Data from FDA - Curated by EPG Health - Last updated 15 June 2018

Indication(s)

1 INDICATIONS AND USAGE TIVICAY is indicated in combination with:TIVICAY is indicated in combination with: other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 30 kg [see Microbiology ( 12.4)] . rilpivirine 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 per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent.rilpivirine 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 per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent. TIVICAY is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with: other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 30 kg. ( 1) rilpivirine 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 per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent.

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Advisory information

contraindications
4 CONTRAINDICATIONS TIVICAY is contraindicated in patients: with previous hypersensitivity reaction to dolutegravir [see Warnings and Precautions ( 5.1)]. receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions ( 7)] . Previous hypersensitivity reaction to dolutegravir. ( 4) Coadministration with dofetilide. ( 4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse drug reactions are discussed in other sections of the labeling: Hypersensitivity reactions [see Warnings and Precautions ( 5.1)] . Hepatotoxicity [see Warnings and Precautions ( 5.2)]. Immune Reconstitution Syndrome [see Warnings and Precautions ( 5.4)] . The most common adverse reactions of moderate to severe intensity and incidence at least 2% (in those receiving TIVICAY in any one adult trial) are insomnia, fatigue, and headache. ( 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. Clinical Trials Experience in Adult Subjects Treatment-Naïve Subjects: The safety assessment of TIVICAY in HIV‑1‑infected treatment-naïve subjects is based on the analyses of data from 2 international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and data from the international, multicenter, open-label FLAMINGO (ING114915) trial. In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were 808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms. In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rates of adverse events leading to discontinuation were 4% in subjects receiving TIVICAY 50 mg once daily + EPZICOM and 14% in subjects receiving ATRIPLA once daily. Treatment-emergent adverse reactions (ARs) of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 3. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 3. Treatment-Emergent Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naïve Subjects in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis) System Organ Class/ Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Psychiatric Insomnia <1% <1% 3% 3% Depression <1% <1% 1% 2% Abnormal dreams <1% <1% <1% 2% Nervous System Dizziness <1% <1% <1% 5% Headache <1% <1% 2% 2% Gastrointestinal Nausea 1% 1% <1% 3% Diarrhea <1% <1% <1% 2% Skin and Subcutaneous Tissue Rash a 0 <1% <1% 6% General Disorders Fatigue <1% <1% 2% 2% Ear and Labyrinth Vertigo 0 <1% 0 2% a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting. In a multicenter, open-label trial (FLAMINGO), 243 subjects received TIVICAY 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY and 6% in subjects receiving darunavir/ritonavir. The ARs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV‑1‑infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen. The only treatment-emergent AR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving TIVICAY 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48. Treatment-emergent ARs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials. Virologically Suppressed Subjects: The ARs observed for TIVICAY plus rilpivirine in the Week 48 analysis of pooled data from two identical, international, multicenter, open-label trials (SWORD-1 and SWORD-2) of 513 HIV–1-infected, virologically suppressed subjects switching from their current antiretroviral regimen to dolutegravir plus rilpivirine, were consistent with the AR profiles and severities for the individual components when administered with other antiretroviral agents. There were no ARs (Grades 2 to 4) with an incidence of at least 2% in either treatment arm. The rates of adverse events leading to discontinuation were 4% in subjects receiving TIVICAY plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Trials: The following ARs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving TIVICAY in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting. Hepatobiliary Disorders: Hepatitis. Musculoskeletal Disorders: Myositis. Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Treatment-Naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 4. The mean change from baseline observed for selected lipid values is presented in Table 5. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 4. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naïve Subjects in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis) Laboratory Parameter Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) ALT Grade 2 (>2.5-5.0 x ULN) 4% 4% 3% 5% Grade 3 to 4 (>5.0 x ULN) 2% 2% 1% <1% AST Grade 2 (>2.5-5.0 x ULN) 5% 3% 3% 4% Grade 3 to 4 (>5.0 x ULN) 3% 2% 1% 3% Total Bilirubin Grade 2 (1.6-2.5 x ULN) 3% 2% <1% <1% Grade 3 to 4 (>2.5 x ULN) <1% <1% <1% <1% Creatine kinase Grade 2 (6.0-9.9 x ULN) 2% 5% 5% 3% Grade 3 to 4 (≥10.0 x ULN) 7% 4% 7% 8% Hyperglycemia Grade 2 (126-250 mg/dL) 6% 6% 9% 6% Grade 3 (>250 mg/dL) <1% 2% 2% <1% Lipase Grade 2 (>1.5-3.0 x ULN) 7% 7% 11% 11% Grade 3 to 4 (>3.0 x ULN) 2% 5% 5% 4% Total neutrophils Grade 2 (0.75-0.99 x 10 9) 4% 3% 4% 5% Grade 3 to 4 (<0.75 x 10 9) 2% 2% 3% 3% ULN = Upper limit of normal. Table 5. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naïve Subjects in SPRING-2 (Week 96 Analysis a) and SINGLE Trials (Week 144 Analysis a) Laboratory Parameter Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Cholesterol (mg/dL) 8.1 10.1 24.0 26.7 HDL cholesterol (mg/dL) 2.0 2.3 5.4 7.2 LDL cholesterol (mg/dL) 5.1 6.1 16.0 14.6 Triglycerides (mg/dL) 6.7 6.6 13.6 31.9 a Subjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Ninety-four subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (SPRING-2: TIVICAY n = 9, raltegravir n = 13; SINGLE: TIVICAY + EPZICOM n = 36 and ATRIPLA: n = 36). Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported. Virologically Suppressed Adults: Laboratory abnormalities observed in SWORD-1 and SWORD-2 were generally similar compared with observations seen in the other Phase 3 trials. Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase 3 trials, subjects with hepatitis B and/or C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving TIVICAY were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn [see Warnings and Precautions ( 5.2)] . Changes in Serum Creatinine: Dolutegravir has 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 and remained stable through 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects. Clinical Trials Experience in Pediatric Subjects IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV‑1‑infected pediatric subjects aged 4 weeks to less than 18 years, of which 46 treatment-experienced, INSTI-naïve subjects aged 6 to less than 18 years have been enrolled [see Use in Specific Populations ( 8.4), Clinical Studies ( 14.2)]. The adverse reaction profile was similar to that for adults. Grade 2 ARs reported by more than one subject were decreased neutrophil count (n = 3) and diarrhea (n = 2). There were no Grade 3 or 4 drug-related ARs reported. No ARs led to discontinuation. The Grade 3 or 4 laboratory abnormalities reported in more than one subject were elevated total bilirubin (n = 3) and decreased neutrophil count (n = 2). The changes in mean serum creatinine were similar to those observed in adults. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. 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. Musculoskeletal Arthralgia, myalgia. Psychiatric Anxiety

