2.1 Pregnancy Testing before Initiation of JULUCA

Pregnancy testing is recommended before initiation of JULUCA in individuals of childbearing potential [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].

2.2 Recommended Dosage

The recommended dosage of JULUCA is one tablet taken orally once daily with a meal [see Clinical Pharmacology (12.3)]. One tablet of JULUCA contains 50 mg of dolutegravir and 25 mg of rilpivirine.

2.3 Recommended Dosage with Rifabutin Coadministration

If JULUCA is coadministered with rifabutin, take an additional 25-mg tablet of rilpivirine with JULUCA once daily with a meal for the duration of the rifabutin coadministration [see Drug Interactions (7.4)].

5.1 Skin and Hypersensitivity Reactions

Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in less than 1% of subjects receiving dolutegravir in Phase 3 clinical trials.

Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials of rilpivirine, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects. No Grade 4 rash was reported [see Adverse Reactions (6.2)].

Discontinue JULUCA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including laboratory parameters with liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with JULUCA after the onset of hypersensitivity may result in a life-threatening reaction [see Contraindications (4)].

5.2 Hepatotoxicity

Hepatic adverse events have been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen [see Adverse Reactions (6.1)]. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Additionally, in some patients receiving dolutegravir-containing regimens, 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 and hepatitis, have also been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to acute liver failure has been reported with dolutegravir-containing products, including liver transplant with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

5.3 Embryo-Fetal Toxicity

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.

5.4 Depressive Disorders

Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation) have been reported with rilpivirine [see Adverse Reactions (6.1)]. For information regarding depressive disorders reported in patients taking dolutegravir, see Adverse Reactions (6.1). Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to JULUCA and to determine whether the risks of continued therapy outweigh the benefits.

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

The concomitant use of JULUCA and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4), Drug Interactions (7.4)]:

•

Loss of therapeutic effect of JULUCA and possible development of resistance.

•

Possible clinically significant adverse reactions from greater exposures of concomitant drugs.

In healthy subjects, 75 mg once daily of rilpivirine (3 times the dose in JULUCA) and 300 mg once daily (12 times the dose in JULUCA) have been shown to prolong the QTc interval of the electrocardiogram [see Drug Interactions (7.3), Clinical Pharmacology (12.2)]. Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes.

See Table 4 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 JULUCA; review concomitant medications during therapy with JULUCA; and monitor for the adverse reactions associated with the concomitant drugs.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety assessment of JULUCA is based on the pooled primary Week 48 analyses of data from 2 identical, international, multicenter, open-label trials, SWORD-1 and SWORD-2, including additional follow up through Week 148.

A total of 1,024 adult HIV-1–infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus either an integrase strand transfer inhibitor [INSTI], a non-nucleoside reverse transcriptase inhibitor [NNRTI], or a protease inhibitor [PI]) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine, were randomized and received treatment. Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to dolutegravir plus rilpivirine administered once daily. Subjects originally assigned to continue their current antiretroviral regimen and who remained virologically suppressed at Week 48 switched to dolutegravir plus rilpivirine at Week 52. In the pooled analyses, the proportion of subjects who discontinued treatment due to an adverse event through Week 48 was 4% in subjects receiving dolutegravir plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. The most common adverse events leading to discontinuation through Week 48 were psychiatric disorders: 2% of subjects receiving dolutegravir plus rilpivirine and less than 1% on the current antiretroviral regimen. In the pooled analyses, the proportion of subjects receiving dolutegravir plus rilpivirine who discontinued treatment due to an adverse event through Week 148 was 8%.

The most common adverse reactions (ARs) (all grades) reported in at least 2% of subjects in the Week 48 pooled analyses from SWORD-1 and SWORD-2 are provided in Table 2.

In the Week 148 pooled analyses, the only adverse reaction (all grades) occurring in at least 2% of subjects who received dolutegravir plus rilpivirine and that was not observed during the Week 48 analyses was nausea (2%).

