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Women of childbearing potential: Women of childbearing potential (WOCBP) should be counselled about the potential risk of neural tube defects with dolutegravir (a component of Dovato, see as follows), including consideration of effective contraceptive measures.
If a woman plans pregnancy, the benefits and the risks of continuing treatment with Dovato should be discussed with the patient.
Pregnancy: The safety and efficacy of a dual regimen has not been studied in pregnancy.
Human experience from a birth outcome surveillance study in Botswana shows a small increase of neural tube defects; 7 cases in 3,591 deliveries (0.19%; 95% CI 0.09%, 0.40%) to mothers taking dolutegravir-containing regimens at the time of conception compared to 21 cases in 19,361 deliveries (0.11%: 95% CI 0.07%, 0.17%) to women exposed to non-dolutegravir regimens at the time of conception.
The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If a pregnancy is confirmed in the first trimester while on Dovato, the benefits and risks of continuing Dovato versus switching to another antiretroviral regimen should be discussed with the patient taking the gestational age and the critical time period of neural tube defect development into account.
Data analysed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women exposed to dolutegravir during pregnancy but are currently insufficient to address the risk of neural tube defects.
In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified (see Pharmacology: Toxicology: Preclinical safety data under Actions). Dolutegravir was shown to cross the placenta in animals.
More than 1000 outcomes from exposure to dolutegravir during second and third trimester pregnancy indicate no evidence of increased risk of foeto/neonatal toxicity. Dovato may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus.
A large amount of data on the use of lamivudine in pregnant women (more than 5200 outcomes from first trimester) indicates no malformative toxicity.
Animal studies showed lamivudine may inhibit cellular DNA replication (see Pharmacology: Toxicology: Preclinical safety data under Actions). The clinical relevance of these findings is unknown.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see Precautions).
Breast-feeding: Dolutegravir is excreted in human milk in small amounts. There is insufficient information on the effects of dolutegravir in neonates/infants.
Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.
It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Fertility: There are no data on the effects of dolutegravir or lamivudine on human male or female fertility. Animal studies indicate no effects of dolutegravir or lamivudine on male or female fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).
