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.

TIVICAY (NDA-204790)

(DOLUTEGRAVIR SODIUM)

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

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10/28/2025 (SUPPL-33)

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-31)

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-30)

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%.

…

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.

07/09/2021 (SUPPL-28)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Virologically Suppressed Subjects: The adverse reactions observed for TIVICAY plus rilpivirine in the Week 48 analysis of pooled data from 2 identical, international, multicenter, open-label trials (SWORD-1 and SWORD-2) of 513 HIV-1–infected, virologically suppressed subjects switching from their current antiretroviral regimen to TIVICAY plus rilpivirine, were consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents. There were no adverse reactions (Grades 2 to 4) with an incidence of at least 2% in either treatment arm at Week 48. The safety profile during the additional follow-up period through Week 148 were consistent with Week 48. The rate of adverse events leading to discontinuation through Week 48 was 4% in subjects receiving TIVICAY plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. In the pooled analyses, the proportion of subjects receiving TIVICAY plus rilpivirine who discontinued treatment due to an adverse event through Week 148 was 8%.

03/23/2021 (SUPPL-29)

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.

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.

06/12/2020 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

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 dolutegravir in adolescents and adults of childbearing potential to exclude use of dolutegravir during the first trimester of pregnancy. Initiation of dolutegravir 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.

Dolutegravir 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.

5.6 Different Formulations Are Not Interchangeable

(Newly added subsection)

TIVICAY and TIVICAY PD are not bioequivalent and are not interchangeable on a milligram- per-milligram basis. If a pediatric patient switches from one formulation to the other, the dose must be adjusted for the new dosage formulation. Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure of dolutegravir.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Clinical Trials Experience in Pediatric Subjects

The safety and pharmacokinetics of TIVICAY and TIVICAY PD in HIV-1–infected pediatric subjects 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. 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.

IMPAACT P1093 is an ongoing, multicenter, open-label, non-comparative trial of HIV-1– infected pediatric subjects aged 4 weeks to less than 18 years .

The safety analysis based on subjects (n = 75) who received the recommended dose (determined by weight and age) through Week 24 showed that 11% of subjects experienced drug-related clinical adverse reactions. The only Grade 1 to 2 drug-related clinical adverse reactions reported by more than one subject was immune reconstitution inflammatory syndrome (IRIS) (n = 2).

There were no Grade 3 or 4 drug-related adverse reactions reported. No adverse reactions led to discontinuation.

The Grade 3 or 4 laboratory abnormalities reported in more than one subject were decreased neutrophil count (n = 11), decreased blood bicarbonate (n = 4), decreased hemoglobin (n = 3), increased lipase (n = 2), and increased blood potassium (n = 2). These laboratory events were not considered to be drug-related. Median laboratory values were similar at baseline and Week 24.

Changes in median serum creatinine were similar to those observed in adults.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

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 dolutegravir should be considered at the time of conception through the first trimester of pregnancy. Initiation of dolutegravir is not recommended in adolescents and adults actively trying to become pregnant unless there is no suitable alternative.

In adolescents and adults of childbearing potential currently on dolutegravir who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing dolutegravir 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 dolutegravir 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 dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. The background risk for major

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

It is not known whether dolutegravir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, dolutegravir was present in milk.

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 dolutegravir.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Pregnancy Testing

Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of dolutegravir.

Contraception

Counsel adolescents and adults of childbearing potential who are taking dolutegravir to consistently use effective contraception.

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety, pharmacokinetics, and effectiveness of TIVICAY and TIVICAY PD were evaluated in 75 HIV-1–infected, treatment-naïve or treatment-experienced, INSTI-naïve pediatric and adolescent subjects aged 4 weeks to less than 18 years weighing at least 3 kg in an ongoing, open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Additional pharmacokinetics data were evaluated in 2 pharmacokinetic substudies in ODYSSEY, an ongoing open-label, randomized, non-inferiority trial to evaluate the safety, efficacy, and pharmacokinetic parameters of TIVICAY or TIVICAY PD plus two NRTIs compared with standard of care in HIV-1– infected pediatric subjects younger than 18 years.

Overall, the safety data in pediatric subjects from the IMPAACT P1093 trial were comparable to those observed in adults. The pharmacokinetic parameters of TIVICAY or TIVICAY PD in pediatric subjects from IMPAACT P1093 and ODYSSEY were comparable to those of adults receiving 50 mg once daily or twice daily. The effectiveness observed in IMPAACT P1093 is comparable to that of treatment-experienced adult subjects.

