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Dolutegravir / rilpivirine Pregnancy and Breastfeeding Warnings

Dolutegravir / rilpivirine is also known as: Juluca

Medically reviewed on Feb 12, 2018

Dolutegravir / rilpivirine Pregnancy Warnings

Animal studies have failed to reveal evidence of adverse developmental outcomes with the components of this drug. Animal studies with dolutegravir showed no adverse effects on embryofetal development at up to the highest dose tested in rats and rabbits; systemic exposures to this component were less than (rabbits) and about 38 times (rats) the exposure in humans at the recommended dose (50 mg/day). Animal studies with rilpivirine showed no evidence of significant embryofetal toxicity at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose (25 mg/day). There are no controlled data in human pregnancy; experts are evaluating the potential risk of neural tube birth defects with dolutegravir (data analyzed to date are insufficient).

Placental transfer to the fetus has been reported as high with dolutegravir. Placental transfer to the fetus has been reported as moderate to high (cord blood/maternal delivery plasma drug ratio at least 0.3) with rilpivirine. In studies of pregnant women using rilpivirine, the cord blood-to-maternal plasma ratio ranged from 0.3 to 0.81.

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 dolutegravir 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 dolutegravir 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 dolutegravir 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 dolutegravir), 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 dolutegravir 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 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 400 exposures to rilpivirine-containing regimens (over 250 exposed in the first trimester; over 150 exposed in the second/third trimester) resulting in live births; there was no difference between rilpivirine 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 to rilpivirine was 1% and 1.2%, respectively.

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.
-According to some authorities: Use is not recommended.

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 with dolutegravir at time of conception (compared to non-dolutegravir-containing regimens).

Comments:
-A pregnancy exposure registry is available.
-Lower exposures of both components have been observed during pregnancy.
-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 / rilpivirine 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 (dolutegravir); Unknown (rilpivirine)
Excreted into animal milk: Yes (rilpivirine)

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.

DOLUTEGRAVIR:
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.

RILPIVIRINE:
No published data available regarding use during breastfeeding.

See references

References for pregnancy information

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

References for breastfeeding information

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

Further information

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

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