Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

DOVATO (NDA-211994)

(DOLUTEGRAVIR SODIUM; LAMIVUDINE)

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

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10/28/2025 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Hemic and Lymphatic

Anemia (including pure red cell aplasia, sideroblastic anemia, and severe anemias progressing on therapy).

…

04/18/2024 (SUPPL-21)

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 DOVATO during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. However, available human data from the APR with the individual components of DOVATO 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 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data). Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the RHD; however, no adverse developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see Data).

Data

Human Data:

Dolutegravir:

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%.

…

Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,600 exposed in the first trimester and over 7,500 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

…

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

PATIENT INFORMATION

Additions and/or revisions underlined:

…

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

…

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

…

04/05/2024 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Clinical Trial Experience in Adolescents

The safety of DOVATO was evaluated in HIV-1 infected treatment-naïve subjects between the ages of 12 to less than 18 years and weighing at least 25 kg (N = 32) through Week 48, in an open label clinical trial, DANCE (Trial 205861). Overall, the observed safety profile in adolescent subjects was similar to those seen in adults [see Use in Specific Populations (8.4), and Clinical Studies (14.4)].

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Dolutegravir and lamivudine are present in human milk. There is no information on the effects of DOVATO or the components of DOVATO on the breastfed infant or the effects of the drugs on milk production.

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.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and efficacy of DOVATO for the treatment of HIV-1 infection have been established in adolescents 12 years of age and older and weighing at least 25 kg. Use of DOVATO for this indication is supported by DANCE trial in treatment-naïve adolescents and evidence from adequate and well-controlled trials in adults, GEMINI-1, GEMINI-2 (treatment-naïve adults) and TANGO (virologically suppressed adults) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies(14)]. Overall, the safety and efficacy data in adolescent subjects from the DANCE trial were comparable to those observed in adults, and there was no clinically significant difference in exposure for the components of DOVATO [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.4)].

The safety and efficacy of DOVATO have not been established in pediatric patients less than 12 years of age or weighing less than 25 kg.

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:

…

What is DOVATO?

DOVATO is a prescription medicine that is used without other HIV-1 medicines to treat HIV-1 infection in adults and adolescents 12 years of age and older who weigh at least 55 pounds (25 kg):

who have not received HIV-1 medicines in the past, or
to replace their current HIV-1 medicines when their healthcare provider determines that they meet certain requirements.
HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).
It is not known if DOVATO is safe and effective in children less than 12 years of age or weighing less than 55 pounds (25 kg).
…
Before you take DOVATO, tell your healthcare provider about all of your medical conditions, including if you:
…

are breastfeeding or plan to breastfeed. DOVATO passes to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with DOVATO:
- 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 DOVATO.
  …

04/05/2024 (SUPPL-19)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

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

PATIENT INFORMATION

Additions and/or revisions underlined:

…

What is DOVATO?

DOVATO is a prescription medicine that is used without other HIV-1 medicines to treat HIV-1 infection in adults and adolescents 12 years of age and older who weigh at least 55 pounds (25 kg):

who have not received HIV-1 medicines in the past, or
to replace their current HIV-1 medicines when their healthcare provider determines that they meet certain requirements.
HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).
It is not known if DOVATO is safe and effective in children less than 12 years of age or weighing less than 55 pounds (25 kg).
…
Before you take DOVATO, tell your healthcare provider about all of your medical conditions, including if you:
…

are breastfeeding or plan to breastfeed. DOVATO passes to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with DOVATO:
- 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 DOVATO.
  …

01/25/2023 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

The safety of DOVATO in virologically suppressed adults was based on Week 144 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 148 weeks; at Week 148, the subjects randomized to continue with their TBR were switched to DOVATO once daily. All subjects are followed up to Week 200. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials [see Clinical Studies (14.3)]. Adverse reactions observed in at least 2% of subjects in the TANGO trial who were treated with DOVATO were weight increased (3%) and insomnia (2%).

…

10/07/2022 (SUPPL-15)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Musculoskeletal

Arthralgia, creatinine phosphokinase elevation, muscle weakness, myalgia, rhabdomyolysis.

8 Use in Specific Populations

8.1 Pregnancy

Data

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.

Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving DOVATO.

01/20/2022 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

Clinical Trials in Virologically Suppressed Adults

The safety of DOVATO in virologically suppressed adults was based on Week 96 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials [see Clinical Studies (14.3)].

…

01/20/2022 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

Clinical Trials in Adults with No Antiretroviral Treatment History

The safety assessment of DOVATO in HIV-1–infected adults with no antiretroviral treatment history and with a plasma viral load less than or equal to 500,000 HIV-1 RNA copies/mL at the screening visit, is based on the pooled Week 144 analyses of data from 2 identical, multicenter, double-blind, controlled trials, GEMINI-1 and GEMINI-2.

…

The rates of adverse events leading to discontinuation in the pooled analysis were 4% of subjects who received TIVICAY plus EPIVIR and 5% in subjects who received TIVICAY plus TRUVADA. The most common adverse events leading to discontinuation were psychiatric disorders: 2% of subjects who received TIVICAY plus EPIVIR and 1% in subjects who received TIVICAY plus TRUVADA.

Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm of the Week 144 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 2.

The adverse reactions observed for TIVICAY plus EPIVIR in the Week 144 analysis of the pooled data from GEMINI-1 and GEMINI-2 were generally consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents.

Table 2. Adverse Reactions (All Grades) Reported in greater than or equal to 2% of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 (Week 144 Pooled Analysis)

Please refer to label to view Table 2

Adverse reactions of at least Grade 2 occurring in greater than or equal to1% of subjects treated with TIVICAY plus EPIVIR were headache, anxiety, suicidal ideation, and insomnia (all at 1%).

Less Common Adverse Reactions: The following adverse reactions (all grades) occurred in <2% of subjects receiving dolutegravir plus lamivudine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine). Some events have been included because of their seriousness and assessment of potential causal relationship.

…

Table 3. Selected Laboratory Abnormalities (Grades 2 to 4; Week 144 Pooled Analyses) in GEMINI-1 and GEMINI-2 Trials

Please refer to label to view Table 3

Table 4. Mean Change from Baseline in Fasted Lipid Values (Week 144 Pooled Analysesa) in GEMINI-1 and GEMINI-2 Trials

Please refer to label to view Table 4

…A total of 51 and 28 subjects receiving TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively, initiated lipid-lowering agents post- baseline.

Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first 4 weeks of treatment in both arms and remained stable through 144 weeks. A mean change from baseline of 0.144 mg/dL and 0.176 mg/dL was observed after 144 weeks of treatment with TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively. These changes are not considered to be clinically relevant.

03/23/2021 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 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 individuals of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with DOVATO. Assess the risks and benefits of DOVATO 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 DOVATO in individuals of childbearing potential [see Dosage and Administration (2.1)].

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

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 DOVATO 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 have identified an increased risk of neural tube defects when dolutegravir, a component of DOVATO, 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 individuals of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of DOVATO. Assess the risks and benefits of DOVATO 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 Precaution (5.4)].

There are insufficient human data on the use of DOVATO 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 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data). Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the RHD; however, no adverse developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see Data).

Data

Human Data: Dolutegravir: 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.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

In individuals of childbearing potential currently on DOVATO who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing DOVATO and discuss with the patient if an alternative treatment should be considered [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

Pregnancy Testing

Pregnancy testing is recommended in individuals of childbearing potential before initiation of DOVATO [see Dosage and Administration (2.1)].

Contraception

Individuals of childbearing potential who are taking DOVATO 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)

Advise individuals of childbearing potential, including those actively trying to become pregnant, to discuss the risks and benefits of DOVATO 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 Precaution (5.4), Use in Specific Populations (8.1, 8.3)].

Individuals of childbearing potential taking DOVATO should be counseled on the consistent use of effective contraception [see Warnings and Precautions (5.4), 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 DOVATO.

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

birth control (contraception) during treatment with DOVATO.

03/01/2021 (SUPPL-10)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Data

Additions and/or revisions underlined:

Based on prospective reports to the APR of exposures to dolutegravir during pregnancy resulting in live births (including over 450 exposed in the first trimester and over 280 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for dolutegravir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The prevalence of defects in live births was 3.5% (95% CI: 2.0% to 5.6%) following first trimester exposure to dolutegravir-containing regimens and 4.2% (95% CI: 2.2% to 7.2%) following second/third trimester exposure to dolutegravir-containing regimens.

Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

8.6 Renal Impairment

Additions and/or revisions underlined:

DOVATO is not recommended for patients with creatinine clearance <30 mL/min because DOVATO is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of DOVATO, is required for patients with creatinine clearance <30 mL/min, then the individual components should be used.

Patients with a creatinine clearance between 30 and 49 mL/min receiving DOVATO may experience a 1.6- to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance greater than or equal to50 mL/min. There are no safety data from randomized, controlled trials comparing DOVATO to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects. Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive DOVATO should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, DOVATO should be discontinued and the individual components should be used to construct the treatment regimen.

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

PATIENT INFORMATION

Do not take DOVATO if you:

have ever had an allergic reaction to a medicine that contains dolutegravir or lamivudine. See the end of this Patient Information for a complete list of ingredients in DOVATO.
take dofetilide. Taking DOVATO and dofetilide can cause side effects that may be serious or life- threatening.

08/06/2020 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Clinical Trials in Adults with No Antiretroviral Treatment History

The safety assessment of DOVATO in HIV-1–infected adults with no antiretroviral treatment history and with a plasma viral load greater than or equal to 500,000 HIV-1 RNA copies/mL at the screening visit, is based on the pooled primary Week 96 analyses of data from 2 identical, multicenter, double- blind, controlled trials, GEMINI-1 and GEMINI-2. A total of 1,433 HIV-1–infected adults with no antiretroviral treatment history received either dolutegravir (TIVICAY) 50 mg plus lamivudine (EPIVIR) 300 mg, as a complete regimen once daily, or TIVICAY 50 mg plus fixed- dose combination tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (TRUVADA), administered once daily.

