ADVERSE REACTIONS SECTION.


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 5.5)] . Hypersensitivity reactions [see Warnings and Precautions 5.1)] . Hepatotoxicity [see Warnings and Precautions 5.2)]. Immune Reconstitution Syndrome [see Warnings and Precautions 5.5)] . 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 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 SubjectsTreatment-Naive Subjects: The safety assessment of TIVICAY in HIV-1-infected treatment-naive subjects is based on the analyses of data from 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 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 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 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 5. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 5. Treatment-Emergent Adverse Reactions of at Least Moderate Intensity (Grades to 4) and at Least 2% Frequency in Treatment-Naive Subjects in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis)a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. System Organ Class/Preferred TermSPRING-2SINGLETIVICAY 50 mg Once Daily 2 NRTIs(n 403)Raltegravir400 mg Twice Daily 2 NRTIs(n 405)TIVICAY 50 mg EPZICOM Once Daily(n 414)ATRIPLAOnce 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 Nausea1%1%<1%3% Diarrhea<1%<1%<1%2%Skin and Subcutaneous Tissue Rash 0<1%<1%6%General Disorders Fatigue<1%<1%2%2%Ear and Labyrinth Vertigo0<1%02%In addition, Grade 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 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 adverse reactions observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE.Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naive 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 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 adverse reaction 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 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 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 adverse reactions in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase trials.Virologically Suppressed Subjects: The adverse reactions observed for TIVICAY plus rilpivirine in the Week 48 analysis of pooled data from 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 adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents. There were no adverse reactions (Grades 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-Naive and Treatment-Experienced Trials: The following adverse reactions occurred in less than 2% of treatment-naive or treatment-experienced subjects receiving TIVICAY in 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 pre-existing history of depression or other psychiatric illness. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Treatment-Naive Subjects: Selected laboratory abnormalities (Grades to 4) with worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 6. The mean change from baseline observed for selected lipid values is presented in Table 7. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 6. Selected Laboratory Abnormalities (Grades to 4) in Treatment-Naive Subjects in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis)ULN Upper limit of normal.Laboratory ParameterPreferred TermSPRING-2SINGLETIVICAY50 mg Once Daily +2 NRTIs(n 403)Raltegravir400 mg Twice Daily 2 NRTIs(n 405)TIVICAY50 mg EPZICOM Once Daily(n 414)ATRIPLAOnce Daily(n 419)ALT Grade (>2.5-5.0 ULN)4%4%3%5% Grade to (>5.0 ULN)2%2%1%<1%AST Grade (>2.5-5.0 ULN)5%3%3%4% Grade to (>5.0 ULN)3%2%1%3%Total Bilirubin Grade (1.6-2.5 ULN)3%2%<1%<1% Grade to (>2.5 ULN)<1%<1%<1%<1%Creatine kinase Grade (6.0-9.9 ULN)2%5%5%3% Grade to (>=10.0 ULN)7%4%7%8%Hyperglycemia Grade (126-250 mg/dL)6%6%9%6% Grade (>250 mg/dL)<1%2%2%<1%Lipase Grade (>1.5-3.0 ULN)7%7%11%11% Grade to (>3.0 ULN)2%5%5%4%Total neutrophils Grade (0.75-0.99 10 9) 4%3%4%5% Grade to (<0.75 10 9) 2%2%3%3%Table 7. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naive Subjects in SPRING-2 (Week 96 Analysisa) and SINGLE Trials (Week 144 Analysis 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 = 30 and ATRIPLA = 27). Ninety-four subjects initiated 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 = 9, raltegravir = 13; SINGLE: TIVICAY EPZICOM = 36, ATRIPLA = 36). Laboratory ParameterPreferred TermSPRING-2SINGLETIVICAY 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)ATRIPLAOnce 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 Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naive Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naive (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 to 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 Grade to 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 trials. Hepatitis and/or Hepatitis Virus Co-infection: In Phase trials, subjects with hepatitis and/or virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed times the upper limit of normal. Overall, the safety profile in subjects with hepatitis and/or virus co-infection was similar to that observed in subjects without hepatitis or co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis and/or virus co-infection for all treatment groups. Grades to ALT abnormalities in hepatitis and/or 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 and/or 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 weeks of treatment and remained stable through 96 weeks. In treatment-naive subjects, 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 SubjectsThe safety and pharmacokinetics of TIVICAY and TIVICAY PD in HIV-1-infected pediatric subjects aged at least weeks and weighing at least kg was evaluated in the IMPAACT P1093 trial and weight-band-based pharmacokinetic substudies of the ODYSSEY trial [see Use in Specific Populations 8.4), Clinical Pharmacology 12.3)] Overall, the safety data in these pediatric studies were similar to those seen in adults, and there was no clinically significant difference in dolutegravir exposure [see Clinical Pharmacology 12.3)] IMPAACT P1093 is an ongoing, multicenter, open-label, non-comparative trial of HIV-1-infected pediatric subjects aged weeks to less than 18 years [see Use in Specific Populations 8.4), Clinical Pharmacology 12.3), Clinical Studies 14.3)] The safety analysis based on subjects (n 75) who received the recommended dose (determined by weight and age) through Week 24 showed that 11% of subjects experienced drug-related clinical adverse reactions. The only Grade to drug-related clinical adverse reactions reported by more than one subject was immune reconstitution inflammatory syndrome (IRIS) (n 2). There were no Grade or drug-related adverse reactions reported. No adverse reactions led to discontinuation.The Grade or laboratory abnormalities reported in more than one subject were decreased neutrophil count (n 11), decreased blood bicarbonate (n 4), decreased hemoglobin (n 3), increased lipase (n 2), and increased blood potassium (n 2). These laboratory events were not considered to be drug-related. Median laboratory values were similar at baseline and Week 24. Changes in median 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hepatobiliary DisordersAcute liver failure, hepatotoxicity.InvestigationsWeight increased.MusculoskeletalArthralgia, myalgia. PsychiatricAnxiety.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisTwo-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14 times higher than those in humans at the maximum recommended dose. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10 times and 15 times higher in males and females, respectively, than those in humans at the maximum recommended dose.MutagenesisDolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.Impairment of FertilityIn study conducted in rats, there were no effects on mating or fertility with dolutegravir up to 1,000 mg per kg per day. This dose is associated with an exposure that is approximately 24 times higher than the exposure in humans at the maximum recommended dose.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Dolutegravir is an HIV-1 antiretroviral agent [see Microbiology 12.4)]. 12.2 Pharmacodynamics. Effects on ElectrocardiogramIn randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3-fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). TIVICAY did not prolong the QTc interval over 24 hours postdose.Effects on Renal FunctionThe effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n 37) who received dolutegravir 50 mg once daily (n 12), dolutegravir 50 mg twice daily (n 13), or placebo once daily (n 12) for 14 days. decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.. 