Animal studies have failed to reveal evidence of adverse developmental outcomes at up to the highest dose tested in rats and rabbits; systemic exposures to this drug were less than (rabbits) and about 27 times (rats) the exposure in humans at the maximum recommended human dose. There are no controlled data in human pregnancy; experts are evaluating the potential risk of neural tube birth defects with this drug (data analyzed to date are insufficient).

Placental transfer to the fetus has been reported as high with this drug.

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 (0.94%); in comparison, neural tube defect prevalence rates were 0.12% (14/11,300) and 0.09% (61/66,057) in the non-dolutegravir and HIV-uninfected arms, respectively. The 4 cases reported with this drug included 1 case each of encephalocele, anencephaly, myelomeningocele, and iniencephaly. This study showed no neural tube defects in infants born to 116 women who started a dolutegravir-containing regimen in the first trimester; no neural tube defects were reported in infants born to mothers who started this drug during pregnancy (n = 2812). More data expected from about 600 additional births among pregnant women using a dolutegravir-containing regimen from conception.

Defects related to neural tube closure occur from conception through the first 6 weeks of gestation; embryos exposed to this drug from time of conception through the first 6 weeks of gestation may be at risk. Encephalocele and iniencephaly (2 of the 4 birth defects reported with this drug), although often called neural tube defects, may occur after neural tube closure, which may be past 6 weeks of gestation (but within the first trimester). Understanding of the reported types of neural tube defects associated with this drug is limited and conception date may not be ascertained with precision. Females of reproductive potential should avoid using this drug at the time of conception through the first trimester due to potential risk of neural tube defects.

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

Insufficient prospective pregnancy data from the APR to adequately assess risk of birth defects. Neural tube defects have not been seen with preconception exposure to this drug 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 this drug in pregnancy can be made.

AU TGA pregnancy category B1: 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 not shown evidence of an increased occurrence of fetal damage.

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.

Use should be avoided at time of conception through the first trimester of pregnancy; this drug should be used during the second and third trimesters of pregnancy only if the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: B1
US FDA pregnancy category: Not assigned.

Risk summary: Insufficient data available on use of this drug in pregnant women to definitively inform a drug-related risk; possible increased risk of neural tube defects when used at time of conception (compared to non-dolutegravir-containing regimens).

Comments:
-A pregnancy exposure registry is available.
-If patient plans to become pregnant or if pregnancy is confirmed while using this drug during the first trimester, the patient should be switched to an alternative regimen, if possible.
-Pregnant patients should be apprised of the potential harm to the embryo exposed to this drug from time of conception through the first trimester of pregnancy.
-Females of Reproductive Potential: Pregnancy testing should be performed before starting this drug; patients should be advised to consistently use effective contraception while using this drug.

See references

Dolutegravir 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 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.

Limited published data available regarding use during breastfeeding.

An HIV-infected mother took a combination tablet (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg) 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. With exclusive nursing for about 30 weeks and partial nursing for about 20 weeks, the infant showed no obvious side effects.

See references

References for pregnancy information

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. 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]):
  3. Cerner Multum, Inc. "Australian Product Information." O 0
  4. 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]):
  5. "Product Information. Tivicay (dolutegravir)." ViiV Healthcare, Research Triangle Park, NC.

References for breastfeeding information

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  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. "Product Information. Tivicay (dolutegravir)." ViiV Healthcare, Research Triangle Park, NC.
  5. "Infant feeding and transmission of human immunodeficiency virus in the United States." Pediatrics 131 (2013): 391-6
  6. 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 -]):

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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