Safety and effectiveness of TIVICAY or TIVICAY PD have not been established in pediatric patients aged less than 4 weeks or weighing less than 3 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)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Different Formulations Are Not Bioequivalent

Advise patients that TIVICAY and TIVICAY PD are not bioequivalent and are not interchangeable on a milligram-per-milligram basis. Advise patients or their care provider that patients switching from one formulation to the other must adjust the dose for the new dosage formulation.

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to TIVICAY or TIVICAY PD during pregnancy.

Lactation

Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

Administration Instructions

To avoid a dosing error from using the wrong formulation of dolutegravir, strongly advise patients and caregivers to visually inspect the tablets to verify the correct formulation each time the prescription is filled.

Inform patients and caregivers that TIVICAY PD tablets for oral suspension may be swallowed whole or dispersed in drinking water and should not be chewed, cut or crushed. The amount of water needed to disperse the tablet will depend on the dose (number of tablets prescribed).

Instruct patients and caregivers that if a dose of TIVICAY or TIVICAY PD is missed, to take it as soon as they remember. Advise patients and caregivers not to double the next dose or take more than the prescribed dose.

Storage

Instruct patients and caregivers to store the TIVICAY 10-mg tablets and TIVICAY PD 5-mg tablets for oral suspension in the original package, keep the bottle tightly closed, and protect from moisture. Do not remove desiccant.

Other

("Tivicay PD" added throughout labeling with Tivicay to read as “TIVICAY or TIVICAY PD”)

(“AR” replaced by “adverse reaction” throughout labeling)

03/24/2020 (SUPPL-23)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents

(addition underlined)

7.3 Established and Other Potentially Significant Drug Interactions

(additions and revisions to Table 6, please refer to label for complete information)

8 Use in Specific Populations

8.7 Renal Impairment

(subsection revised, revision underlined)

… There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis.

10/24/2019 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Embryo-Fetal Toxicity

(additions and/or revisions are underlined)

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. 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.

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.

8 Use in Specific Populations

8.1 Pregnancy

(additions and/or revisions are underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TIVICAY 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 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.

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.

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.

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/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (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/post-natal 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 are underlined)

Pregnancy Testing

Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of TIVICAY.

Contraception

Counsel adolescents and adults of childbearing potential who are taking TIVICAY to consistently use effective contraception.

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

PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Drug Interactions

TIVICAY may interact with other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort.

Hypersensitivity Reactions

Advise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking TIVICAY and other suspect agents, and seek medical attention if they develop a rash associated with any of the following symptoms, as it may be a sign of a more serious reaction such as severe hypersensitivity: fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters or peeling of the skin; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; breathing difficulty; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes, dark or tea-colored urine, pale-colored stools or bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on the right side below the ribs).

Hepatotoxicity

Inform patients that hepatotoxicity has been reported with dolutegravir. Advise patients that laboratory monitoring for hepatoxicity during therapy with TIVICAY is recommended, especially for patients with liver disease, such as hepatitis B or C.

Embryo-Fetal Toxicity

Advise adolescents and adults of childbearing potential to consider an alternative treatment to TIVICAY at the time of conception through the first trimester of pregnancy. Advise adolescents and adults of childbearing potential to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with TIVICAY.

Counsel adolescents and adults of childbearing potential taking TIVICAY to consistently use effective contraception.

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any signs or symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TIVICAY is started.

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to TIVICAY during pregnancy.

Lactation

Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

Missed Dosage

Instruct patients that if they miss a dose of TIVICAY, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.

Storage

Instruct patients to store the TIVICAY 10-mg tablets in the original package, keep the bottle tightly closed, and protect from moisture. Do not remove desiccant.

PATIENT INFORMATION

(additions and/or revisions are underlined)

…

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

have ever had an allergic reaction to dolutegravir.
have or have had liver problems, including hepatitis B or C infection.
are pregnant or plan to become pregnant. TIVICAY may harm your unborn baby.

Your healthcare provider may prescribe a different medicine than TIVICAY if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.
If you can become pregnant, your healthcare provider will perform a pregnancy test before you start treatment with TIVICAY.
If you can become pregnant, you should consistently use effective birth control (contraception) during treatment with TIVICAY.
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 TIVICAY.