12.3 Pharmacokinetics. The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1-infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV-1-infected subjects Table 9) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. Table 9. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1-Infected Adultsa Based on population pharmacokinetic analyses using data from SPRING-1 and SPRING-2. Based on population pharmacokinetic analyses using data from VIKING (ING112961) and VIKING-3. Parameter50 mg Once DailyGeometric Mean (%CV) 50 mg Twice DailyGeometric Mean (%CV) AUC (0-24) (mcg.h/mL) 53.6 (27)75.1 (35)C max (mcg/mL) 3.67 (20)4.15 (29)C min (mcg/mL) 1.11 (46)2.12 (47)TIVICAY tablets and TIVICAY PD tablets for oral suspension are not bioequivalent. The relative bioavailability of TIVICAY PD is approximately 1.6-fold higher than TIVICAY; therefore, the dosage forms are not interchangeable on milligram-per-milligram basis [see Dosage and Administration 2.3)]. AbsorptionFollowing oral administration of dolutegravir, peak plasma concentrations were observed to hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately days with average accumulation ratios for AUC, max, and 24 ranging from 1.2 to 1.5. Dolutegravir plasma concentrations increased in less than dose-proportional manner above 50 mg. Dolutegravir is P-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.Effect of Food: TIVICAY or TIVICAY PD may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir following 50-mg dose of TIVICAY. Low-, moderate-, and high-fat meals increased dolutegravir AUC (0-) by 33%, 41%, and 66%; increased max by 46%, 52%, and 67%; and prolonged max to 3, 4, and hours from hours under fasted conditions, respectively. DistributionDolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 based on population pharmacokinetic analysis.Cerebrospinal Fluid (CSF): In 12 treatment-naive subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per mL (range: 3.74 ng per mL to 18.3 ng per mL) to hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established. EliminationDolutegravir has terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 per hour based on population pharmacokinetic analyses.Metabolism: Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. Polymorphisms in Drug- Metabolizing Enzymes: In meta-analysis of healthy subject trials, subjects with UGT1A1 (n 7) genotypes conferring poor dolutegravir metabolism had 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n 41). Excretion: After single oral dose of 14C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose). Specific PopulationsPediatric Patients: The pharmacokinetics of dolutegravir were evaluated in the IMPAACT P1093 trial and in weight-band-based pharmacokinetic substudies from the ODYSSEY trial. Steady-state plasma exposure at doses by weight band are summarized in Table 10 [see Clinical Studies 14.3)] Mean dolutegravir AUC 0-24h and 24h in HIV-1-infected pediatric subjects were comparable to those in adults after 50 mg once daily or 50 mg twice daily. Mean max is higher in pediatrics, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects [see Use in Specific Populations 8.4)] Table 10. Summary of Pharmacokinetic Parameters in Pediatric HIV-1-Infected Subjects (Pooled Analyses for IMPAACT P1093 and ODYSSEY Trials) Data from weight-band-based pharmacokinetic substudies in the ODYSSEY trial. The bioavailability of TIVICAY PD tablets for oral suspension is ~1.6-fold that of TIVICAY tablets. Weight BandDose of TIVICAY or TIVICAY PD nPharmacokinetic ParameterGeometric Mean (%CV)C max (mcg/mL)AUC 0-24h (mcgh/mL)C 24h (ng/mL)3 kg to <6 kgTIVICAY PD mg once daily 83.80 (34)49.37 (49)962 (98)6 kg to <10 kgTIVICAY PD 15 mg once daily 175.27 (50)57.17 (76)706 (177)10 kg to <14 kgTIVICAY PD 20 mg once daily 135.99 (33)68.75 (48)977 (100)14 kg to <20 kgTIVICAY PD 25 mg once daily 195.97 (42)58.97 (44)725 (75)20 kg to <25 kgTIVICAY PD 30 mg once daily 97.16 (26)71.53 (26)759 (73)>=20 kgTIVICAY 50 mg once daily 494.92 (40)54.98 (43)778 (62)Geriatric Patients: Population pharmacokinetic analysis indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. Patients with Hepatic Impairment: In trial comparing subjects with moderate hepatic impairment (Child-Pugh Score B) with matched healthy controls, exposure of dolutegravir from single 50-mg dose was similar between the groups. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Patients with Renal Impairment: In trial evaluating the pharmacokinetics of single 50-mg tablet of dolutegravir comparing subjects with severe renal impairment (CrCl less than 30 mL per min) with matched healthy controls, AUC, max, and 24 of dolutegravir were lower by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis. HBV or HCV Co-infected Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection. Gender and Race: Population analyses using pooled pharmacokinetic data from adult trials indicated gender and race had no clinically relevant effect on the exposure of dolutegravir. Drug Interaction StudiesDrug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of dolutegravir on the exposure of coadministered drugs are summarized in Table 11 and the effects of coadministered drugs on the exposure of dolutegravir are summarized in Table 12. Dosing or regimen recommendations as result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table [see Dosage and Administration 2.2), Drug Interactions 7.3)] Table 11. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugsa The number of subjects represents the maximum number of subjects that were evaluated. Coadministered Drug(s)and Dose(s)Dose of TIVICAYnGeometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without DolutegravirNo Effect 1.00C max AUCC or 24 Daclatasvir 60 mg once daily 50 mg once daily 121.03 (0.84 to 1.25) 0.98 (0.83 to 1.15) 1.06 (0.88 to 1.29) Elbasvir 50 mg once daily50 mgsingle dose120.97(0.89, 1.05)0.98(0.93, 1.04)0.98(0.93, 1.03)Ethinyl estradiol 0.035 mg 50 mg twice daily 150.99 (0.91 to 1.08) 1.03 (0.96 to 1.11) 1.02 (0.93 to 1.11) Grazoprevir 200 mg once daily50 mgsingle dose120.64(0.44, 0.93)0.81(0.67, 0.97)0.86(0.79, 0.93)Metformin 500 mg twice daily 50 mg once daily 15 1.66 (1.53 to 1.81) 1.79 (1.65 to 1.93) Metformin 500 mg twice daily 50 mg twice daily 15 2.11 (1.91 to 2.33) 2.45 (2.25 to 2.66) Methadone 16 to 150 mg 50 mg twice daily 111.00 (0.94 to 1.06) 0.98 (0.91 to 1.06) 0.99 (0.91 to 1.07) Midazolam mg 25 mg once daily 100.95 (0.79 to 1.15) Norelgestromin 0.25 mg 50 mg twice daily 150.89 (0.82 to 0.97) 0.98 (0.91 to 1.04) 0.93 (0.85 to 1.03) Rilpivirine 25 mg once daily 50 mg once daily 161.10 (0.99 to 1.22) 1.06 (0.98 to 1.16) 1.21 (1.07 to 1.38) Sofosbuvir 400 mg once daily Metabolite (GS-331007)50 mgonce daily240.88(0.80, 0.98)0.92 (0.85, 0.99)NULL1.01(0.93, 1.10)0.99(0.97, 1.01)0.99(0.97, 1.01)Tenofovir disoproxil fumarate 300 mg once daily 50 mg once daily 151.09 (0.97 to 1.23) 1.12 (1.01 to 1.24) 1.19 (1.04 to 1.35) Velpatasvir 100 mg once daily50 mgonce daily240.94 (0.86, 1.02)0.91(0.84, 0.98)0.88(0.82, 0.94)Table 12. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravira Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. The number of subjects represents the maximum number of subjects that were evaluated. Coadministered Drug(s)and Dose(s)Dose of TIVICAYnGeometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered DrugsNo Effect 1.00C max AUCC or 24 Atazanavir 400 mg once daily 30 mg once daily 121.50 (1.40 to 1.59) 1.91 (1.80 to 2.03) 2.80 (2.52 to 3.11) Atazanavir/ritonavir 300/100 mg once daily 30 mg once daily 121.34 (1.25 to 1.42) 1.62 (1.50 to 1.74) 2.21 (1.97 to 2.47) Darunavir/ritonavir 600/100 mg twice daily 30 mg once daily 150.89 (0.83 to 0.97) 0.78 (0.72 to 0.85) 0.62 (0.56 to 0.69) Efavirenz 600 mg once daily 50 mg once daily 120.61 (0.51 to 0.73) 0.43 (0.35 to 0.54) 0.25 (0.18 to 0.34) Elbasvir/grazoprevir 50/200 mg once daily50 mgsingle dose121.22(1.05, 1.40)1.16(1.00, 1.34)1.14(0.95, 1.36)Etravirine 200 mg twice daily 50 mg once daily 160.48 (0.43 to 0.54) 0.29 (0.26 to 0.34) 0.12 (0.09 to 0.16) Etravirine darunavir/ritonavir 200 mg 600/100 mg twice daily 50 mg once daily 90.88 (0.78 to 1.00) 0.75 (0.69 to 0.81) 0.63 (0.52 to 0.76) Etravirine lopinavir/ritonavir 200 mg 400/100 mg twice daily 50 mg once daily 81.07 (1.02 to 1.13) 1.11 (1.02 to 1.20) 1.28 (1.13 to 1.45) Fosamprenavir/ritonavir 700 mg/100 mg twice daily 50 mg once daily 120.76 (0.63 to 0.92) 0.65 (0.54 to 0.78) 0.51 (0.41 to 0.63) Lopinavir/ritonavir 400/100 mg twice daily 30 mg once daily 151.00 (0.94 to 1.07) 0.97 (0.91 to 1.04) 0.94 (0.85 to 1.05) Rilpivirine 25 mg once daily 50 mg once daily 161.13 (1.06 to 1.21) 1.12 (1.05 to 1.19) 1.22 (1.15 to 1.30) Tenofovir 300 mg once daily 50 mg once daily 150.97 (0.87 to 1.08) 1.01 (0.91 to 1.11) 0.92(0.82 to 1.04)Tipranavir/ritonavir 500/200 mg twice daily 50 mg once daily 140.54 (0.50 to 0.57) 0.41 (0.38 to 0.44) 0.24 (0.21 to 0.27) Antacid (MAALOX) simultaneous administration 50 mg single dose 160.28 (0.23 to 0.33) 0.26 (0.22 to 0.32) 0.26 (0.21 to 0.31) Antacid (MAALOX) h after dolutegravir 50 mg single dose 160.82 (0.69 to 0.98) 0.74 (0.62 to 0.90) 0.70 (0.58 to 0.85) Calcium carbonate 1,200 mg simultaneous administration (fasted) 50 mg single dose 120.63 (0.50 to 0.81) 0.61 (0.47 to 0.80) 0.61 (0.47 to 0.80) Calcium carbonate 1,200 mg simultaneous administration (fed) 50 mg single dose 111.07 (0.83 to 1.38) 1.09 (0.84 to 1.43) 1.08 (0.81 to 1.42) Calcium carbonate 1,200 mg h after dolutegravir 50 mg single dose 111.00 (0.78 to 1.29) 0.94 (0.72 to 1.23) 0.90 (0.68 to 1.19) Carbamazepine 300 mg twice daily 50 mg once daily 16 0.67 (0.61 to 0.73) 0.51 (0.48 to 0.55) 0.27 (0.24 to 0.31) Daclatasvir 60 mg once daily 50 mg once daily 121.29 (1.07 to 1.57) 1.33 (1.11 to 1.59) 1.45 (1.25 to 1.68) Ferrous fumarate 324 mg simultaneous administration (fasted) 50 mg single dose 110.43 (0.35 to 0.52) 0.46 (0.38 to 0.56) 0.44 (0.36 to 0.54) Ferrous fumarate 324 mg simultaneous administration (fed) 50 mg single dose 111.03 (0.84 to 1.26) 0.98 (0.81 to 1.20) 1.00 (0.81 to 1.23) Ferrous fumarate 324 mg h after dolutegravir 50 mg single dose 100.99 (0.81 to 1.21) 0.95 (0.77 to 1.15) 0.92 (0.74 to 1.13) Multivitamin (One-A-Day) simultaneous administration 50 mg single dose 160.65 (0.54 to 0.77) 0.67 (0.55 to 0.81) 0.68 (0.56 to 0.82) Omeprazole 40 mg once daily 50 mg single dose 120.92 (0.75 to 1.11) 0.97 (0.78 to 1.20) 0.95 (0.75 to 1.21) Prednisone 60 mg once daily with taper 50 mg once daily 121.06 (0.99 to 1.14) 1.11 (1.03 to 1.20) 1.17 (1.06 to 1.28) Rifampin 600 mg once daily 50 mg twice daily 110.57 (0.49 to 0.65) 0.46 (0.38 to 0.55) 0.28 (0.23 to 0.34) Rifampin 600 mg once daily 50 mg twice daily 111.18 (1.03 to 1.37) 1.33 (1.15 to 1.53) 1.22 (1.01 to 1.48) Rifabutin 300 mg once daily 50 mg once daily 91.16 (0.98 to 1.37) 0.95 (0.82 to 1.10) 0.70 (0.57 to 0.87) 12.4 Microbiology. Mechanism of ActionDolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNULL) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNULL resulted in IC 50 values of 2.7 nM and 12.6 nM. Antiviral Activity in Cell CultureDolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC 50 values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade isolates with mean EC 50 value of 0.52 nM in viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against panel of HIV-1 clinical isolates (3 in each group of clades A, B, C, D, E, F, and G, and in group O) with EC 50 values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC 50 values against HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM. Antiviral Activity in Combination with Other Antiviral AgentsThe antiviral activity of dolutegravir was not antagonistic when combined with the INSTI, raltegravir; non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz or nevirapine; the NRTIs, abacavir or stavudine; the protease inhibitors (PIs), amprenavir or lopinavir; the CCR5 co-receptor antagonist, maraviroc; or the fusion inhibitor, enfuvirtide. Dolutegravir antiviral activity was not antagonistic when combined with the HBV reverse transcriptase inhibitor, adefovir, or inhibited by the antiviral, ribavirin.ResistanceCell Culture: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Passage of mutant viruses containing the Q148R or Q148H substitutions selected for additional substitutions in integrase that conferred decreased susceptibility to dolutegravir (fold-change increase of 13 to 46). The additional integrase substitutions included T97A, E138K, G140S, and M154I. Passage of mutant viruses containing both G140S and Q148H selected for L74M, E92Q, and N155H. Treatment-Naive Subjects: No subject who received dolutegravir 50-mg once-daily in the treatment-naive trials SPRING-2 (96 weeks) and SINGLE (144 weeks) had detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n 12 with HIV-1 RNULL greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and subject with 275 copies per mL HIV-1 RNULL had treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to the background regimen was observed in the dolutegravir arm in either the SPRING-2 or SINGLE trials. No treatment-emergent primary resistance substitutions were observed in either treatment group in the FLAMINGO trial through Week 96. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naive Subjects: In the dolutegravir arm of the SAILING trial for treatment-experienced and INSTI-naive subjects (n 354), treatment-emergent integrase substitutions were observed in of 28 (21%) subjects who had virologic failure and resistance data. In of the subjects isolates emergent INSTI substitutions included L74L/M/I, Q95Q/L, V151V/I (n 1 each), and R263K (n 2). The change in dolutegravir phenotypic susceptibility for these subject isolates was less than 2-fold. One subject isolate had pre-existing raltegravir resistance substitutions E138A, G140S, and Q148H at baseline and had additional emergent INSTI-resistance substitutions T97A and E138A/T with corresponding 148-fold reduction in dolutegravir susceptibility at failure. In the comparator raltegravir arm, 21 of 49 (43%) subjects with post-baseline resistance data had evidence of emergent INSTI-resistance substitutions (L74M, E92Q, T97A, E138Q, G140S/A, Y143R/C, Q148H/R, V151I, N155H, E157Q, and G163K/R) and raltegravir phenotypic resistance. Virologically Suppressed Subjects: SWORD-1 and SWORD-2 are identical trials in virologically suppressed subjects receiving NRTIs plus either an INSTI, an NNRTI, or PI, that switched to dolutegravir plus rilpivirine (n 513) or remained on their current antiviral regimen (n 511). Two subjects in each treatment arm had confirmed virologic failure at any time through Week 48. The subjects in the dolutegravir/rilpivirine arm had detectable resistance substitutions at rebound. One subject had the NNRTI-resistance-associated substitution K101K/E with no decreased susceptibility to rilpivirine (fold-change 1.2) at Week 36, had no INSTI resistance-associated substitutions or decreased susceptibility to dolutegravir (fold-change less than 2), and had HIV-1 RNULL less than 50 copies per mL at the withdrawal visit. The other subject had the dolutegravir resistance-associated substitution G193E at baseline (by exploratory HIV proviral DNULL archive sequencing) and at Week 24 (by conventional sequencing) without decreased susceptibility to dolutegravir (fold-change 1.02) at Week 24. No resistance-associated substitutions were observed for the other subjects in the comparative current antiretroviral regimen arm. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: VIKING-3 examined the efficacy of dolutegravir 50 mg twice daily plus optimized background therapy in subjects with prior or current virologic failure on an INSTI- (elvitegravir or raltegravir) containing regimen. Use of TIVICAY in INSTI-experienced patients should be guided by the number and type of baseline INSTI substitutions. The efficacy of TIVICAY 50 mg twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. Response by Baseline GenotypeOf the 183 subjects with baseline data, 30% harbored virus with substitution at Q148, and 33% had no primary INSTI-resistance substitutions (T66A/I/K, E92Q/V, Y143R/C/H, Q148H/R/K, and N155H) at baseline, but had historical genotypic evidence of INSTI-resistance substitutions, phenotypic evidence of elvitegravir or raltegravir resistance, or genotypic evidence of INSTI-resistance substitutions at screening.Response rates by baseline genotype were analyzed in an as-treated analysis at Week 48 (n 175) Table 13). The response rate at Week 48 to dolutegravir-containing regimens was 47% (24 of 51) when Q148 substitutions were present at baseline; Q148 was always present with additional INSTI-resistance substitutions Table 13). In addition, diminished virologic response of 40% (6 of 15) was observed when the substitution E157Q or was present at baseline with other INSTI-resistance substitutions but without Q148H or substitution. Table 13. Response by Baseline Integrase Genotype in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3a Includes INSTI-resistance substitutions Y143R/C/H and N155H. INSTI-resistance