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.

JULUCA (NDA-210192)

(DOLUTEGRAVIR SODIUM; RILPIVIRINE HYDROCHLORIDE)

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

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10/28/2025 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

…

Blood and Lymphatic Systems Sideroblastic anemia.

…

04/18/2024 (SUPPL-14)

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 JULUCA 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 JULUCA 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 the components of JULUCA at systemic exposures (AUC) to dolutegravir less than (rabbits) and 38 times (rats) and exposures to rilpivirine 15 (rats) and 70 (rabbits) times the exposure at the recommended human dose (RHD) of JULUCA (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%.

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 to 2.11) (n = 15).

Rilpivirine: Based on prospective reports to the APR of over 870 exposures to rilpivirine- containing regimens during pregnancy resulting in live births (including over 660 exposed during the first trimester and over 210 exposed in the second/third trimester), there was no significant difference between the overall risk of birth defects for rilpivirine 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 2.1% (95% CI: 1.1% to 3.5%) and 0.9% (95% CI: 0.1% to 3.4%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens.

Rilpivirine in combination with a background regimen was evaluated in a clinical trial of

19 HIV-1–infected pregnant subjects during the second and third trimesters and postpartum. Each of the subjects were on a rilpivirine-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6 to 12 weeks after delivery) and pregnancy outcomes are missing for 6 subjects.…

8.2 Lactation

Additions and/or revisions underlined:

Dolutegravir is present in human milk. It is not known whether dolutegravir affects human milk production or have effects on the breastfed infant. When administered to lactating rats, rilpivirine was present in milk (see Data).

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.

Data

Animal Data: Rilpivirine: In animals, no studies have been conducted to assess the excretion of rilpivirine into milk directly; however, rilpivirine was present in plasma of rat pups exposed through the milk of lactating rats (dosed up to 400 mg/kg/day).

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 JULUCA, 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 JULUCA during pregnancy.
Pregnancy Registry. There is a pregnancy registry for those who take JULUCA 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. One of the medicines in JULUCA 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 JULUCA:
- 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 JULUCA.
…

10/07/2022 (SUPPL-13)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Potential for Other Drugs to Affect the Components of JULUCA

Dolutegravir

Additions and/or revisions underlined:

Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from cytochrome P450 (CYP)3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir [see Drug Interactions (7.4)].

Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.

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%.

…

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 JULUCA or components of JULUCA affect human milk production or have effects on the breastfed infant. When administered to lactating rats, rilpivirine was present in milk (see Data).

07/09/2021 (SUPPL-11)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes with data from SWORD-1, SWORD-2, and DEXA substudy; please refer to label)

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

Patient Information

(Additions and/or revisions underlined)

• The most common side effects of JULUCA include:

o diarrhea o headache

o nausea

03/23/2021 (SUPPL-12)

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 individuals of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with JULUCA. Assess the risks and benefits of JULUCA 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 JULUCA 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)].

JULUCA 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

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to JULUCA 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, a component of JULUCA, 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 JULUCA. Assess the risks and benefits of JULUCA 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 (5.3)].

There are insufficient human data on the use of JULUCA 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 the components of JULUCA at systemic exposures (AUC) to dolutegravir less than (rabbits) and 38 times (rats) and exposures to rilpivirine 15 (rats) and 70 (rabbits) times the exposure at the recommended human dose (RHD) of JULUCA (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.

Rilpivirine: Based on prospective reports to the APR of over 610 exposures to rilpivirine- containing regimens during pregnancy resulting in live births (including over 420 exposed during the first trimester and over 190 exposed in the second/third trimester), there was no significant difference between the overall risk of birth defects for rilpivirine 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 1.4% (95% CI: 0.5% to 3.0%) and 1.6% (95% CI: 0.3% to 4.5%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens.

8.3 Females and Males of Reproductive Potential

In individuals of childbearing potential currently on JULUCA who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing JULUCA 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 individuals of childbearing potential before initiation of JULUCA [see Dosage and Administration (2.1)].

Contraception

Individuals of childbearing potential who are taking JULUCA 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 JULUCA 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 (5.3), Use in Specific Populations (8.1, 8.3)].

Individuals of childbearing potential taking JULUCA 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 JULUCA.

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

birth control (contraception) during treatment with JULUCA.

07/14/2020 (SUPPL-7)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

JULUCA is contraindicated in patients:

with previous hypersensitivity reaction to dolutegravir or rilpivirine.
receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events.
receiving other coadministered drugs in Table 1 that significantly decrease rilpivirine plasma concentrations.

7 Drug Interactions

7.2 Potential for JULUCA to Affect Other Drugs

(Additions and/or revisions underlined)

Dolutegravir, a component of JULUCA, 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.

8 Use in Specific Populations

8.1 Pregnancy

(Extensive changes; please refer to label)

10/24/2019 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Embryo-Fetal Toxicity

(additions and/or revisions are underlined)

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

Perform pregnancy testing before initiation of JULUCA in individuals of childbearing potential to exclude use of JULUCA during the first trimester of pregnancy. Initiation of JULUCA 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.

