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.

TRIUMEQ PD (NDA-215413)

(ABACAVIR SULFATE; 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-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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Blood and Lymphatic Systems

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

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04/18/2024 (SUPPL-3)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

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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 TRIUMEQ 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 TRIUMEQ 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 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data).

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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 over 1,300 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).

Abacavir: Based on prospective reports to the APR of over 2,800 exposures to abacavir during pregnancy resulting in live births (including 1,455 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir 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 3.2% (95% CI: 2.4% to 4.3%) following first trimester exposure to abacavir-containing regimens and 3.0% (95% CI: 2.2% to 4.1%) following second/third trimester exposure to abacavir-containing regimens.

Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)].

Lamivudine: Based on prospective reports to the APR of over 13,000 exposures to lamivudine during pregnancy resulting in live births (including 5,613 exposed in the first 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 birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%).

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8.2 Lactation

Additions and/or revisions:

Risk Summary

Abacavir, dolutegravir and lamivudine are present in human milk. There is no information on the effects of TRIUMEQ or its components on the breastfed infant or the effects of the drug 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.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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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)].

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MEDICATION GUIDE

Additions and/or revisions underlined:

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

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are pregnant or plan to become pregnant. Talk to your healthcare provider about the benefits and risks of treatment with TRIUMEQ during pregnancy.
Pregnancy Registry. There is a pregnancy registry for those who take TRIUMEQ 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. TRIUMEQ 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 TRIUMEQ:
- 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 TRIUMEQ.
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06/15/2023 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Clinical Trials Experience in Pediatric Subjects

Abacavir, Dolutegravir and Lamivudine: The safety of TRIUMEQ PD and TRIUMEQ in pediatric subjects with HIV-1 infection weighing at least 6 kg was evaluated in the IMPAACT 2019 trial. This was a multicenter, open-label, non-comparative trial of pediatric subjects with HIV-1 infection, younger than 12 years of age. Fifty-seven subjects weighing at least 6 kg to less than 40 kg were enrolled in this trial [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Overall, the safety data in this pediatric study was similar to that seen in adults.

The safety analysis through Week 48 included 57 subjects weighing at least 6 kg at enrollment who received the recommended dose (determined by weight) and formulation. This analysis showed that 26% of subjects experienced clinical adverse reactions. The most common adverse reactions were classified as laboratory abnormalities and included decreased glomerular filtration rate (n = 13, 23%), increased blood creatinine (n = 10, 18%), and increased ALT (n = 3, 5%). All other adverse reactions occurred at a rate of <2% of participants. Two subjects reported Grade 3 or 4 adverse reactions. One subject, an 8-year-old female who weighed 22 kg at baseline, experienced Grade 3 increased blood creatinine and Grade 3 decreased glomerular filtration rate. By Week 48, the glomerular filtration rate was improving, and the events did not lead to drug discontinuation. Another subject, a 7-year-old male who weighed 20 kg at baseline, experienced drug-induced liver injury with Grade 4 increased ALT and AST following 36 weeks of treatment with TRIUMEQ PD. Clinical signs or symptoms of hepatitis were not reported, and ALT and AST values normalized after TRIUMEQ PD was discontinued.

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Dolutegravir: The safety of dolutegravir in pediatric subjects with HIV-1 infection weighing at least 6 kg was evaluated in the IMPAACT P1093 trial [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3)]. Overall, the safety data in this pediatric study was similar to that seen in adults.

IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of pediatric subjects with HIV-1 infection, aged <18 years. One hundred and forty-two subjects weighing at least 6 kg were enrolled in this trial [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

The safety analysis through Week 24 included 60 subjects weighing at least 6 kg at enrollment who received the recommended dose (determined by weight and age) and formulation. This analysis showed that 13% of subjects experienced adverse reactions. Grade 1 to 2 adverse reactions reported by more than one subject was immune reconstitution inflammatory syndrome (n = 2). There were no Grade 3 or 4 adverse reactions reported. No adverse reactions led to discontinuation.

The Grade 3 or 4 laboratory abnormalities reported in more than one subject weighing at least 6 kg at enrollment were decreased neutrophil count (n = 5), decreased blood bicarbonate (n = 3), increased lipase (n = 2), and increased blood potassium (n = 2). These laboratory events were not considered to be drug related. Changes in median serum creatinine were similar to those observed in adults.

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Extensive changes to table 6; please refer to label for complete information

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The clinical data supporting use of TRIUMEQ and TRIUMEQ PD in pediatric patients with HIV-1 infection aged at least 3 months and weighing at least 6 kg is derived from the following previously conducted pediatric trials using TRIUMEQ and TRIUMEQ PD or the individual components:

The safety, pharmacokinetics, and antiviral activity (efficacy) of TRIUMEQ and TRIUMEQ PD were established through an open-label, multicenter clinical trial (IMPAACT 2019), in which HIV-1–infected, treatment-naive or treatment-experienced, pediatric subjects younger than 12 years and weighing at least 6 kg to less than 40 kg were treated with TRIUMEQ or TRIUMEQ PD [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

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The safety and effectiveness of TRIUMEQ PD have not been established in pediatric patients aged less than 3 months or weighing less than 6 kg.

8.6 Patients with Impaired Renal Function

Additions and/or revisions underlined:

TRIUMEQ and TRIUMEQ PD are not recommended for patients with creatinine clearance

<30 mL/min and pediatric patients with a similar degree of renal impairment based on age- appropriate assessment of renal function because TRIUMEQ and TRIUMEQ PD are fixed-dose combinations and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of TRIUMEQ and TRIUMEQ PD, is required for patients with creatinine clearance <30 mL/min and in pediatric patients with a similar degree of renal impairment based on age-appropriate assessment of renal function, then the individual components should be used [see Clinical Pharmacology (12.3)].

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Patients with a sustained creatinine clearance between 30 and 49 mL/min or pediatric patients with a similar degree of renal impairment based on age-appropriate assessment of renal function who receive TRIUMEQ or TRIUMEQ PD should be monitored for hematologic toxicities.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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Inform patients and caregivers that TRIUMEQ PD tablets for oral suspension should be dispersed in drinking water and should not be chewed, cut, crushed or swallowed whole [see Dosage and Administration (2.5)]. Inform patients and caregivers that an appropriate-sized syringe may be used to administer the oral suspension if the patient is unable to use the supplied cup [see Dosage and Administration (2.5)].

MEDICATION GUIDE

Additions and/or revisions underlined:

What is TRIUMEQ and TRIUMEQ PD?

TRIUMEQ and TRIUMEQ PD are prescription medicines used to treat HIV-1 infection in adults and children who are at least 3 months of age and weigh at least 13.2 pounds (6 kg).

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It is not known if TRIUMEQ PD is safe and effective in children who are less than 3 months of age or weigh less than 13.2 pounds (6 kg).

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How should I take TRIUMEQ or TRIUMEQ PD?

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Do not chew, cut, or crush TRIUMEQ tablets or TRIUMEQ PD tablets for oral suspension. Do not swallow TRIUMEQ PD tablets for oral suspension whole.
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If you need to take iron or calcium supplements, or multivitamin supplements that contain iron or
calcium, by mouth during treatment with TRIUMEQ or TRIUMEQ PD:
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10/07/2022 (SUPPL-1)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Data

Additions and/or revisions underlined:

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Based on prospective reports to the APR of over 1,000 exposures to dolutegravir during pregnancy resulting in live births (including 634 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.1% to 5.0%) following first-trimester exposure to dolutegravir-containing regimens and 5.1% (95% CI: 3.2% to 7.7%) 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%.

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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 TRIUMEQ.