substitutions included T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. Two additional subjects had baseline genotypes of Q148Q/R plus L74L/I/M (virologic failure) and Q148R plus E138K (responder). The most common pathway with Q148H/R greater than or equal to INSTI-resistance substitutions had Q148+G140+E138 substitutions (n 16). Baseline GenotypeWeek 48(<50 copies/mL)n 175Overall Response66% (116/175)No Q148 substitution 74% (92/124)Q148H/R G140S/A/C without additional INSTI-resistance substitution 61% (17/28)Q148H/R >=2 INSTI-resistance substitutions b,c 29% (6/21)Response by Baseline PhenotypeResponse rates by baseline phenotype were analyzed in an as-treated analysis using all subjects with available baseline phenotypes through Week 48 (n 163) Table 14). These baseline phenotypic groups are based on subjects enrolled in VIKING-3 and are not meant to represent definitive clinical susceptibility cut points for dolutegravir. The data are provided to guide clinicians on the likelihood of virologic success based on pretreatment susceptibility to dolutegravir in INSTI-resistant patients. Table 14. Response by Baseline Dolutegravir Phenotype (Fold-Change from Reference) in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3Baseline Dolutegravir Phenotype(Fold-Change from Reference)Response at Week 48(<50 copies/mL)Subset = 163Overall Response64% (104/163)<3-fold change72% (83/116)3- <10-fold change53% (18/34)>=10-fold change23% (3/13)Integrase Strand Transfer Inhibitor Treatment-Emergent ResistanceThere were 50 subjects with virologic failure on the dolutegravir twice-daily regimen in VIKING-3 with HIV-1 RNULL greater than 400 copies per mL at the failure timepoint, Week 48 or beyond, or the last timepoint on trial. Thirty-nine subjects with virologic failure had resistance data that were used in the Week 48 analysis. In the Week 48 resistance analysis 85% (33 of 39) of the subjects with virologic failure had treatment-emergent INSTI-resistance substitutions in their isolates. The most common treatment-emergent INSTI-resistance substitution was T97A. Other frequently emergent INSTI-resistance substitutions included L74M, or V, E138K or A, G140S, Q148H, or K, M154I, or N155H. Substitutions E92Q, Y143R or C/H, S147G, V151A, and E157E/Q each emerged in to subjects isolates. At failure, the median dolutegravir fold-change from reference was 61-fold (range: 0.75 to 209) for isolates with emergent INSTI-resistance substitutions (n 33). Resistance to one or more background drugs in the dolutegravir twice-daily regimen also emerged in 49% (19 of 39) of subjects in the Week 48 resistance analysis In VIKING-4 (ING116529), 30 subjects with current virological failure on an INSTI-containing regimen and genotypic evidence of INSTI-resistance substitutions at screening were randomized to receive either dolutegravir 50 mg twice daily or placebo with the current failing regimen for days and then all subjects received open-label dolutegravir plus optimized background regimen from Day 8. Virologic responses at Week 48 by baseline genotypic and phenotypic INSTI-resistance categories and the INSTI resistance-associated substitutions that emerged on dolutegravir treatment in VIKING-4 were consistent with those seen in VIKING-3.Cross-ResistanceSite-Directed Integrase Strand Transfer Inhibitor-Resistant Mutant HIV-1 and HIV-2 Strains: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with or more substitutions) and INSTI-resistant site-directed mutant HIV-2 viruses. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively. Reverse Transcriptase Inhibitor- and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent antiviral activity against NNRTI-resistant, NRTI-resistant, and PI-resistant HIV-1 mutant clones compared with the wild-type strain.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 Description of Clinical Studies. The efficacy and safety of TIVICAY or TIVICAY PD were evaluated in the studies summarized in Table 15. Table 15. Trials Conducted with TIVICAY or TIVICAY PD in HIV-1-Infected SubjectsBR Background regimen; CAR Current antiretroviral regimen; OBT Optimized background therapy.PopulationTrialTrial ArmsTimepoint (Week)Adults:Treatment-naive SPRING-2 (ING113086) (NCT01227824) TIVICAY 2 NRTIs (n 403)Raltegravir 2 NRTIs (n 405)96SINGLE (ING114467) (NCT01263015) TIVICAY EPZICOM (n 414)ATRIPLA (n 419)144FLAMINGO (ING114915) (NCT01449929) TIVICAY NRTI BR (n 243)Darunavir/ritonavir NRTI BR (n 242)96Treatment-experienced, INSTI-naive SAILING (ING111762) (NCT01231516) TIVICAY BR (n 354)Raltegravir BR (n 361)48INSTI-experienced VIKING-3 (ING112574)(NCT01328041)TIVICAY OBT (n 183)48Virologically suppressed SWORD-1 (NCT02429791)SWORD-2 (NCT02422797)Pooled presentationTIVICAY Rilpivirine (n 513)CAR (n 511)48Pediatrics:4 weeks and older and weighing at least kg without INSTI resistance IMPAACT P1093 (NCT01302847) TIVICAY or TIVICAY PD BR (n 75) 24 Treatment-naive Treatment-experienced, INSTI-naive INSTI-experienced Virologically suppressed 4 weeks and older and weighing at least kg without INSTI resistance 14.2 Adult Subjects Treatment-Naive SubjectsIn SPRING-2, 822 subjects were randomized and received at least dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual NRTI treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were 808 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 36 years, 13% female, 15% non-white, 11% had hepatitis and/or virus co-infection, 2% were CDC Class (AIDS), 28% had HIV-1 RNULL greater than 100,000 copies per mL, 48% had CD4+ cell count less than 350 cells per mm 3, and 39% received EPZICOM; these characteristics were similar between treatment groups. In SINGLE, 833 subjects were randomized and received at least dose of either TIVICAY 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis co-infection (hepatitis virus co-infection was excluded), 4% were CDC Class (AIDS), 32% had HIV-1 RNULL greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm 3; these characteristics were similar between treatment groups. Outcomes for SPRING-2 (Week 96 analysis) and SINGLE (Week 144 open-label phase analysis which followed the Week 96 double-blind phase) are provided in Table 16. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 16. Virologic Outcomes of Randomized Treatment in SPRING-2 at Week 96 and SINGLE at Week 144 (Snapshot Algorithm)a Adjusted for pre-specified stratification factors. Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window. Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation. The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 86% in the raltegravir group, with treatment difference of 2.6% and 95% CI of (-1.9%, 7.2%). The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with treatment difference of 7.4% and 95% CI of (2.5%, 12.3%). SPRING-2Week 96SINGLEWeek 144TIVICAY50 mg Once Daily 2 NRTIs(n 403)Raltegravir400 mg Twice Daily 2 NRTIs(n 405)TIVICAY50 mg EPZICOM Once Daily(n 414)ATRIPLA Once Daily(n 419)HIV-1 RNULL <50 copies/mL 82%78%71%63% Treatment difference 4.9% (95% CI: -0.6%, 10.3%) 8.3% (95% CI: 2.0%, 14.6%) Virologic nonresponse5%10%10%7% Data in window not <50 copies/mL1%3%4%<1% Discontinued for lack of efficacy2%3%3%3% Discontinued for other reasons while not suppressed<1%3%3%4% Change in ART regimen<1%<1%00No virologic data 12%12%18%30%Reasons Discontinued study/study drug due to adverse event or death 2%2%4%14% Discontinued study/study drug for other reasons 8%9%12%13% Missing data during window but on study2%<1%2%3%Proportion (%) of Subjects with HIV-1 RNULL <50 copies/mL by Baseline CategoryPlasma viral load (copies/mL) <=100,000 84%83%73%64% >100,00079%63%69%61%Gender Male 84%79%72%66% Female 70%68%69%48%Race White 83%78%72%71% African-American/African Heritage/Other77%75%71%47%SPRING-2: Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen. The median change in CD4+ cell counts from baseline was 276 cells per mm in the group receiving TIVICAY and 264 cells per mm for the raltegravir group at 96 weeks. There was no treatment-emergent resistance to dolutegravir or to the NRTI background.SINGLE: Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race. The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm in the group receiving TIVICAY EPZICOM and 332 cells per mm for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm (15.6 cells per mm 3, 78.2 cells per mm 3) (adjusted for pre-specified stratification factors: baseline HIV-1 RNULL, and baseline CD4+ cell count). There was no treatment-emergent resistance to dolutegravir, abacavir, or lamivudine.FLAMINGO: In FLAMINGO, 485 subjects