JULUCA 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

Risk Summary

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

In individuals of childbearing potential currently on JULUCA who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing JULUCA 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 JULUCA 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.

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.

…

8.3 Females and Males of Reproductive Potential

(additions and/or revisions are underlined)

Pregnancy Testing

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

Contraception

Counsel individuals of childbearing potential who are taking JULUCA 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).

Severe Skin and Hypersensitivity Reactions

Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking JULUCA 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 DRESS 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). Advise patients that if hypersensitivity occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated.

Hepatotoxicity

Inform patients that hepatotoxicity has been reported with rilpivirine and dolutegravir, components of JULUCA. Inform patients that monitoring for hepatotoxicity is recommended.

Embryo-Fetal Toxicity

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

Counsel individuals of childbearing potential taking JULUCA to consistently use effective contraception.

Depressive Disorders

Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with the components of JULUCA. Advise patients to seek immediate medical evaluation if they experience depressive symptoms.

Drug Interactions

JULUCA may interact with many 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.

Administration Instruction

Inform patients that it is important to take JULUCA once daily on a regular dosing schedule with a meal and to avoid missing doses as it can result in development of resistance. Instruct patients that if they miss a dose of JULUCA, to take it as soon as they remember with a meal. Advise patients not to double their next dose. Advise the patient a protein drink alone does not replace a meal.

Pregnancy Registry

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

Storage

Instruct patients to store JULUCA in the original bottle to protect from moisture and keep the bottle tightly closed. Do not remove desiccant.

PATIENT INFORMATION

(additions and/or revisions are underlined)

…

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

have ever had a severe skin rash or an allergic reaction to medicines that contain dolutegravir or rilpivirine.
have or have had liver problems, including hepatitis B or C infection.
have ever had a mental health problem.
are pregnant or plan to become pregnant. One of the medicines in JULUCA called dolutegravir may harm your unborn baby.

Your healthcare provider may prescribe a different medicine than JULUCA 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 JULUCA.
If you can become pregnant, you should consistently use effective birth control (contraception) during treatment with JULUCA.

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 JULUCA.

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

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 JULUCA 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-2)

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 Disorders

Arthralgia, myalgia.

…

09/06/2018 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Embryo-Fetal Toxicity

(Newly added subsection)

Preliminary data from an observational study showed that dolutegravir, a component of JULUCA, 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 JULUCA 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 JULUCA, if possible, switch to an alternative regimen.

Perform pregnancy testing before initiation of JULUCA in adolescents and adults of childbearing potential to exclude use of JULUCA 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 dolutegravir, a component of JULUCA, 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 JULUCA 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 dolutegravir after the first trimester of pregnancy.

If there are plans to become pregnant or if pregnancy is confirmed while on JULUCA 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 JULUCA from the time of conception through the first trimester of pregnancy.

Data

Human Data: Dolutegravir: 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.

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8.2 Lactation

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Risk Summary

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.

It is not known whether JULUCA or components of JULUCA are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rats, dolutegravir and rilpivirine were present in milk (see Data).

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 JULUCA.

Data

Animal Data: Dolutegravir: 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.

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8.3 Females and Males of Reproductive Potential

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Pregnancy Testing

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

Contraception

Adolescents and adults of childbearing potential should avoid use of JULUCA 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 JULUCA to consistently use effective contraception.

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

17 PATIENT COUNSELING INFORMATION

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Embryo-Fetal Toxicity

Advise adolescents and adults of childbearing potential to avoid use of JULUCA 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 JULUCA.

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

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Pregnancy Registry

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

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PATIENT INFORMATION JULUCA

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

have ever had a severe skin rash or an allergic reaction to medicines that contain dolutegravir or rilpivirine.
have or have had liver problems, including hepatitis B or C infection.
have ever had a mental health problem.
are pregnant or plan to become pregnant. One of the medicines in JULUCA called dolutegravir may harm your unborn baby.
- You should not take JULUCA 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 JULUCA.
- If you can become pregnant, you should consistently use effective birth control (contraception)
  during treatment with JULUCA.

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 JULUCA.

are breastfeeding or plan to breastfeed. Do not breastfeed if you take JULUCA.
- 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 JULUCA can pass to your baby in your breast milk. Talk with your healthcare provider about the best way to feed your baby

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01/17/2018 (SUPPL-1)

Approved Drug Label (PDF)

7 Drug Interactions

7.4 Established and Other Potentially Significant Drug Interactions

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Table 4. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions

Clinical Comment

Administer JULUCA and supplements containing calcium or iron together with a meal or take JULUCA 4 hours before or 6 hours after taking these supplements.

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

PATIENT INFORMATION JULUCA (Jah-LOO-kah) (dolutegravir and rilpivirine) tablets

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How should I take JULUCA?

If you need to take iron or calcium supplements by mouth during treatment with JULUCA:
- If you do not take these supplements with JULUCA and food, take JULUCA at least 4 hours before or 6 hours after you take these supplements.