Less Common Adverse Reactions

The following ARs occurred in less than 2% of subjects receiving dolutegravir plus rilpivirine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EDURANT (rilpivirine). Some events have been included because of their seriousness and assessment of potential causal relationship.

General Disorders: Fatigue.

Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, nausea, upper abdominal pain, vomiting.

Hepatobiliary Disorders: Cholecystitis, cholelithiasis, hepatitis.

Immune System Disorders: Immune reconstitution syndrome.

Metabolism and Nutrition Disorders: Decreased appetite.

Musculoskeletal Disorders: Myositis.

Nervous System Disorders: Dizziness, somnolence.

Psychiatric Disorders: Depressive disorders including depressed mood; depression; suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Other reported psychiatric adverse reactions include anxiety, insomnia, sleep disorders, and abnormal dreams.

Renal and Urinary Disorders: Glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis, renal impairment.

Skin and Subcutaneous Tissue Disorders: Pruritus, rash.

Laboratory Abnormalities

Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in the Week 48 pooled analysis are presented in Table 3.

In the Week 148 pooled analyses, there were no additional selected laboratory abnormalities with dolutegravir plus rilpivirine compared with those shown in Table 3.

Changes in Serum Creatinine: Dolutegravir and rilpivirine have been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first 4 weeks of treatment with dolutegravir plus rilpivirine and remained stable through 148 weeks. Mean changes from baseline of 0.093 mg per dL (range: -0.30 to 0.58 mg per dL) and 0.112 mg per dL (range: -0.24 to 0.81 mg per dL) were observed after 48 and 148 weeks of treatment with dolutegravir plus rilpivirine, respectively. These changes are not considered to be clinically relevant.

Serum Lipids: At 48 weeks, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol to HDL ratio were similar between the treatment arms, with no further notable changes beyond Week 48.

Bone Mineral Density Effects

Mean bone mineral density (BMD) increased from baseline to Week 48 in subjects who switched from an antiretroviral treatment (ART) regimen containing tenofovir disoproxil fumarate (TDF) to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with those who continued on treatment with a TDF-containing antiretroviral regimen (0.05% total hip and 0.15% lumbar spine) in a dual-energy X-ray absorptiometry (DXA) substudy. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of subjects receiving JULUCA and 5% of subjects who continued their TDF-containing regimen. In subjects who received dolutegravir plus rilpivirine from study start and were continuing JULUCA at Week 148, mean BMD increases from baseline were 0.98% (total hip) and 0.53% (lumbar spine). The long-term clinical significance of these BMD changes is not known.

Fractures (excluding fingers and toes) were reported in 3 (0.6%) subjects who switched to dolutegravir plus rilpivirine and 9 (1.8%) subjects who continued their current antiretroviral regimen through 48 weeks.

Adrenal Function

In the pooled Phase 3 trials results analysis of rilpivirine, at Week 96, there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the rilpivirine group and of -0.02 (-0.48, 0.44) micrograms/dL in the efavirenz group. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the rilpivirine group is not known. Refer to the EDURANT (rilpivirine) Prescribing Information for additional information.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir- or rilpivirine-containing regimen. 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.

Hepatobiliary Disorders

Acute liver failure, hepatotoxicity.

Investigations

Weight increased.

Musculoskeletal Disorders

Arthralgia, myalgia.

Renal and Genitourinary Disorders

Nephrotic syndrome.

Skin and Subcutaneous Tissue Disorders

Severe skin and hypersensitivity reactions, including DRESS.

7.1 Concomitant Use with Other Antiretroviral Medicines

Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1)]. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications (4), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].

7.2 Potential for JULUCA to Affect Other Drugs

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 [see Contraindications (4), Drug Interactions (7.4)].

7.3 Potential for Other Drugs to Affect the Components of JULUCA

Dolutegravir

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.

Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased absorption of dolutegravir [see Drug Interactions (7.4)].