were randomized and received at least dose of either TIVICAY 50 mg once daily (n 243) or darunavir ritonavir 800 mg/100 mg once daily (n 242), both in combination with investigator-selected NRTI background regimen (either fixed-dose abacavir and lamivudine [EPZICOM] or fixed-dose emtricitabine/tenofovir disoproxil fumarate [TRUVADA]). There were 484 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years, 15% female, 28% non-white, 10% had hepatitis and/or virus co-infection, 3% were CDC Class (AIDS), 25% had HIV-1 RNULL greater than 100,000 copies per mL, and 35% had CD4+ cell count less than 350 cells per mm 3; these characteristics were similar between treatment groups. Overall response rates by Snapshot algorithm through Week 96 were 80% for TIVICAY and 68% for darunavir/ritonavir. The proportion of subjects who were non-responders (HIV-1 RNULL greater than or equal to 50 copies per mL) at Week 96 was 8% and 12% in the arms receiving TIVICAY and darunavir ritonavir, respectively; no virologic data were available for 12% and 21% for subjects treated with TIVICAY and darunavir ritonavir, respectively. The adjusted overall response rate difference in proportion and 95% CI was 12.4% (4.7%, 20.2%). No treatment-emergent primary resistance substitutions were observed in either treatment group. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naive SubjectsIn the international, multicenter, double-blind trial (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 agents, including at least fully active agent. There were 715 subjects included in the efficacy and safety analyses. At baseline, the median age was 43 years, 32% were female, 50% non-white, 16% had hepatitis and/or virus co-infection, 46% were CDC Class (AIDS), 20% had HIV-1 RNULL greater than 100,000 copies per mL, and 72% had CD4+ cell count less than 350 cells per mm 3; these characteristics were similar between treatment groups. All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline. Week 48 outcomes for SAILING are shown in Table 17. Table 17. Virologic Outcomes of Randomized Treatment in SAILING at 48 Weeks (Snapshot Algorithm)a BR Background regimen. Background regimen was restricted to less than or equal to antiretroviral treatments with at least fully active agent. Adjusted for pre-specified stratification factors. Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation. TIVICAY 50 mg Once Daily BR (n 354)Raltegravir 400 mg Twice Daily BR (n 361)HIV-1 RNULL <50 copies/mL 71%64% Adjusted treatment difference 7.4% (95% CI: 0.7%, 14.2%)Virologic nonresponse20%28%No virologic data 9%9%Reasons Discontinued study/study drug due to adverse event or death3%4% Discontinued study/study drug for other reasons 5%4% Missing data during window but on study2%1%Proportion (%) with HIV-1 RNULL <50 copies/mL by Baseline CategoryPlasma viral load (copies/mL) <=50,000 copies/mL75%71% >50,000 copies/mL62%47%Background regimen No darunavir use 67%60% Darunavir use with primary PI substitutions85%67% Darunavir use without primary PI substitutions69%70%Gender Male 70%66% Female 74%60%Race White 75%71% African-American/African Heritage/Other67%57%Treatment differences were maintained across the baseline characteristics including CD4+ cell count and age.The mean changes in CD4+ cell counts from baseline were 162 cells per mm in the group receiving TIVICAY and 153 cells per mm in the raltegravir group. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced SubjectsVIKING-3 examined the effect of TIVICAY 50 mg twice daily over days of functional monotherapy, followed by OBT with continued treatment of TIVICAY 50 mg twice daily.In the multicenter, open-label, single-arm VIKING-3 trial, 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 days, then received TIVICAY with OBT from Day 8. total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening). At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis and/or virus co-infection. Median baseline CD4+ cell count was 140 cells per mm 3, median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C. Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had greater than or equal to NRTI, 75% greater than or equal to NNRTI, and 71% greater than or equal to PI major substitutions; 62% had non-R5 virus. Mean reduction from baseline in HIV-1 RNULL at Day (primary endpoint) was 1.4 log 10 (95% CI: 1.3 log 10, 1.5 log 10). Response at Week 48 was affected by baseline INSTI substitutions [see Microbiology 12.4)] After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. Week 48 virologic outcomes for VIKING-3 are shown in Table 18. Table 18. Virologic Outcomes of Treatment of VIKING-3 at 48 Weeks (Snapshot Algorithm)TIVICAY 50 mg Twice Daily OBT(n 183)HIV-1 RNULL <50 copies/mL63%Virologic nonresponse32%No virologic dataReasons Discontinued study/study drug due to adverse event or death3%Proportion (%) with HIV-1 RNULL <50 copies/mL by Baseline CategoryGender Male 63% Female 64%Race White 63% African-American/African Heritage/Other64%Subjects harboring virus with Q148 and with additional Q148-associated secondary substitutions also had reduced response at Week 48 in stepwise fashion [see Microbiology 12.4)]. The median change in CD4+ cell count from baseline was 80 cells per mm at Week 48. Virologically Suppressed SubjectsSWORD-1 and SWORD-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials. total of 1,024 adult HIV-1-infected subjects who were on stable suppressive antiretroviral regimen (containing NRTIs plus either an INSTI, an NNRTI, or PI) for at least months (HIV-1 RNULL less than 50 copies per mL), with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine received treatment in the trials. Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to TIVICAY 50 mg plus rilpivirine 25 mg administered once daily. The primary efficacy endpoint for the SWORD trial was the proportion of subjects with plasma HIV-1 RNULL less than 50 copies per mL at Week 48. The proportion of subjects with HIV-1 RNULL less than 50 copies per mL at Week 48 was 95% for both treatment groups; treatment difference and 95% CI was -0.2% (-3.0%, 2.5%). The proportion of subjects with HIV-1 RNULL greater than or equal to 50 copies per mL (virologic failure) at Week 48 was 0.6% and 1.2% for the dolutegravir plus rilpivirine treatment group and the current antiretroviral regimen treatment groups, respectively; treatment difference and 95% CI was -0.6% (-1.7%, 0.6%). Refer to the prescribing information for JULUCA (dolutegravir and rilpivirine) tablet for complete virologic outcome information.. 14.3 Pediatric Subjects. IMPAACT P1093 is an ongoing Phase 1/2, multicenter, open-label trial to evaluate the pharmacokinetic parameters, safety, tolerability, and efficacy of TIVICAY or TIVICAY PD in combination treatment regimens in HIV-1-infected infants, children, and adolescents aged at least weeks to 18 years. Subjects were stratified by age cohorts: Cohort 1, aged 12 to less than 18 years; Cohort 2A, aged to less than 12 years; Cohort 3, aged to less than years; Cohort 4, aged months to less than years; and Cohort 5, aged weeks to less than months. Seventy-five subjects received the recommended dose (determined by weight and age) of TIVICAY or TIVICAY PD [see Dosage and Administration 2.3, 2.4, 2.5)] These 75 subjects had median age of 27 months (range: to 214), were 59% female, and 68% were black or African American. At baseline, mean plasma HIV-1 RNULL was 4.4 log 10 copies per mL, median CD4+ cell count was 1,225 cells per mm (range: to 8,255), and median CD4+% was 23% (range: 0.3% to 49%). Overall, 33% had baseline plasma HIV-1 RNULL greater than 50,000 copies per mL and 12% had CDC HIV clinical classification of category C. The majority (80%) of subjects were treatment-experienced, but all were INSTI-naive. Most subjects had previously used at least NNRTI (44%) or PI (76%). Virologic outcomes from IMPAACT P1093 include subjects who received either TIVICAY tablets or TIVICAY PD tablets for oral suspension as per the dosing recommendations for their weight band and who had reached Week 24 (n 58) or Week 48 (n 42). At Week 24, 62% of subjects achieved HIV-1 RNULL less than 50 copies per mL and 86% achieved HIV-1 RNULL less than 400 copies per mL (Snapshot algorithm). The median CD4 count (percent) increase from baseline to Week 24 was 105 cells per mm (5%). At Week 48, 69% of subjects achieved HIV-1 RNULL less than 50 copies per mL and 79% achieved HIV-1 RNULL less than 400 copies per mL (Snapshot algorithm). The median CD4 count (percent) increase from baseline to Week 48 was 141 cells per mm (7%).

