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TIVICAY(Dolutegravir)

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TIVICAY(Dolutegravir) HIGHLIGHTS OF PRESCRIBING INFORMATION ------------------------ WARNINGS and PRECAUTIONS ------------------------ These highlights do not include all the information needed to use • Hypersensitivity reactions characterized by rash, constitutional findings, TIVICAY safely and effectively. See full prescribing information for and sometimes organ dysfunction, including liver injury, have been TIVICAY. reported. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in TIVICAY (dolutegravir) Tablets for Oral Use stopping treatment may result in a life-threatening reaction. TIVICAY Initial U.S. Approval: 2013 should not be used in patients who have experienced a previous hypersensitivity reaction to TIVICAY. (5.1) ----------------------------INDICATIONS AND USAGE ---------------------------- • Patients with underlying hepatitis B or C may be at increased risk for TIVICAY is a human immunodeficiency virus type 1 (HIV-1) integrase worsening or development of transaminase elevations with use of strand transfer inhibitor (INSTI) indicated in combination with other TIVICAY. Appropriate laboratory testing prior to initiating therapy and antiretroviral agents for the treatment of HIV-1 infection in adults and monitoring for hepatotoxicity during therapy with TIVICAY is children aged 12 years and older and weighing at least 40 kg. (1) recommended in patients with underlying hepatic disease such as hepatitis B or C. (5.2) The following should be considered prior to initiating TIVICAY: • Redistribution/accumulation of body fat and immune reconstitution • Poor virologic response was observed in subjects treated with TIVICAY syndrome have been reported in patients treated with combination 50 mg twice daily with an INSTI-resistance Q148 substitution plus 2 or antiretroviral therapy. (5.3, 5.4) more additional INSTI-resistance substitutions including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or ------------------------------ ADVERSE REACTIONS ------------------------------ G193E/R. (12.4) The most common adverse reactions of moderate to severe intensity and incidence ≥2% (in those receiving TIVICAY in any one adult trial) are ----------------------- DOSAGE AND ADMINISTRATION ----------------------- insomnia and headache. (6.1) May be taken without regard to meals. (2) Adult Population Recommended Dose To report SUSPECTED ADVERSE REACTIONS, contact ViiV Treatment-naïve or treatment-experienced INSTI- 50 mg once daily Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or naïve www.fda.gov/medwatch. Treatment-naïve or treatment-experienced INSTI- 50 mg twice daily ------------------------------- DRUG INTERACTIONS ------------------------------- naïve when coadministered with the following • Drugs that are metabolic inducers may decrease the plasma potent UGT1A/CYP3A inducers: efavirenz, concentrations of dolutegravir. (7.2, 7.3) fosamprenavir/ritonavir, tipranavir/ritonavir, or • TIVICAY should be taken 2 hours before or 6 hours after taking cation- rifampin containing antacids or laxatives, sucralfate, oral iron supplements, oral INSTI-experienced with certain INSTI-associated 50 mg twice daily calcium supplements, or buffered medications. (7.3) resistance substitutions or clinically suspected a INSTI resistance (12.4) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------- a Alternative combinations that do not include metabolic inducers should be • Pregnancy: TIVICAY should be used during pregnancy only if the considered where possible. potential benefit justifies the potential risk. (8.1) • Nursing mothers: Breastfeeding is not recommended due to the potential Pediatric Patients: (Treatment-naïve or treatment-experienced INSTI-naïve, for HIV transmission. (8.3) aged 12 years and older, and weighing at least 40 kg). (2.2) • Pediatric patients: Safety and efficacy of TIVICAY have not been • The recommended dose is TIVICAY 50 mg once daily. established in pediatric patients younger than 12 years or weighing less • If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin are than 40 kg, or in pediatric patients who are INSTI-experienced with coadministered, then the dose is TIVICAY 50 mg twice daily. documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir). (8.4) --------------------- DOSAGE FORMS AND STRENGTHS --------------------- See 17 for PATIENT COUNSELING INFORMATION and FDA- Tablets: 50 mg (3) approved patient labeling. ------------------------------- CONTRAINDICATIONS ------------------------------- Revised: August 2013 Coadministration with dofetilide is