S:15” BRIEF SUMMARY JULUCA (dolutegravir and rilpivirine) tablets The following is a brief summary only; see full prescribing information for complete product information. CONTRAINDICATIONS JULUCA is contraindicated in patients: with previous hypersensitivity reaction to dolutegravir or rilpivirine; receiving the following coadministered drugs for which elevated plasma concentrations are associated with serious and/or life-threatening events or that significantly decrease rilpivirine plasma concentrations: Drug Class Clinical Comment Antiarrhythmic: Dofetilide Potential for serious and/or life-threatening events due to the potential for increased dofetilide plasma concentrations. Anticonvulsants: Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin Potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response. Antimycobacterials: Rifampin, Rifapentine Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) Herbal Products: St John’s wort (Hypericum perforatum) Proton Pump Inhibitors: e.g., Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response. WARNINGS AND PRECAUTIONS 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. 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. Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen. 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. 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. For information regarding depressive disorders reported in patients taking dolutegravir, see Adverse Reactions. 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. 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: 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 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. Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes. See the Drug Interactions section 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. ADVERSE REACTIONS The safety assessment of JULUCA in HIV-1–infected, virologically suppressed subjects switching from their current antiretroviral regimen to dolutegravir plus rilpivirine is based on the pooled primary Week 48 analyses of data from 2 identical, international, multicenter, open-label trials, SWORD-1 and SWORD-2. 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. In the pooled analyses, the proportion of subjects who discontinued treatment due to an adverse event was 4% in subjects receiving dolutegravir plus rilpivirine once daily and was <1% in subjects who remained on their current antiretroviral regimen. The most common adverse events leading to discontinuation were psychiatric disorders: 2% of subjects receiving dolutegravir plus rilpivirine and <1% on their current antiretroviral regimen. The most common 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) in either treatment arm – JULUCA (n=513) vs current antiretroviral regimen (n=511), respectively: diarrhea (2%, <1%), headache (2%, 0). Less Common Adverse Reactions 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 (grades 2 and 3 to 4; week 48 pooled analyses) and representing the worst-grade toxicity in at least 2% of subjects in SWORD-1 and SWORD-2 trials were – JULUCA (n=513) vs current antiretroviral regimen (n=511), respectively: ALT Grade 2 (>2.5-5.0 x Upper Limit of Normal [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%. 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. Increases in serum creatinine occurred within the first 4 weeks of treatment with dolutegravir plus rilpivirine and remained stable through 48 weeks. A mean change from baseline of 0.093 mg per dL (range: -0.30 to 0.58 mg per dL) was observed after 48 weeks of treatment with dolutegravir plus rilpivirine. 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. 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 TDFcontaining regimen. 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 (cont’d on next page) BRIEF S tests in adverse receivin reporte reliably Muscul failure, Skin an includin DRUG Concom regime HIV-1 interact JULUC renal o (MATE) or MAT Compo (UDP)P450 ( resistan enzyme reduce drugs Coadm to decr by CYP Coadm plasma resistan drugs t Coadm plasma resistan subject daily (1 electroc with a k Drug In and rilp interact magnit Alterati predict • Anta JULU • Antia • Antic - co conc • Antid metf or st bloo reco • Antim JULU • Antim with • Gluc - co conc • H2-R shou H2-re • Herb cont • Macr poss • Med prod 4 ho