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. TIVICAY and TIVICAY PD are 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)] . 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) Previous hypersensitivity reaction to dolutegravir. 4) Coadministration with dofetilide. 4).

DESCRIPTION SECTION.


11 DESCRIPTION. TIVICAY contains dolutegravir, as dolutegravir sodium, an HIV INSTI. The chemical name of dolutegravir sodium is sodium (4 R,12a S)-9-[(2,4-difluorophenyl)methyl]carbamoyl-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2 H-pyrido[1,2:4,5]pyrazino[2,1- b][1,3]oxazin-7-olate. The empirical formula is 20H 18F 2N 3NaO and the molecular weight is 441.36 per mol. It has the following structural formula: Dolutegravir sodium is white to light yellow powder and is slightly soluble in water.Each film-coated tablet of TIVICAY for oral administration contains 10.5, 26.3, or 52.6 mg of dolutegravir sodium, which is equivalent to 10, 25, or 50 mg dolutegravir free acid, respectively, and the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients iron oxide yellow (25-mg and 50-mg tablets only), macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.Each TIVICAY PD tablet for oral suspension contains 5.26 mg of dolutegravir sodium, which is equivalent to mg dolutegravir free acid, and the following inactive ingredients: calcium sulfate dihydrate, crospovidone, mannitol, microcrystalline cellulose, povidone K29/32, silicified microcrystalline cellulose, sodium starch glycolate, strawberry cream flavor, sucralose, and sodium stearyl fumarate. The tablet film-coating contains hypromellose, polyethylene glycol, and titanium dioxide.. dolutegravir chemical structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Pregnancy Testing: Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential. 2.1, 5.3, 8.1, 8.3) May be taken without regard to food. 2.2, 2.6) 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. Adult PopulationRecommended DoseTreatment-naive or treatment-experienced INSTI-naive or virologically suppressed (HIV-1 RNULL <50 copies per mL) adults switching to dolutegravir plus rilpivirine ( 2.2) 50 mg once dailyTreatment-naive or treatment-experienced INSTI-naive when coadministered with certain UGT1A or CYP3A inducers 2.2, 7.2, 7.3) 50 mg twice dailyINSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance ( 2.2, 12.4) 50 mg twice dailyPediatric Patients: Treatment-naive or treatment-experienced INSTI-naive patients aged at least weeks and weighing at least kg. See Tables 2, and for complete pediatric dosing recommendations. 2.3, 2.4, 2.5). TIVICAY and TIVICAY PD are not bioequivalent and are not interchangeable on milligram-per-milligram basis. If certain UGT1A or CYP3A inducers are coadministered, then adjust the weight-based dose of TIVICAY to twice daily. 2.4, 2.5, 7.2, 7.3) Pediatric PopulationBody WeightRecommended Dose TIVICAY PDTablets for Oral Suspension kg to less than kg5 mg once daily kg to less than 10 kg15 mg once daily 10 kg to less than 14 kg20 mg once daily 14 kg to less than 20 kg25 mg once daily 20 kg and greater30 mg once dailyAlternative dosing recommendations for TIVICAY tablets for patients weighing at least 14 kg Table 4): 14 kg to less than 20 kg: 40 mg once daily. 20 kg and greater: 50 mg once daily. Pregnancy Testing: Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential. 2.1, 5.3, 8.1, 8.3) May be taken without regard to food. 2.2, 2.6) 14 kg to less than 20 kg: 40 mg once daily. 20 kg and greater: 50 mg once daily. 2.1 Pregnancy Testing before Initiation. Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential [see Warnings and Precautions 5.3), Use in Specific Populations 8.1, 8.3)] . 2.2 Recommended Dosage in Adults. TIVICAY tablets may be taken with or without food.Table 1. Dosing Recommendations for TIVICAY Tablets in Adult Patientsa 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 [see Drug Interactions 7.3)] PopulationRecommended DosageTreatment-naive or treatment-experienced INSTI-naive or virologically suppressed (HIV-1 RNULL <50 copies per mL) adults switching to dolutegravir plus rilpivirine 50 mg once dailyTreatment-naive or treatment-experienced INSTI-naive when coadministered with certain uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A) or cytochrome P450 (CYP)3A inducers [see Drug Interactions 7.2, 7.3)] 50 mg twice dailyINSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology 12.4)] 50 mg twice daily. 2.3 General Dosing and Administration Instructions for Pediatric Patients. Do not interchange TIVICAY tablets and TIVICAY PD tablets for oral suspension on milligram-per-milligram basis due to differing pharmacokinetic profiles [see Warnings and Precautions 5.6), Clinical Pharmacology 12.3)]. If switching from the tablets to the tablets for oral suspension, follow the recommended dosage in Table 3. If switching from the tablets for oral suspension to the tablets, follow the recommended dosage in Table 4. See administration instructions in Dosage and Administration 2.6) . 2.4 Recommended Dosage in Pediatric Patients Weighing to 14 kg The recommended weight-based dosage of TIVICAY PD tablets for oral suspension in pediatric patients weighing to 14 kg (4 weeks and older, treatment-naive or treatment-experienced but naive to INSTI treatment) is described in Table 2. Do not use TIVICAY tablets in patients weighing to 14 kg. See administration instructions in Dosage and Administration 2.6) Table 2. Recommended Dosage of TIVICAY PD in Pediatric Patients Weeks and Older Weighing to 14 kga If certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions 7.2, 7.3)] Body WeightTIVICAY PD Tablets for Oral SuspensionDaily Dose Number of5-mg Tablets3 kg to less than kg5 mg once daily16 kg to less than 10 kg15 mg once daily310 kg to less than 14 kg20 mg once daily4. 2.5 Recommended Dosage in Pediatric Patients Weighing 14 kg or Greater For pediatric patients weighing 14 kg or greater (4 weeks and older, treatment-naive or treatment-experienced but naive to INSTI treatment) administer either: TIVICAY PD tablets for oral suspension (preferred in pediatric patients weighing less than 20 kg) Table 3), or TIVICAY tablets for oral use Table 4) Table 3. Recommended Dosage of TIVICAY PD Tablets for Oral Suspension in Pediatric Patients Weighing 14 kg or Greatera If certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions 7.2, 7.3)] Body WeightTIVICAY PD Tablets for Oral SuspensionDaily Dose Number of5-mg Tablets14 kg to less than 20 kg25 mg once daily520 kg and greater30 mg once daily6Table 4. Recommended Dosage of TIVICAY Tablets in Pediatric Patients Weighing 14 kg or Greatera If certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions 7.2, 7.3)] Body WeightTIVICAY TabletsDaily Dose Number of Tablets14 kg to less than 20 kg40 mg once daily4 10-mg20 kg and greater50 mg once daily1 50-mg. 2.6 Additional Administration Instructions Administer TIVICAY tablets and TIVICAY PD tablets for oral suspension with or without food.Administration Instructions for TIVICAY PDDo not chew, cut, or crush TIVICAY PD [see Instructions for Use]. Instruct patients (or instruct caregivers) to either: Swallow the tablets for oral suspension whole (if more than one tablet is required, swallow one tablet at time to reduce the risk of choking), or Fully disperse the tablets for oral suspension in mL of drinking water (if using or tablets for oral suspension) or 10 mL (if using 4, 5, or tablets for oral suspension) in the supplied cup; swirl the suspension so that no lumps remain. After full dispersion, administer the oral suspension within 30 minutes of mixing [see Instructions for Use].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. TIVICAY Tablets:10 mg: Each tablet contains 10 mg of dolutegravir (as dolutegravir sodium). Tablets are white, round, film-coated, biconvex tablets debossed with SV 572 on one side and 10 on the other side.25 mg: Each tablet contains 25 mg of dolutegravir (as dolutegravir sodium). Tablets are pale yellow, round, film-coated, biconvex tablets debossed with SV 572 on one side and 25 on the other side.50 mg: Each tablet contains 50 mg of dolutegravir (as dolutegravir sodium). Tablets are yellow, round, film-coated, biconvex tablets debossed with SV 572 on one side and 50 on the other side.TIVICAY PD Tablets for Oral Suspension:Each tablet contains mg of dolutegravir (as dolutegravir sodium). Tablets are white, round, strawberry cream flavored, film-coated, biconvex tablets debossed with SV H7S on one side and 5 on the other side. TIVICAY tablets: 10 mg, 25 mg, and 50 mg 3) TIVICAY PD tablets for oral suspension: mg 3) TIVICAY tablets: 10 mg, 25 mg, and 50 mg 3) TIVICAY PD tablets for oral suspension: mg 3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Refer to the full prescribing information for important drug interactions with TIVICAY or TIVICAY PD. 4, 7) Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir. 7.2, 7.3) TIVICAY or TIVICAY PD should be taken hours before or hours after taking cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. When taken with food, TIVICAY and supplements containing calcium or iron can be taken at the same time. 7.3) Refer to the full prescribing information for important drug interactions with TIVICAY or TIVICAY PD. 4, 7) Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir. 7.2, 7.3) TIVICAY or TIVICAY PD should be taken hours before or hours after taking cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. When taken with food, TIVICAY and supplements containing calcium or iron can be taken at the same time. 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) (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, dalfampridine, and metformin, Table 8) [see Contraindications 4), Drug Interactions 7.3)] In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) (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: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, 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 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 8) [see Drug Interactions 7.3), Clinical Pharmacology 12.3)] In vitro, dolutegravir was not substrate of OATP1B1 or OATP1B3.. 