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION May be taken without regard to food. ( 2) Adult Population Recommended Dose Treatment-naïve or treatment-experienced INSTI-naïve or virologically suppressed (HIV-1 RNA <50 copies per mL) adults switching to dolutegravir plus rilpivirine a ( 2.1) 50 mg once daily Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers ( 2.1, 7.3) 50 mg twice daily INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance b ( 12.4) 50 mg twice daily a Rilpivirine dose is 25 mg once daily for those switching to dolutegravir plus rilpivirine. b Alternative combinations that do not include metabolic inducers should be considered where possible. Pediatric Patients: (Treatment-naïve or treatment-experienced INSTI-naïve patients weighing at least 30 kg). ( 2.2) If at least 40 kg: The recommended dose is TIVICAY 50 mg once daily. Patients 30 kg to less than 40 kg: The recommended dose is TIVICAY 35 mg once daily. If certain UGT1A or CYP3A inducers are coadministered, then adjust the weight-based dose of TIVICAY to twice daily. ( 2.2, 7.3) 2.1 Adults TIVICAY tablets may be taken with or without food.TIVICAY tablets may be taken with or without food. Table 1. Dosing Recommendations for TIVICAY in Adult Patients Population Recommended Dose Treatment-naïve or treatment-experienced INSTI-naïve or virologically suppressed (HIV-1 RNA <50 copies per mL) adults switching to dolutegravir plus rilpivirine a 50 mg once daily Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers [see Drug Interactions ( 7.3)] 50 mg twice daily50 mg twice daily INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance b [see Microbiology ( 12.4)] 50 mg twice daily50 mg twice daily Rilpivirine dose is 25 mg once daily for those switching to dolutegravir plus rilpivirine. a Rilpivirine dose is 25 mg once daily for those switching to dolutegravir plus rilpivirine. Alternative combinations that do not include metabolic inducers should be considered where possible . b Alternative combinations that do not include metabolic inducers should be considered where possible [see Drug Interactions ( 7)] . 2.2 Pediatric Patients TIVICAY tablets may be taken with or without food. Treatment-Naïve or Treatment-Experienced INSTI-Naïve The recommended dose of TIVICAY in pediatric patients weighing at least 30 kg is provided in Table 2. Table 2. Dosing Recommendations for TIVICAY in Pediatric Patients Weighing at Least 30 kg Body Weight (kg) Daily Dose a (Number of Tablets per Dose when Different Strength(s) are Required) 30 to less than 40 35 mg once daily (One 25-mg tablet and one 10-mg tablet) 40 or greater 50 mg once daily a If certain UGT1A or CYP3A inducers are coadministered, then increase the weight-based dose of TIVICAY to twice daily [see Drug Interactions ( 7.3) for relevant inducers] . Safety and efficacy of TIVICAY have not been established in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: TIVICAY should be used during pregnancy only if the potential benefit justifies the potential risk. ( 8.1) Lactation: Breastfeeding is not recommended. ( 8.2) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TIVICAY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of TIVICAY during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Given the limited number of pregnancies exposed to dolutegravir-based regimens reported to the APR, no definitive conclusions can be drawn on the safety of TIVICAY in pregnancy, and continued monitoring is ongoing through the APR. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir (see Data). During organogenesis in the rat and rabbit, systemic exposures (AUC) to dolutegravir were less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD). In the rat pre/post-natal developmental study, maternal systemic exposure (AUC) to dolutegravir was approximately 27 times the exposure in humans at the MRHD. Data Animal Data: 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 also to rats on gestation day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) 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 at the MRHD and in rats were approximately 27 times the exposure in humans at the MRHD. 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 27 times human exposure at the MRHD). 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV‑1‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether TIVICAY is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, dolutegravir was present in milk (see Data). Because of the potential for (1) HIV‑1 transmission (in HIV-negative infants), and (2) developing viral resistance (in HIV-positive infants), instruct mothers not to breastfeed if they are receiving TIVICAY. Data Animal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg per kg on lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours post-dose. 8.4 Pediatric Use The safety, virologic, and immunologic responses in subjects who received TIVICAY were evaluated in 46 treatment-experienced, INSTI-naïve, HIV‑1–infected subjects aged 6 to less than 18 years in an open-label, multicenter, dose-finding clinical trial, IMPAACT P1093 [see Clinical Pharmacology ( 12.3), Clinical Studies ( 14.2)] . Frequency, type, and severity of adverse reactions among the 46 pediatric subjects were comparable to those observed in adults [see Adverse Reactions ( 6.2)] . In 17 subjects weighing at least 30 kg, pharmacokinetic parameters of dolutegravir were comparable to adults receiving 50 mg once daily [see Clinical Pharmacology ( 12.3)]. Safety and efficacy of TIVICAY have not been established in pediatric patients weighing less than 30 kg or in any pediatric patients who are INSTI-experienced. 8.5 Geriatric Use Clinical trials of TIVICAY 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 the administration of TIVICAY in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3)] . 8.6 Hepatic Impairment No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. 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 has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology ( 12.3)] . 8.7 Renal Impairment Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology ( 12.4)] ) with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents [see Clinical Pharmacology ( 12.3)] . Dolutegravir has not been studied in patients on dialysis.