Rilpivirine

Rilpivirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of rilpivirine. Coadministration of JULUCA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs [see Contraindications (4), Drug Interactions (7.4)]. Coadministration of JULUCA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of JULUCA with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs [see Contraindications (4), Drug Interactions (7.4), Clinical Pharmacology (12.3)].

QT-Prolonging Drugs: In healthy subjects, 75 mg once daily of rilpivirine (3 times the dose in JULUCA) and 300 mg once daily (12 times the dose in JULUCA) have been shown to prolong the QTc interval of the electrocardiogram [see Clinical Pharmacology (12.2)]. Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes.

7.4 Established and Other Potentially Significant Drug Interactions

Information regarding potential drug interactions with dolutegravir and rilpivirine are provided in Table 4. These recommendations are based on either drug interaction trials of individual components or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy [see Contraindications (4), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].

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.

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

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

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.

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. The exposure (C0h and AUC) of total rilpivirine was approximately 30% to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and the postpartum period [see Clinical Pharmacology (12.3)]. One subject discontinued the trial following fetal death at 25 weeks’ gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6- to 12-week postpartum visit. Virologic outcomes during the third trimester visit were missing for 2 subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-1–infected pregnant subjects, all had negative test results for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1–infected adults.

Animal Data: Dolutegravir: 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) 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, and in rats were approximately 38 times the exposure in humans (50 mg once daily). 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 32 times the human exposure with 50 mg once daily).

Rilpivirine: Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg per kg per day) and rabbits (5, 10, or 20 mg per kg per day) through organogenesis (on Gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with rilpivirine, where rats were administered up to 400 mg per kg per day through lactation, no significant adverse effects directly related to drug were noted in the offspring.

8.2 Lactation

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.

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).

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: 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 per kg per day).

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.

8.4 Pediatric Use

The safety and efficacy of JULUCA have not been established in pediatric patients.

8.5 Geriatric Use

Clinical trials of JULUCA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of JULUCA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dosage adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min) [see Clinical Pharmacology (12.3)]. In patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease, increased monitoring for adverse effects is recommended.

8.7 Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir or rilpivirine is unknown [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

JULUCA is a fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir and rilpivirine [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of JULUCA on the QT interval has not been studied.

In a randomized, placebo-controlled, crossover trial, 42 healthy subjects received single-dose oral administration of placebo, dolutegravir 250-mg suspension (exposures approximately 3-fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.

The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo- and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern). When 75 mg and 300 mg once daily of rilpivirine (3 times and 12 times the recommended dosage in JULUCA, respectively) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25-mg once-daily dose of rilpivirine [see Drug Interactions (7.4)].

Effects on Renal Function

The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic (PK) properties of the components of JULUCA are provided in Table 5. The multiple-dose pharmacokinetic parameters are provided in Table 6.

Specific Populations

Pediatric Patients: The pharmacokinetics of dolutegravir plus rilpivirine has not been studied in pediatric subjects [see Use in Specific Populations (8.4)].

Geriatric Patients: Population pharmacokinetic analyses from studies with the individual components indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine. Pharmacokinetic data in subjects 65 years of age and older are limited [see Use in Specific Populations (8.5)].

Patients with Renal Impairment: Population pharmacokinetic analyses indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. Dolutegravir AUC, Cmax, and C24 were lower by 40%, 23%, and 43%, respectively, in subjects (n = 8) with severe renal impairment (creatinine clearance less than 30 mL/min) as compared with matched healthy controls. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis [see Use in Specific Populations (8.6)].

Population pharmacokinetic analyses indicated that mild renal impairment had no clinically relevant effect on the exposure of rilpivirine. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment, end-stage renal disease, or patients requiring dialysis.

Patients with Hepatic Impairment: Dolutegravir exposures were similar in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) as compared with matched healthy controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied.

Rilpivirine exposure was 47% higher in subjects (n = 8) with mild hepatic impairment (Child-Pugh Score A) and 5% higher in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) compared with matched controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of rilpivirine has not been studied [see Use in Specific Populations (8.7)].

