1 INDICATIONS AND USAGE JULUCA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of JULUCA.

JULUCA, a two-drug combination of dolutegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of JULUCA.

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6 ADVERSE REACTIONS The following adverse reactions are described below and in other sections of the labeling: • Skin and hypersensitivity reactions [see Warnings and Precautions ( 5.1 )].

• Hepatotoxicity [see Warnings and Precautions ( 5.2 )].

• Depressive disorders [see Warnings and Precautions ( 5.3 )].

The most common adverse reactions (all grades) observed in at least 2% of subjects were diarrhea, headache, and nausea.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 .

Table 2.

Adverse Reactions (Grades 1 to 4) Reported in at Least 2% of Virologically Suppressed Subjects with HIV-1 Infection in SWORD-1 and SWORD-2 Trials (Week 48 Pooled Analyses) Adverse Reaction Dolutegravir plus Rilpivirine (n = 513) Current Antiretroviral Regimen (n = 511) Diarrhea 2% <1% Headache 2% 0 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 .

Table 3.

Selected Laboratory Abnormalities (Grades 2 and 3 to 4; Week 48 Pooled Analyses) in SWORD-1 and SWORD-2 Trials ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal.

Laboratory Parameter Preferred Term Dolutegravir plus Rilpivirine (n = 513) Current Antiretroviral Regimen (n = 511) ALT Grade 2 (>2.5-5.0 x ULN) 2% <1% Grade 3 to 4 (>5.0 x ULN) <1% <1% AST Grade 2 (>2.5-5.0 x ULN) <1% 2% Grade 3 to 4 (>5.0 x ULN) <1% <1% Total Bilirubin Grade 2 (1.6-2.5 x ULN) 2% 4% Grade 3 to 4 (>2.5 x ULN) 0 3% Creatine kinase Grade 2 (6.0-9.9 x ULN) <1% <1% Grade 3 to 4 (≥10.0 x ULN) 1% 2% Hyperglycemia Grade 2 (126-250 mg/dL) 4% 5% Grade 3 to 4 (>250 mg/dL) <1% <1% Lipase Grade 2 (>1.5-3.0 x ULN) 5% 5% Grade 3 to 4 (>3.0 x ULN) 2% 2% 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/dL (range: -0.30 to 0.58 mg/dL) and 0.112 mg/dL (range: -0.24 to 0.81 mg/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.

Blood and Lymphatic Systems Sideroblastic anemia.

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 .