Interactions

7 DRUG INTERACTIONS Refer to the full prescribing information for important drug interactions with TIVICAY. ( 4, 7) Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir. ( 7.2, 7.3) TIVICAY should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food. ( 7.3) 7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC 50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC 50 = 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 (dofetilide and metformin, Table 6) [see Contraindications ( 4), Drug Interactions ( 7.3)] . In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC 50 = 2.12 microM) and OAT3 (IC 50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. In vitro, dolutegravir did not inhibit (IC 50 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (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. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters. 7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir ( Table 6) [see Drug Interactions ( 7.3), Clinical Pharmacology ( 12.3)] . In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. 7.3 Established and Other Potentially Significant Drug Interactions Table 6 provides clinical recommendations as a result of drug interactions with TIVICAY. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [See Dosage and Administration ( 2), Clinical Pharmacology ( 12.3).] Table 6. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration ( 2)] Concomitant Drug Class: Drug Name Effect on Concentration of Dolutegravir and/or Concomitant Drug Clinical Comment HIV-1 Antiviral Agents Non-nucleoside reverse transcriptase inhibitor: Etravirine a ↓Dolutegravir Use of TIVICAY with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Efavirenz a ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily ( Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Non-nucleoside reverse transcriptase inhibitor: Nevirapine ↓Dolutegravir Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations. Protease inhibitor: Fosamprenavir/ritonavir a Tipranavir/ritonavir a ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily ( Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Other Agents Dofetilide ↑Dofetilide Coadministration is contraindicated with TIVICAY [see Contraindications ( 4)] . Carbamazepine a ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily ( Table 2). Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Oxcarbazepine Phenytoin Phenobarbital St. John’s wort ( Hypericum perforatum) ↓Dolutegravir Avoid coadministration with TIVICAY because there are insufficient data to make dosing recommendations. Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids a or laxatives Sucralfate Buffered medications ↓Dolutegravir Administer TIVICAY 2 hours before or 6 hours after taking medications containing polyvalent cations. Oral calcium or iron supplements, including multivitamins containing calcium or iron a ↓Dolutegravir Administer TIVICAY 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food. Metformin ↑Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY. When stopping TIVICAY, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended. Rifampin a ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily ( Table 2). Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b a See Clinical Pharmacology ( 12.3) Table 9 or Table 10 for magnitude of interaction. b The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology ( 12.4)] ) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. 7.4 Drugs without Clinically Significant Interactions with Dolutegravir Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, daclatasvir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir [see Clinical Pharmacology ( 12.3)] .

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Category Value
Authorisation number NDA204790
Agency product number 1Q1V9V5WYQ
Orphan designation No
Product NDC 61786-771
Date Last Revised 06-06-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder REMEDYREPACK INC.