Patients with HBV/HCV Co-infection: Population pharmacokinetic analyses indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure of dolutegravir or rilpivirine. Subjects with hepatitis B co-infection were excluded from studies with dolutegravir plus rilpivirine.

Gender and Race: Population pharmacokinetic analyses from studies with the individual components revealed that gender and race had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine.

Pregnancy and Postpartum: Rilpivirine: The exposure (C0h and AUC24h) to total rilpivirine after taking rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30% to 40% lower during pregnancy (similar for the second and third trimesters) compared with postpartum (see Table 7). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of rilpivirine-containing regimens. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum.

Drug Interaction Studies

Drug interaction trials were conducted with dolutegravir or rilpivirine as individual components and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-gp, 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.

In vitro, dolutegravir inhibited the renal OCT2 (IC50 = 1.93 microM) and MATE1 (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 such as dofetilide, dalfampridine, and metformin [see Contraindications (4), Drug Interactions (7.4)].

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.

Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.

Rilpivirine is primarily metabolized by CYP3A. Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

Dosing recommendations as a result of established and other potentially significant drug-drug interactions with dolutegravir or rilpivirine are provided in Table 4 [see Drug Interactions (7.4)].

12.4 Microbiology

Mechanism of Action

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and γ.

Antiviral Activity in Cell Culture

Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC50 values of 0.5 nM to 2.1 nM (0.21 to 0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0.52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M [clades A, B, C, D, E, F, and G] and 3 in group O) with EC50 values ranging from 0.02 nM to 2.14 nM.

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM (0.27 ng per mL). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 nM to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL).

Antiviral Activity in Combination with Other Antiviral Agents

Neither dolutegravir nor rilpivirine were antagonistic to all tested anti-HIV agents or with each other when tested in combination.

Resistance

Cell Culture: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV‑1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E, or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold.

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and clades as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I; K101E; V106I and A; V108I; E138K and G, Q, R; V179F and I; Y181C and I; V189I; G190E; H221Y; F227C; and M230I and L.

Virologically Suppressed Subjects: In the pooled SWORD-1 and SWORD-2 trials, 12 subjects (7 in SWORD-1 and 5 in SWORD-2) had confirmed virologic failure (HIV-1 RNA greater than 200 copies/mL) while receiving dolutegravir plus rilpivirine at any time through Week 148. Ten of the confirmed virologic failures had post-baseline resistance data, with 6 isolates showing evidence of rilpivirine resistance, and 2 with evidence of dolutegravir resistance substitutions. Six isolates showed genotypic and/or phenotypic resistance to rilpivirine with emergent NNRTI-resistance substitutions E138E/A (rilpivirine 1.6-fold change), M230M/L (rilpivirine 2-fold change), L100L/I, K101Q and E138A (rilpivirine 4.1-fold change), K101K/E (rilpivirine 1.2-fold change), K101K/E, M230M/L (rilpivirine 2-fold change), and L100L/V/M, M230M/L (rilpivirine 31-fold change). In addition, 1 virologic failure subject had NNRTI-resistance substitutions K103N and V179I at Week 88 with rilpivirine phenotypic fold change of 5.2 but had no baseline sample.

One virologic failure isolate had emergent INSTI-resistance substitution V151V/I present post-baseline with baseline INSTI-resistance substitutions N155N/H and G163G/R (by exploratory HIV proviral DNA archive sequencing); no integrase phenotypic data were available for this isolate at virologic failure. One other subject had the dolutegravir-resistance substitution G193E at baseline and virologic failure, but no detectable phenotypic resistance (fold change = 1.02) at Week 24.

No resistance-associated substitutions were observed for the 2 subjects meeting confirmed virologic failure in the comparative current antiretroviral regimen arms at Week 48.

Cross-Resistance

Dolutegravir: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions). The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M; E92Q/N155H; G140C/Q148R; G140S/Q148H, R or K; Q148R/N155H; T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).

