Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

TIVICAY PD (NDA-213983)

(DOLUTEGRAVIR SODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

Expand all

08/25/2026 (SUPPL-7)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Clinical Trials Experience in Adult Participants

…

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Participants: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 participants with HIV-1, were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. Participants were antiretroviral treatment-experienced adults. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in participants receiving TIVICAY 50 mg once daily + background regimen and 4% in participants receiving raltegravir 400 mg twice daily + background regimen.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Participants: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 participants with HIV-1 received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. Participants were antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance. The rate of adverse events leading to discontinuation was 4% of participants at Week 48.

…

Clinical Trials Experience in Pediatric Participants

Children and Adolescent Participants with HIV-1: The safety and pharmacokinetics of TIVICAY and TIVICAY PD in pediatric participants with HIV-1 aged at least 4 weeks and weighing at least 3 kg was evaluated in the IMPAACT P1093 trial and 2 weight-band-based pharmacokinetic substudies of the ODYSSEY trial [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3)]. Overall, the safety data in these pediatric studies were similar to those seen in adults, and there was no clinically significant difference in dolutegravir exposure [see Clinical Pharmacology (12.3)].

IMPAACT P1093 is a multicenter, open-label, non-comparative trial of pediatric participants with HIV-1 aged 4 weeks to less than 18 years [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.3)].

…

Neonates Exposed to HIV-1: Forty-eight term neonates exposed to HIV-1 (from birth and weighing at least 2 kg) received dolutegravir for up to 6 weeks, and followed for a total of 16 weeks in IMPAACT 2023. The safety profile in neonates was similar to that observed in older populations and there were no new safety findings identified [see Use in Specific Populations (8.4)].

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Additions and/or revisions underlined:

Table 8 provides clinical recommendations as a result of drug interactions with TIVICAY or TIVICAY PD. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy [see Dosage and Administration (2), Clinical Pharmacology (12.3)].

Changes to Table 8. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration (2)]; please refer to label for complete information

…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

Neonates Exposed to HIV-1

The safety and pharmacokinetics of dolutegravir were evaluated in 48 term HIV-1 exposed neonates in a Phase I, open-label, multicenter clinical study (IMPAACT 2023). Dolutegravir was orally administered in 2 cohorts of neonates exposed to HIV-1, weighing at least 2 kg, receiving standard of care antiretroviral prophylaxis in the first 4 to 6 weeks of life. All enrolled neonates were followed for safety data for a duration of 16 weeks. Neonates in cohorts 1 and 2 were grouped based on dolutegravir exposure in utero. Cohort 1 included 18 neonates (12 were exposed, and 6 were unexposed to dolutegravir in utero) and received 2 single doses of dolutegravir: the first dose was administered within 5 days of birth, and the second dose 7 days later. Cohort 2 included 30 neonates (16 were exposed, and 14 were unexposed to dolutegravir in utero) who received a chronic dolutegravir dosing regimen through 4 to 6 weeks of life. Demographics included 63% female; 54% Black, 33% Asian, 6% White, 4% unknown, and 2% multi-racial. Among the 43 neonates with HIV test results available at Week 16 (End of Study), all were HIV-1 negative. Estimated dolutegravir exposures in neonates were higher compared to older pediatric and adult populations receiving dolutegravir once daily; however, the safety profile was similar [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].

Safety and effectiveness of TIVICAY or TIVICAY PD have not been established in pre-term neonates, pediatric patients weighing less than 2 kg, or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (e.g., raltegravir, elvitegravir).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label for complete information

10/28/2025 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Blood and Lymphatic Systems Sideroblastic anemia.

…

04/18/2024 (SUPPL-4)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Risk Summary

Data from two, ongoing birth outcome surveillance studies in Botswana and Eswatini which together include over 14,000 individuals evaluated during pregnancy show similar prevalence of neural tube defects among infants born to individuals taking dolutegravir at the time of conception compared to those born to individuals taking non-dolutegravir-containing regimens at conception or infants born to HIV negative individuals (see Data).

There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. However, available human data from the APR do not indicate an increased risk of birth defects (see Data). 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 (including neural tube defects) 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:

Observational studies: The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. A subsequent analysis was conducted based on a larger cohort from the birth outcome surveillance study in Botswana and included over 9,460 individuals exposed to dolutegravir at conception, 23,664 individuals exposed to non-dolutegravir-containing regimens and 170,723 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11% (95% CI: 0.05-0.19%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.11%, 95% CI: 0.07-0.16%), or to HIV-negative individuals (0.06%, 95% CI: 0.05-0.08%).

The Eswatini birth outcome surveillance study includes 9,743 individuals exposed to dolutegravir at conception, 1,838 individuals exposed to non-dolutegravir-containing regimens, and 32,259 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08% (95% CI: 0.04-0.16%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%, 95% CI: 0.06-0.56%) or to HIV-negative individuals (0.08%, 95% CI: 0.06-0.12%). The observed prevalence of neural tube defects in infants delivered to individuals taking non-dolutegravir-containing regimens had a wide confidence interval due to low sample size.

