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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Severe skin and hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported with the individual components. Discontinue JULUCA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. ( 5.1 ) • Hepatotoxicity has been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen. Monitoring for hepatotoxicity is recommended. ( 5.2 ) • Depressive disorders have been reported with the use of rilpivirine- or dolutegravir-containing regimens. Immediate medical evaluation is recommended for severe depressive symptoms. ( 5.3 , 6.1 ) 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 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. 5.4 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 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 .