Rilpivirine: Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E or P; E138A, G, K, R, or Q; V179L; Y181C, I, or V; Y188L; H221Y; F227C; M230I or L.

Cross-resistance in site-directed mutant virus has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52 times, 15 times, and 12 times decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7 times reduced susceptibility to rilpivirine compared with 2.8 times for E138K alone. The K103N substitution did not show reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7 times reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a reduced susceptibility to rilpivirine of 9 times for clinical isolates and 6 times for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to rilpivirine (fold-change range: 3.7 to 554) in 38% and 66% of mutants, respectively.

Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of rilpivirine resistance.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 20 times higher than those in humans at the recommended dose of 50 mg once daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures approximately 17 times higher than those in humans at the recommended dose of 50 mg once daily.

Rilpivirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1,500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to rilpivirine were 21 (mice) and 3 (rats) times higher than those observed in humans at the recommended dose (25 mg once daily).

Mutagenesis

Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Rilpivirine tested negative in the absence and presence of a metabolic activation system in the in vitro Ames reverse mutation assay and the in vitro clastogenicity mouse lymphoma assay. Rilpivirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

Impairment of Fertility

Dolutegravir did not affect male or female fertility in rats at doses associated with exposures approximately 33 times higher than the exposures in humans at the doses of 50 mg once daily.

No human data on the effect of rilpivirine on fertility are available. In a study conducted in rats, there were no effects on mating or fertility with rilpivirine up to 400 mg per kg per day, a dose of rilpivirine that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily.

14.1 Clinical Trials in Adult Subjects Switching to JULUCA

The efficacy of JULUCA is supported by data from 2 open-label, controlled trials (SWORD-1 [NCT02429791] and SWORD-2 [NCT02422797]) in virologically suppressed patients switching from their current antiretroviral regimen to dolutegravir plus rilpivirine.

SWORD-1 and SWORD-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials. A total of 1,024 adult HIV-1–infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 NRTIs plus either an INSTI, an NNRTI, or a PI) for at least 6 months (HIV-1 RNA less than 50 copies per mL), with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine received treatment in the trials. Subjects were randomized 1:1 to continue their current antiretroviral regimen (n = 511) or be switched to dolutegravir plus rilpivirine administered once daily (n = 513). Subjects originally assigned to continue their current antiretroviral regimen and who remained virologically suppressed at Week 48 switched to dolutegravir plus rilpivirine at Week 52 (n = 477).

The primary efficacy endpoint for the SWORD trials was the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL at Week 48.

At baseline, in the pooled analysis, the median age of subjects was 43 years (range: 21 to 79), 22% female, 20% non-white, 11% were CDC Class C (AIDS), and 11% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment arms. In the pooled analysis, 54%, 26%, and 20% of subjects were receiving an NNRTI, PI, or INSTI, respectively, as their baseline third-treatment-agent class prior to randomization. This distribution was similar between treatment arms.

The primary endpoint and other outcomes (including outcomes by key baseline covariates) for the pooled SWORD-1 and SWORD-2 trials are shown in Table 12. The virologic outcome results for SWORD-1 and SWORD-2 were similar to the pooled SWORD-1 and SWORD-2 virologic outcome results.

Treatment differences were maintained across baseline characteristics including, CD4+ cell count, age, gender, race, and baseline third-treatment-agent class.

At Week 148 in the pooled SWORD-1 and SWORD-2 trials, 84% of subjects who received dolutegravir plus rilpivirine from study start had plasma HIV-1 RNA less than 50 copies/mL (Snapshot algorithm). In subjects who initially remained on their current antiretroviral regimen and switched to dolutegravir plus rilpivirine at Week 52, 90% had plasma HIV-1 RNA less than 50 copies/mL at Week 148 (Snapshot algorithm), which was comparable to the response rate (89%) observed at Week 100 (similar exposure duration) in subjects receiving dolutegravir plus rilpivirine from study start.