The rates of adverse events leading to discontinuation in the pooled analysis were 3% of subjects in both treatment arms. The most common adverse events leading to discontinuation were psychiatric disorders: 1% of subjects in both treatment arms.

Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm of the Week 96 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 2.

The adverse reactions observed for TIVICAY plus EPIVIR in the Week 96 analysis of the pooled data from GEMINI-1 and GEMINI-2 were generally consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents. Adverse reactions of at least Grade 2 occurring in greater than or equal to 1% of subjects treated with TIVICAY plus EPIVIR were headache, anxiety, and suicidal ideation (all at 1%).

Clinical Trials in Virologically Suppressed Adults

The safety of DOVATO in virologically suppressed adults was based on Week 48 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials [see Clinical Studies (14.3)].

Laboratory Abnormalities

The last available fasted, on-treatment lipid value prior to initiation of a lipid-lowering agent was carried forward in place of observed values after initiation of a lipid-lowering agent. A total of 40 and 16 subjects receiving TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively, initiated lipid-lowering agents post- baseline.

Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first 4 weeks of treatment in both arms and remained stable through 96 weeks. A mean change from baseline of 0.138 mg/dL and 0.176 mg/dL was observed after 96 weeks of treatment with TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively. These changes are not considered to be clinically relevant.

7 Drug Interactions

7.2 Potential for DOVATO to Affect Other Drugs

(Additions and/or revisions underlined)

Dolutegravir, a component of DOVATO, inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1; thus, it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin [see Contraindications (4), Drug Interactions (7.4), Clinical Pharmacology (12.3)].

08/06/2020 (SUPPL-7)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Clinical Trials in Adults with No Antiretroviral Treatment History

Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm of the Week 96 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 2.

Clinical Trials in Virologically Suppressed Adults

Laboratory Abnormalities

Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first 4 weeks of treatment in both arms and remained stable through 96 weeks. A mean change from baseline of 0.138 mg/dL and 0.176 mg/dL was observed after 96 weeks of treatment with TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively. These changes are not considered to be clinically relevant.

7 Drug Interactions

7.2 Potential for DOVATO to Affect Other Drugs

(Additions and/or revisions underlined)

03/24/2020 (SUPPL-4)

Approved Drug Label (PDF)

7 Drug Interactions

7.2 Potential for DOVATO to Affect Other Drugs

(addition underlined)

Dolutegravir, a component of DOVATO, inhibits the renal OCT2 and multidrug and toxin extrusion transporter (MATE)1; thus, it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin.

7.4 Established and Other Potentially Significant Drug Interactions

(addition of potassium channel blocker to Table 5, please refer to label for complete information)

10/24/2019 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Embryo-Fetal Toxicity

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An observational study showed an association between dolutegravir, a component of DOVATO, 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 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 DOVATO should be considered at the time of conception through the first trimester of pregnancy.

Perform pregnancy testing before initiation of DOVATO in individuals of childbearing potential to exclude use of DOVATO during the first trimester of pregnancy. Initiation of DOVATO is not recommended in individuals actively trying to become pregnant unless there is no suitable alternative.

Counsel individuals of childbearing potential to consistently use effective contraception.

DOVATO 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

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Pregnancy Exposure Registry

Risk Summary

Data from a birth outcome surveillance study have identified an increased risk of neural tube defects when dolutegravir, a component of DOVATO, 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) that 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 DOVATO should be considered at the time of conception through the first trimester of pregnancy. Initiation of DOVATO is not recommended in individuals actively trying to become pregnant unless there is no suitable alternative.

In individuals of childbearing potential currently on DOVATO who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing DOVATO versus switching to another antiretroviral regimen and consider switching to an alternative regimen. Advise pregnant individuals of the potential risk to the embryo exposed to DOVATO 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.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and 50 times (rats) the exposure in humans at the recommended human dose (RHD). Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the RHD; however, no adverse developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD.

Data

Human Data: Dolutegravir: 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.

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8.3 Females and Males of Reproductive Potential

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Pregnancy Testing

Perform pregnancy testing in individuals of childbearing potential before initiation of DOVATO.

Contraception

Counsel individuals of childbearing potential who are taking DOVATO to consistently use effective contraception.

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

PATIENT INFORMATION

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Before you take DOVATO, 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.
have kidney problems.
are pregnant or plan to become pregnant. One of the medicines in DOVATO (dolutegravir) may harm your unborn baby.
- Your healthcare provider may prescribe a different medicine than DOVATO if you are planning to become pregnant or if pregnancy is confirmed in the first 12 weeks of pregnancy.
- If you can become pregnant, your healthcare provider will perform a pregnancy test before you start treatment with DOVATO.
- If you can become pregnant, you should consistently use effective birth control (contraception) during treatment with DOVATO.
- Tell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with DOVATO.

Pregnancy Registry. There is a pregnancy registry for people who take antiretroviral medicines, including DOVATO, 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. Do not breastfeed if you take DOVATO.

You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
One of the medicines in DOVATO (lamivudine) passes into your breast milk.
Talk with your healthcare provider about the best way to feed your baby.

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