7.3 Established and Other Potentially Significant Drug Interactions. Table provides clinical recommendations as result of drug interactions with TIVICAY or TIVICAY PD. 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 [s ee Dosage and Administration 2), Clinical Pharmacology 12.3).] Table 8. 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)] See Clinical Pharmacology 12.3) Table 11 or Table 12 for magnitude of interaction. 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. Concomitant Drug Class:Drug NameEffect on Concentration of Dolutegravir and/or Concomitant DrugClinical CommentHIV-1 Antiviral AgentsNon-nucleoside reverse transcriptase inhibitor: Etravirine DolutegravirUse of TIVICAY or TIVICAY PD with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.Non-nucleoside reverse transcriptase inhibitor: Efavirenz DolutegravirAdjust dose of TIVICAY to twice daily for treatment-naive and treatment-experienced, INSTI-naive adult patients.In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4). 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. Non-nucleoside reverse transcriptase inhibitor: NevirapineDolutegravirAvoid coadministration with nevirapine because there are insufficient data to make dosing recommendations.Protease inhibitors: Fosamprenavir/ritonavir Tipranavir/ritonavir DolutegravirAdjust dose of TIVICAY to twice daily for treatment-naive and treatment-experienced, INSTI-naive adult patients. In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4). 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. Other Agents DofetilideDofetilideCoadministration is contraindicated with TIVICAY or TIVICAY PD [see Contraindications 4)] Carbamazepine DolutegravirAdjust dose of TIVICAY to twice daily in treatment-naive or treatment-experienced, INSTI-naive adult patients. In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4). 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. Oxcarbazepine Phenytoin Phenobarbital St. Johns wort Hypericum perforatum) DolutegravirAvoid coadministration with TIVICAY or TIVICAY PD because there are insufficient data to make dosing recommendations.Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids or laxatives Sucralfate Buffered medications DolutegravirAdminister TIVICAY or TIVICAY PD hours before or hours after taking medications containing polyvalent cations.Oral calcium or iron supplements, including multivitamins containing calcium or ironaDolutegravirWhen taken with food, TIVICAY and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, TIVICAY or TIVICAY PD should be taken hours before or hours after taking supplements containing calcium or iron.Potassium channel blocker:DalfampridineDalfampridineElevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with TIVICAY or TIVICAY PD should be considered against the risk of seizures in these patients.MetforminMetforminRefer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of TIVICAY or TIVICAY PD and metformin.Rifampin DolutegravirAdjust dose of TIVICAY to twice daily for treatment-naive and treatment-experienced, INSTI-naive adult patients. In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4). Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. . 7.4 Drugs without Clinically Significant Interactions with Dolutegravir Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without 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)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. TIVICAY tablets, 50 mg, are yellow, round, film-coated, biconvex tablets debossed with SV 572 on one side and 50 on the other side.NDC: 70518-1487-00PACKAGING: 30 in BLISTER PACKStore TIVICAY tablets at 25C (77F); excursions permitted 15 to 30C (59 to 86F) [See USP Controlled Room Temperature].Repackaged and Distributed By:Remedy Repack, Inc.625 Kolter Dr. Suite Indiana, PA 1-724-465-8762.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. TIVICAY and TIVICAY PD are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type (HIV- 1) infection in adults (treatment-naive or -experienced) and in pediatric patients (treatment-naive or -experienced but integrase strand transfer inhibitor [INSTI]-naive) aged at least weeks and weighing at least kg [see Microbiology 12.4)]. TIVICAY is indicated in combination with rilpivirine as 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 RNULL less than 50 copies per mL) on stable antiretroviral regimen for at least months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent.TIVICAY is indicated in combination with rilpivirine as 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 RNULL less than 50 copies per mL) on stable antiretroviral regimen for at least months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent.. TIVICAY and TIVICAY PD are human immunodeficiency virus type (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults (treatment-naive or -experienced) and in pediatric patients (treatment-naive or -experienced but INSTI- naive) aged at least weeks and weighing at least kg. 1) TIVICAY is indicated in combination with rilpivirine as 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 RNULL less than 50 copies per mL) on stable antiretroviral regimen for at least months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent. 1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Drug InteractionsTIVICAY or TIVICAY PD may interact with other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. Johns wort [see Contraindications 4), Warnings and Precautions 5.4), Drug Interactions 7)] Hypersensitivity ReactionsAdvise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking TIVICAY or TIVICAY PD and other suspect agents, and seek medical attention if they develop rash associated with any of the following symptoms, as it may be sign of more serious reaction such as severe hypersensitivity: fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters or peeling of the skin; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; breathing difficulty; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes, dark or tea-colored urine, pale-colored stools or bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on the right side below the ribs) [see Warnings and Precautions 5.1)] HepatotoxicityInform patients that hepatotoxicity has been reported with dolutegravir [see Warnings and Precautions 5.2)] Advise patients that laboratory monitoring for hepatoxicity during therapy with TIVICAY or TIVICAY PD is recommended, especially for patients with liver disease, such as hepatitis or C. Embryo-Fetal ToxicityAdvise adolescents and adults of childbearing potential, including those actively trying to become pregnant, to discuss the risks and benefits of TIVICAY and TIVICAY PD with their healthcare provider to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy. If pregnancy is confirmed in the first trimester, advise patients to contact their healthcare provider [see Warnings and Precautions 5.3), Use in Specific Populations 8.1, 8.3)] Adolescents and adults of childbearing potential taking TIVICAY or TIVICAY PD should be counseled on the consistent use of effective contraception [see Warnings and Precautions 5.3), Use in Specific Populations 8.1, 8.3)] Immune Reconstitution SyndromeAdvise patients to inform their healthcare provider immediately of any signs or symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TIVICAY or TIVICAY PD is started [see Warnings and Precautions 5.5)] Different Formulations Are Not BioequivalentAdvise patients that TIVICAY and TIVICAY PD are not bioequivalent and are not interchangeable on milligram-per-milligram basis. Advise patients or their care provider that patients switching from one formulation to the other must adjust the dose for the new dosage formulation [see Dosage and Administration 2.3) and Warnings and Precautions 5.6)]. Pregnancy RegistryInform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to TIVICAY or TIVICAY PD during pregnancy [see Use in Specific Populations 8.1)] LactationInstruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations 8.2)] Administration InstructionsTo avoid dosing error from using the wrong formulation of dolutegravir, strongly advise patients and caregivers to visually inspect the tablets to verify the correct formulation each time the prescription is filled [see Dosage and Administration 2), Warnings and Precautions 5.6), How Supplied/Storage and Handling 16)] Inform patients and caregivers that TIVICAY PD tablets for oral suspension may be swallowed whole or dispersed in drinking water and should not be chewed, cut or crushed. The amount of water needed to disperse the tablet will depend on the dose (number of tablets prescribed).Instruct patients and caregivers that if dose of TIVICAY or TIVICAY PD is missed, to take it as soon as they remember. Advise patients and caregivers not to double the next dose or take more than the prescribed dose [see Dosage and Administration 2)] StorageInstruct patients and caregivers to store the TIVICAY 10-mg tablets and TIVICAY PD 5-mg tablets for oral suspension in the original package, keep the bottle tightly closed, and protect from moisture. Do not remove desiccant [see How Supplied/Storage and Handling 16)] TIVICAY, TIVICAY PD, EPZICOM, JULUCA, and TRIUMEQ are trademarks owned by or licensed to the ViiV Healthcare group of companies.The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT Repackaged By Distributed By: RemedyRepack Inc.625 Kolter Drive, Indiana, PA 15701(724) 465-8762.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Dolutegravir is an HIV-1 antiretroviral agent [see Microbiology 12.4)].

