FDA recently approved changes to the TIVICAY (dolutegravir), TRIUMEQ (abacavir, dolutegravir, and lamivudine, JULUCA (dolutegravir and rilpivirine) and DOVATO (dolutegravir and lamivudine) labeling to include updated information regarding the risk of neural tube defects with dolutegravir based on the final results from Tsepamo Study. Similar changes were made to all four labels. A summary of the changes to the Tivicay label are included below.
Section 5 WARNINGS AND PRECAUTIONS
5.3 Embryo-Fetal Toxicity
An observational study showed an association between TIVICAY and an increased risk of neural tube defects when TIVICAY was administered at the time of conception and in early pregnancy. As there is limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, an alternative treatment to TIVICAY should be considered at the time of conception through the first trimester of pregnancy.
Perform pregnancy testing before initiation of TIVICAY in adolescents and adults of childbearing potential to exclude use of TIVICAY during the first trimester of pregnancy [see Dosage and Administration (2.1)]. Initiation of TIVICAY is not recommended in adolescents and adults actively trying to become pregnant unless there is no suitable alternative.
Counsel adolescents and adults of childbearing potential to consistently use effective contraception.
In adolescents and adults of childbearing potential currently on TIVICAY who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TIVICAY versus switching to another antiretroviral regimen and consider switching to an alternative regimen.
TIVICAY may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus.
Section 8: USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Data from a birth outcome surveillance study has identified an increased risk of neural tube defects when TIVICAY is administered at the time of conception compared with non-dolutegravir-containing antiretroviral regimens. As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk. In addition, 2 of the 5 birth defects (encephalocele and iniencephaly), which have been observed with dolutegravir use, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester. Due to the limited understanding of the types of reported neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, an alternative treatment to TIVICAY should be considered at the time of conception through the first trimester of pregnancy. Initiation of TIVICAY is not recommended in adolescents and adults actively trying to become pregnant unless there is no suitable alternative (see Data).
In adolescents and adults of childbearing potential currently on TIVICAY who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TIVICAY versus switching to another antiretroviral regimen and consider switching to an alternative regimen. Advise pregnant adolescents and adults of the potential risk to the embryo exposed to TIVICAY from the time of conception through the first trimester of pregnancy. A benefit-risk assessment should consider factors such as feasibility of switching, tolerability, ability to maintain viral suppression, and risk of transmission to the infant against the risk of neural tube defects.
There are insufficient human data on the use of TIVICAY during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD) of TIVICAY (see Data).
Data
Human Data: In a birth outcome surveillance study in Botswana, there were 5 cases of neural tube defects reported out of 1,683 deliveries (0.3%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.1% (15/14,792 deliveries) in the non-dolutegravir arm and 0.08% (70/89,372 deliveries) in the HIV-uninfected arm. Five cases reported with dolutegravir included one case each of encephalocele, anencephaly, and iniencephaly, and 2 cases of myelomeningocele. In the same study, one infant out of 3,840 (0.03%) deliveries to women who started dolutegravir during pregnancy had a neural tube defect, compared with 3 infants out of 5,952 (0.05%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy.
Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to address the risk of neural tube defects with dolutegravir.
Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.
The updated labels will soon be available at Drugs@FDA or DailyMed
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Elizabeth Thompson
Division of Antiviral Products
Food and Drug Administration
Michael Stanfield Jr.
Division of Antiviral Products
Food and Drug Administration