Pregnancy Registry. There is a pregnancy registry for individuals who take antiretroviral medicines, including TIVICAY, 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 TIVICAY.

You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.

It is not known if TIVICAY can pass to your baby in your breast milk. Talk with your healthcare provider about the best way to feed your baby.

…

09/06/2018 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are bolded)

…

Hepatobiliary Disorders

Acute liver failure, hepatotoxicity.

Investigations

Weight increased.

Musculoskeletal

Arthralgia, myalgia.

…

09/06/2018 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Embryo-Fetal Toxicity

(Newly added subsection)

Preliminary data from an observational study showed that TIVICAY was associated with increased risk of neural tube defects when 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, avoid use of TIVICAY at the time of conception through the first trimester of pregnancy.

If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on TIVICAY, if possible, switch to an alternative regimen.

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.

Advise adolescents and adults of childbearing potential to consistently use effective contraception.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Pregnancy Exposure Registry

Risk Summary

Preliminary data from an observational study has identified a possible 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 4 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, avoid use of TIVICAY at the time of conception through the first trimester of pregnancy. No neural tube defects have been reported in infants born to mothers who have started TIVICAY after the first trimester of pregnancy.

If there are plans to become pregnant or if pregnancy is confirmed while on TIVICAY during the first trimester, if possible, switch 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.

Data

Human Data: As of May 2018, in an ongoing birth outcome surveillance study in Botswana, there have been 4 cases of neural tube defects reported out of 426 births (0.94%) to mothers who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.12% (14/11,300) in the non-dolutegravir arm and 0.09% (61/66,057) in the HIV-uninfected arm. Four cases reported with dolutegravir included one case each of encephalocele, anencephaly, myelomeningocele, and iniencephaly. No infant born to a woman who started dolutegravir during pregnancy had a neural tube defect (n = 2,812).

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.

…

8.2 Lactation

(Additions and/or revisions are underlined)

…

Data

Animal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg per kg on lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours postdose.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Pregnancy Testing

Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of TIVICAY.

Contraception

Adolescents and adults of childbearing potential should avoid use of TIVICAY at the time of conception through the first trimester of pregnancy because of the potential risk of neural tube defects.

Advise adolescents and adults of childbearing potential who are taking TIVICAY to consistently use effective contraception.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

…

Embryo-Fetal Toxicity

Advise adolescents and adults of childbearing potential to avoid use of TIVICAY at the time of conception through the first trimester of pregnancy. Advise adolescents and adults of childbearing potential to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with TIVICAY.

Advise adolescents and adults of childbearing potential taking TIVICAY to consistently use effective contraception.

…

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to TIVICAY during pregnancy.

PATIENT INFORMATION TIVICAY

(Additions and/or revisions are underlined)

…

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

have ever had an allergic reaction to dolutegravir.
have or have had liver problems, including hepatitis B or C infection.

are pregnant or plan to become pregnant. TIVICAY may harm your unborn baby.

You should not take TIVICAY at the time of becoming pregnant or during the first 12 weeks of pregnancy. Your healthcare provider may change your medicine during this time in your pregnancy.
If you can become pregnant, your healthcare provider will perform a pregnancy test before you start treatment with TIVICAY.
If you can become pregnant, you should consistently use effective birth control (contraception) during treatment with TIVICAY.

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 TIVICAY.

Pregnancy Registry.

medicines

with

…

11/21/2017 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hepatotoxicity

(Newly titled subsection; additions and/or revisions are underlined)

Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

5.3 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

(Newly added subsection)

The concomitant use of TIVICAY and other drugs may result in known or potentially significant drug interactions, some of which may lead to:

Loss of therapeutic effect of TIVICAY and possible development of resistance.
Possible clinically significant adverse reactions from greater exposures of concomitant drugs.

For concomitant drugs for which the interaction can be mitigated, please see Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TIVICAY; review concomitant medications during therapy with TIVICAY; and monitor for the adverse reactions associated with the concomitant drugs.

6 Adverse Reactions

(Additions and/or revisions are underlined)

Hepatotoxicity.

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Clinical Trials Experience in Adult Subjects

…In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, …

Virologically Suppressed Subjects: The ARs observed for TIVICAY plus rilpivirine in the Week 48 analysis of pooled data from two identical, international, multicenter, open-label trials (SWORD-1 and SWORD-2) of 513 HIV–1-infected, virologically suppressed subjects switching from their current antiretroviral regimen to dolutegravir plus rilpivirine, were consistent with the AR profiles and severities for the individual components when administered with other antiretroviral agents. There were no ARs (Grades 2 to 4) with an incidence of at least 2% in either treatment arm. The rates of adverse events leading to discontinuation were 4% in subjects receiving TIVICAY plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen.