contraindicated. (4) 8 USE IN SPECIFIC POPULATIONS FULL PRESCRIBING INFORMATION: CONTENTS* 8.1 Pregnancy 1 INDICATIONS AND USAGE 8.3 Nursing Mothers 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use 2.1 Adults 8.5 Geriatric Use 2.2 Pediatric Patients 8.6 Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 8.7 Renal Impairment 4 CONTRAINDICATIONS 10 OVERDOSAGE 5 WARNINGS AND PRECAUTIONS 11 DESCRIPTION 5.1 Hypersensitivity Reactions 12 CLINICAL PHARMACOLOGY 5.2 Effects on Serum Liver Biochemistries in Patients With 12.1 Mechanism of Action Hepatitis B or C Co-infection 12.2 Pharmacodynamics 5.3 Fat Redistribution 12.3 Pharmacokinetics 5.4 Immune Reconstitution Syndrome 12.4 Microbiology 6 ADVERSE REACTIONS 13 NONCLINICAL TOXICOLOGY 6.1 Clinical Trials Experience in Adult Subjects 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 6.2 Clinical Trials Experience in Pediatric Subjects 14 CLINICAL STUDIES 7 DRUG INTERACTIONS 14.1 Adult Subjects 7.1 Effect of Dolutegravir on the Pharmacokinetics of 14.2 Pediatric Subjects Other Agents 16 HOW SUPPLIED/STORAGE AND HANDLING 7.2 Effect of Other Agents on the Pharmacokinetics of 17 PATIENT COUNSELING INFORMATION Dolutegravir *Sections or subsections omitted from the full prescribing information are 7.3 Established and Other Potentially Significant Drug not listed. Interactions 1 Reference ID: 3356149 1 FULL PRESCRIBING INFORMATION 2 1 INDICATIONS AND USAGE 3 TIVICAY® is indicated in combination with other antiretroviral agents for the treatment 4 of human immunodeficiency virus type 1 (HIV-1) infection in adults and children aged 12 years 5 and older and weighing at least 40 kg. 6 The following should be considered prior to initiating treatment with TIVICAY: 7 • Poor virologic response was observed in subjects treated with TIVICAY 50 mg twice daily 8 with an integrase strand transfer inhibitor (INSTI)-resistance Q148 substitution plus 2 or more 9 additional INSTI-resistance substitutions, including L74I/M, E138A/D/K/T, G140A/S, 10 Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R [see Microbiology (12.4)]. 11 2 DOSAGE AND ADMINISTRATION 12 TIVICAY tablets may be taken with or without food. 13 2.1 Adults 14 15 Table 1. Dosing Recommendations for TIVICAY in Adult Patients Population Recommended Dose Treatment-naïve or treatment-experienced INSTI-naïve 50 mg once daily Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with the following potent UGT1A/CYP3A inducers: efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, 50 mg twice daily or rifampin INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistancea [see 50 mg twice daily Microbiology (12.4)] 16 a Alternative combinations that do not include metabolic inducers should be considered where 17 possible [see Drug Interactions (7)]. 18 19 The safety and efficacy of doses above 50 mg twice daily have not been evaluated. 20 2.2 Pediatric Patients 21 Treatment-Naïve or Treatment-Experienced INSTI-Naïve: The recommended dose 22 of TIVICAY in pediatric patients aged 12 years and older and weighing at least 40 kg is 50 mg 23 administered orally once daily. 24 If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin are coadministered, 25 the recommended dose of TIVICAY is 50 mg twice daily. 26 Safety and efficacy of TIVICAY have not been established in pediatric patients younger 27 than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced 28 with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir). 2 Reference ID: 3356149 29 3 DOSAGE FORMS AND STRENGTHS 30 TIVICAY 50-mg tablets are yellow, round, film-coated, biconvex tablets debossed with 31 SV 572 on one side and 50 on the other side. Each tablet contains 50 mg of dolutegravir (as 32 dolutegravir sodium) [see Description (11)]. 33 4 CONTRAINDICATIONS 34 Coadministration of TIVICAY with dofetilide is contraindicated due to the potential for 35 increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events 36 [see Drug Interactions (7)]. 37 5 WARNINGS AND PRECAUTIONS 38 5.1 Hypersensitivity Reactions 39 Hypersensitivity reactions have been reported and were characterized by rash, 40 constitutional findings, and sometimes organ dysfunction, including liver injury. The events were 41 reported in 1% or fewer subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue 42 TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity 43 reactions develop (including, but not limited to, severe rash or rash accompanied by fever, 44 general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or 45 lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). 46 Clinical status, including liver aminotransferases,
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