Limitations of these birth outcome surveillance studies include insufficient data to determine if baseline characteristics were balanced between the study groups or to assess other factors such as the use of folic acid during the preconception or first trimester periods.

Antiretroviral Pregnancy Registry: Based on prospective reports to the APR, of 1,377 exposures to dolutegravir during pregnancy resulting in live births (including 874 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.2% to 4.7%) following first-trimester exposure to dolutegravir-containing regimens and 5.0% (95% CI: 3.2% to 7.3%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the

U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%.

Dolutegravir has been shown to cross the placenta. In a clinical trial in Uganda and South Africa in women during the last trimester of pregnancy receiving dolutegravir 50 mg once daily, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range 0.51-2.11) (n = 15).

…

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Dolutegravir is present in human milk. It is not known whether dolutegravir affects human milk production or has effects on the breastfed infant.

Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Lactation

Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1– positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before you take TIVICAY or TIVICAY PD, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had liver problems, including hepatitis B or C infection.

• are pregnant or plan to become pregnant. Talk to your healthcare provider about the benefits and risks of treatment with TIVICAY or TIVICAY PD during pregnancy.

  Pregnancy Registry. There is a pregnancy registry for those who take TIVICAY or TIVICAY PD during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.

• are breastfeeding or plan to breastfeed. TIVICAY and TIVICAY PD pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with TIVICAY and TIVICAY PD:

  • the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection.

  • the HIV-1 virus may become harder to treat if your baby has HIV-1 infection.

    your baby may get side effects from TIVICAY.

10/07/2022 (SUPPL-3)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents

Additions and/or revisions underlined:

In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide, dalfampridine, and metformin, Table 8) [see Contraindications (4), Drug Interactions (7.3)].

In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.

In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridyl diphosphate glucuronosyl transferase (UGT)1A1, UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir- containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%.

Dolutegravir has been shown to cross the placenta. In a clinical trial in Uganda and South Africa in women during the last trimester of pregnancy receiving dolutegravir 50 mg once daily, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range 0.51-2.11) (n = 15).

…

8.2 Lactation

Risk Summary

Additions and/or revisions underlined:

The Centers for Disease Control and Prevention recommends that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Dolutegravir is present in human milk. It is not known whether dolutegravir affects human milk production or has effects on the breastfed infant.

03/23/2021 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

An ongoing observational study showed an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform adolescents and adults of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with TIVICAY and TIVICAY PD. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester [see Use in Specific Populations (8.1, 8.3)].

Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential [see Dosage and Administration (2.1)].

Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception [see Use in Specific Populations (8.1, 8.3)].

TIVICAY or TIVICAY PD 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.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TIVICAY or TIVICAY PD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Data from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir is administered at the time of conception. 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.

Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of TIVICAY and TIVICAY PD. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. A benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precautions (5.3)].

There are insufficient human data on the use of dolutegravir 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 7 cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included 3 cases of myelomeningocele, 2 cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had a neural tube defect, compared with 5 infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir- containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.

Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively 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.

Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir- containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%.

Animal Data: Dolutegravir was administered orally at up to 1,000 mg per kg daily to pregnant rats and rabbits on Gestation Days 6 to 17 and 6 to 18, respectively, and to rats on Gestation Day 6 to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the MRHD and in rats were approximately 27 times the exposure in humans at the MRHD. In the rat pre/postnatal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 27 times human exposure at the MRHD).

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

In adolescents and adults of childbearing potential currently on TIVICAY or TIVICAY PD who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TIVICAY or TIVICAY PD and discuss with the patient if an alternative treatment should be considered [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].

Pregnancy Testing

Pregnancy testing is recommended in adolescents and adults of childbearing potential before initiation of TIVICAY or TIVICAY PD [see Dosage and Administration (2.1)].

Contraception

Adolescents and adults of childbearing potential who are taking TIVICAY or TIVICAY PD should be counseled on the consistent use of effective contraception.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Counseling Information

(Additions and/or revisions underlined)

Embryo-Fetal Toxicity

Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, to discuss the risks and benefits of TIVICAY and TIVICAY PD with their healthcare provider to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy. If pregnancy is confirmed in the first trimester, advise patients to contact their healthcare provider [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].

Adolescents and adults of childbearing potential taking TIVICAY or TIVICAY PD should be counseled on the consistent use of effective contraception [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)]

Patient Information

(Additions and/or revisions underlined)

o If you can become pregnant, your healthcare provider may perform a pregnancy test before

you start treatment with TIVICAY or TIVICAY PD.

o If you can become pregnant, you and your healthcare provider should talk about the use of

effective birth control (contraception) during treatment with TIVICAY or TIVICAY PD.