Virologically Suppressed Adults: Laboratory abnormalities observed in SWORD-1 and SWORD-2 were generally similar compared with observations seen in the other Phase 3 trials.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Hepatobiliary Disorders

Acute liver failure, hepatotoxicity.

Musculoskeletal

Arthralgia, myalgia.

Psychiatric

Anxiety

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(Additions and/or revisions are underlined)

Table 6 provides clinical recommendations as a result of drug interactions with TIVICAY. 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.

7.4 Drugs without Clinically Significant Interactions with Dolutegravir

(Newly added subsection)

Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, daclatasvir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

… The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Drug Interactions

Hepatotoxicity

PATIENT INFORMATION TIVICAY (TIV-eh-kay) (dolutegravir) tablets

(Additions and/or revisions are underlined)

How should I take TIVICAY?

· Take TIVICAY exactly as your healthcare provider tells you to take it.

· Take TIVICAY with or without food.

· Do not change your dose or stop taking TIVICAY without talking with your healthcare provider.

· If you take antacids, laxatives, or other medicines that contain aluminum, magnesium, or buffered medicines, TIVICAY should be taken at least 2 hours before or 6 hours after you take these medicines.

· If you need to take iron or calcium supplements by mouth during treatment with TIVICAY:

o If you take TIVICAY with food, you may take these supplements at the same time that you take TIVICAY.

o If you do not take TIVICAY with food, take TIVICAY at least 2 hours before or 6 hours after you take these supplements.

· Do not miss a dose of TIVICAY.

· If you miss a dose of TIVICAY, take it as soon as you remember. Do not take 2 doses at the same time or take more than your prescribed dose.

· Stay under the care of a healthcare provider during treatment with TIVICAY.

· Do not run out of TIVICAY. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.

· If you take too much TIVICAY, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of TIVICAY?

· Allergic reactions. Call your healthcare provider right away if you develop a rash with TIVICAY. Stop taking TIVICAY and get medical help right away if you develop a rash with any of the following signs or symptoms…

· Liver problems. People with a history of hepatitis B or C virus may have an increased risk of developing new or worsening changes in certain liver tests during treatment with TIVICAY. Liver problems, including liver failure, have also happened in people without a history of liver disease or other risk factors. Your healthcare provider may do blood tests to check your liver. Call your healthcare provider right away if you develop any of the following signs or symptoms of liver problems:

your skin or the white part of your eyes turns yellow (jaundice)
dark or “tea-colored” urine
light-colored stools (bowel movements)
nausea or vomiting

03/27/2017 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added subsection:

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal

Arthralgia, myalgia

06/09/2016 (SUPPL-8)

Approved Drug Label (PDF)

8 Use in Specific Populations

Pediatric Patients

The safety, virologic, and immunologic responses in subjects who received TIVICAY were evaluated in 46 treatment-experienced, INSTI-naïve, HIV-1–infected subjects aged 6 to less than 18 years in an open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Frequency, type, and severity of adverse drug reactions among the 46 pediatric subjects were comparable to those observed in adults. In 17 subjects weighing at least 30 kg, pharmacokinetic parameters of dolutegravir were comparable to adults receiving 50 mg once daily.
Safety and efficacy of TIVICAY have not been established in pediatric patients weighing less than 30 kg or in any pediatric patients who are INSTI-experienced.

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

PCI - Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

PCI - Missed Dosage

Instruct patients that if they miss a dose of TIVICAY, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.

PCI - Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TIVICAY during pregnancy.

PCI - Storage

Instruct patients to store the TIVICAY 10-mg tablets in the original package, keep the bottle tightly closed, and protect from moisture. Do not remove desiccant.

PI - Extensive changes to this section; please refer to label.

04/22/2016 (SUPPL-7)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

Week 144 safety and efficacy data from Phase III study ING114467 (SINGLE) in antiretroviral therapy (ART)-naïve subjects.
Week 96 safety and efficacy data from Phase III study ING114915 (FLAMINGO) in ART-naïve subjects.

7 Drug Interactions

Effect of Dolutegravir on the Pharmacokinetics of Other Agents

…daclatasvir…