Dovato Use In Pregnancy & Lactation

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: Pre-clinical Safety Data under Actions).
Pregnancy: DOVATO should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the foetus. Women of childbearing potential (WOCBP) should be informed about the potential risk of neural tube defects with dolutegravir and counselled about the use of effective contraception. It is recommended that pregnancy testing is conducted prior to initiation of DOVATO. If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on DOVATO, the risks and benefits of continuing DOVATO versus switching to another antiretroviral regimen should be discussed with the patient. Factors to consider should include feasibility of switching, tolerability, ability to maintain viral suppression, actual gestational age, risk of transmission to the infant and the available data around the potential risk of neural tube defects and other pregnancy outcomes for dolutegravir and alternative antiretroviral drugs.
In a birth outcome surveillance study in Botswana, a numerically higher rate of neural tube defects was identified with exposure to dolutegravir compared to non-dolutegravir-containing antiretroviral regimens at the time of conception, however, the difference was not statistically significant. Seven cases of neural tube defects were reported in 3,591 deliveries (0.19%) to mothers taking dolutegravir-containing regimens at the time of conception, compared with 21 cases in 19,361 deliveries (0.11%) to mothers taking non-dolutegravir-containing regimens at the time of conception (Prevalence Difference 0.09%; 95% CI -0.03, 0.30).
In the same study, an increased risk of neural tube defects was not identified in women who started dolutegravir during pregnancy. Two out of 4,448 deliveries (0.04%) to mothers who started dolutegravir during pregnancy had a neural tube defect, compared with five out of 6,748 deliveries (0.07%) to mothers who started non-dolutegravir-containing regimens during pregnancy.
A causal relationship of these events to the use of dolutegravir has not been established. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births. As most neural tube defects occur within the first 4 weeks of foetal development (approximately 6 weeks after the last menstrual period) this potential risk would concern women exposed to dolutegravir at the time of conception and in early pregnancy.
Data analysed to date from other sources including the Antiretroviral Pregnancy Registry, clinical trials, and post-marketing data are insufficient to address the risk of neural tube defects with dolutegravir.
More than 1,000 outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.
In animal reproductive toxicity studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified (see PHARMACOLOGY: Toxicology: Pre-clinical Safety Data under Actions).
Dolutegravir and lamivudine use during pregnancy have been evaluated in the Antiretroviral Pregnancy Registry (APR) in over 600 and 12,500 women, respectively (as of July 2019). Available human data from the APR do not show an increased risk of major birth defects for dolutegravir or lamivudine compared to the background rate (see PHARMACOLOGY: Pharmacodynamics: Clinical Studies under Actions).
Dolutegravir readily crosses the placenta in humans. In HIV-infected pregnant women, the median (range) foetal umbilical cord concentrations of dolutegravir were 1.28 (1.21 to 1.28) fold greater compared with maternal peripheral plasma concentrations.
There is insufficient information on the effects of dolutegravir on neonates.
There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Lamivudine was associated with findings in animal reproductive toxicity studies (see PHARMACOLOGY: Toxicology: Pre-clinical Safety Data under Actions).
Lactation: Health experts recommend that where possible HIV infected women do not breast-feed their infants in order to avoid transmission of HIV. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breast feeding during antiretroviral therapy.
Dolutegravir is excreted in human milk in small amounts. In an open-label randomised study in which HIV-infected treatment-naïve pregnant women were administered a dolutegravir based regimen until two weeks post-partum, the median (range) dolutegravir breast milk to maternal plasma ratio was 0.033 (0.021 to 0.050).
In a study following repeat oral dose of either 150 mg lamivudine twice daily (given in combination with 300 mg zidovudine twice daily) or 300 mg lamivudine twice daily, lamivudine was excreted in human breast milk (0.5 to 8.2 micrograms/mL) at similar concentrations to those found in serum. In other studies following repeat oral dose of 150 mg lamivudine twice daily (given either in combination with 300 mg zidovudine or as COMBID300 or TRIZIVIR) the breast milk:maternal plasma ratio ranged between 0.6 and 3.3. Lamivudine median infant serum concentrations ranged between 18 and 28 ng/mL and were not detectable in one of the studies (assay sensitivity 7 ng/mL). Intracellular lamivudine triphosphate (active metabolite of lamivudine) levels in breastfed infants were not measured therefore the clinical relevance of the serum concentrations of the parent compound measured is unknown.