MICROBIOLOGY SECTION.


12.4 Microbiology. Mechanism of ActionDolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNULL) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNULL resulted in IC 50 values of 2.7 nM and 12.6 nM. Antiviral Activity in Cell CultureDolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC 50 values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade isolates with mean EC 50 value of 0.52 nM in viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against panel of HIV-1 clinical isolates (3 in each group of clades A, B, C, D, E, F, and G, and in group O) with EC 50 values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC 50 values against HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM. Antiviral Activity in Combination with Other Antiviral AgentsThe antiviral activity of dolutegravir was not antagonistic when combined with the INSTI, raltegravir; non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz or nevirapine; the NRTIs, abacavir or stavudine; the protease inhibitors (PIs), amprenavir or lopinavir; the CCR5 co-receptor antagonist, maraviroc; or the fusion inhibitor, enfuvirtide. Dolutegravir antiviral activity was not antagonistic when combined with the HBV reverse transcriptase inhibitor, adefovir, or inhibited by the antiviral, ribavirin.ResistanceCell Culture: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Passage of mutant viruses containing the Q148R or Q148H substitutions selected for additional substitutions in integrase that conferred decreased susceptibility to dolutegravir (fold-change increase of 13 to 46). The additional integrase substitutions included T97A, E138K, G140S, and M154I. Passage of mutant viruses containing both G140S and Q148H selected for L74M, E92Q, and N155H. Treatment-Naive Subjects: No subject who received dolutegravir 50-mg once-daily in the treatment-naive trials SPRING-2 (96 weeks) and SINGLE (144 weeks) had detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n 12 with HIV-1 RNULL greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and subject with 275 copies per mL HIV-1 RNULL had treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to the background regimen was observed in the dolutegravir arm in either the SPRING-2 or SINGLE trials. No treatment-emergent primary resistance substitutions were observed in either treatment group in the FLAMINGO trial through Week 96. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naive Subjects: In the dolutegravir arm of the SAILING trial for treatment-experienced and INSTI-naive subjects (n 354), treatment-emergent integrase substitutions were observed in of 28 (21%) subjects who had virologic failure and resistance data. In of the subjects isolates emergent INSTI substitutions included L74L/M/I, Q95Q/L, V151V/I (n 1 each), and R263K (n 2). The change in dolutegravir phenotypic susceptibility for these subject isolates was less than 2-fold. One subject isolate had pre-existing raltegravir resistance substitutions E138A, G140S, and Q148H at baseline and had additional emergent INSTI-resistance substitutions T97A and E138A/T with corresponding 148-fold reduction in dolutegravir susceptibility at failure. In the comparator raltegravir arm, 21 of 49 (43%) subjects with post-baseline resistance data had evidence of emergent INSTI-resistance substitutions (L74M, E92Q, T97A, E138Q, G140S/A, Y143R/C, Q148H/R, V151I, N155H, E157Q, and G163K/R) and raltegravir phenotypic resistance. Virologically Suppressed Subjects: SWORD-1 and SWORD-2 are identical trials in virologically suppressed subjects receiving NRTIs plus either an INSTI, an NNRTI, or PI, that switched to dolutegravir plus rilpivirine (n 513) or remained on their current antiviral regimen (n 511). Two subjects in each treatment arm had confirmed virologic failure at any time through Week 48. The subjects in the dolutegravir/rilpivirine arm had detectable resistance substitutions at rebound. One subject had the NNRTI-resistance-associated substitution K101K/E with no decreased susceptibility to rilpivirine (fold-change 1.2) at Week 36, had no INSTI resistance-associated substitutions or decreased susceptibility to dolutegravir (fold-change less than 2), and had HIV-1 RNULL less than 50 copies per mL at the withdrawal visit. The other subject had the dolutegravir resistance-associated substitution G193E at baseline (by exploratory HIV proviral DNULL archive sequencing) and at Week 24 (by conventional sequencing) without decreased susceptibility to dolutegravir (fold-change 1.02) at Week 24. No resistance-associated substitutions were observed for the other subjects in the comparative current antiretroviral regimen arm. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: VIKING-3 examined the efficacy of dolutegravir 50 mg twice daily plus optimized background therapy in subjects with prior or current virologic failure on an INSTI- (elvitegravir or raltegravir) containing regimen. Use of TIVICAY in INSTI-experienced patients should be guided by the number and type of baseline INSTI substitutions. The efficacy of TIVICAY 50 mg twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. Response by Baseline GenotypeOf the 183 subjects with baseline data, 30% harbored virus with substitution at Q148, and 33% had no primary INSTI-resistance substitutions (T66A/I/K, E92Q/V, Y143R/C/H, Q148H/R/K, and N155H) at baseline, but had historical genotypic evidence of INSTI-resistance substitutions, phenotypic evidence of elvitegravir or raltegravir resistance, or genotypic evidence of INSTI-resistance substitutions at screening.Response rates by baseline genotype were analyzed in an as-treated analysis at Week 48 (n 175) Table 13). The response rate at Week 48 to dolutegravir-containing regimens was 47% (24 of 51) when Q148 substitutions were present at baseline; Q148 was always present with additional INSTI-resistance substitutions Table 13). In addition, diminished virologic response of 40% (6 of 15) was observed when the substitution E157Q or was present at baseline with other INSTI-resistance substitutions but without Q148H or substitution. Table 13. Response by Baseline Integrase Genotype in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3a Includes INSTI-resistance substitutions Y143R/C/H and N155H. INSTI-resistance substitutions included T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. Two additional subjects had baseline genotypes of Q148Q/R plus L74L/I/M (virologic failure) and Q148R plus E138K (responder). The most common pathway with Q148H/R greater than or equal to INSTI-resistance substitutions had Q148+G140+E138 substitutions (n 16). Baseline GenotypeWeek 48(<50 copies/mL)n 175Overall Response66% (116/175)No Q148 substitution 74% (92/124)Q148H/R G140S/A/C without additional INSTI-resistance substitution 61% (17/28)Q148H/R >=2 INSTI-resistance substitutions b,c 29% (6/21)Response by Baseline PhenotypeResponse rates by baseline phenotype were analyzed in an as-treated analysis using all subjects with available baseline phenotypes through Week 48 (n 163) Table 14). These baseline phenotypic groups are based on subjects enrolled in VIKING-3 and are not meant to represent definitive clinical susceptibility cut points for dolutegravir. The data are provided to guide clinicians on the likelihood of virologic success based on pretreatment susceptibility to dolutegravir in INSTI-resistant patients. Table 14. Response by Baseline Dolutegravir Phenotype (Fold-Change from Reference) in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3Baseline Dolutegravir Phenotype(Fold-Change from Reference)Response at Week 48(<50 copies/mL)Subset = 163Overall Response64% (104/163)<3-fold change72% (83/116)3- <10-fold change53% (18/34)>=10-fold change23% (3/13)Integrase Strand Transfer Inhibitor Treatment-Emergent ResistanceThere were 50 subjects with virologic failure on the dolutegravir twice-daily regimen in VIKING-3 with HIV-1 RNULL greater than 400 copies per mL at the failure timepoint, Week 48 or beyond, or the last timepoint on trial. Thirty-nine subjects with virologic failure had resistance data that were used in the Week 48 analysis. In the Week 48 resistance analysis 85% (33 of 39) of the subjects with virologic failure had treatment-emergent INSTI-resistance substitutions in their isolates. The most common treatment-emergent INSTI-resistance substitution was T97A. Other frequently emergent INSTI-resistance substitutions included L74M, or V, E138K or A, G140S, Q148H, or K, M154I, or N155H. Substitutions E92Q, Y143R or C/H, S147G, V151A, and E157E/Q each emerged in to subjects isolates. At failure, the median dolutegravir fold-change from reference was 61-fold (range: 0.75 to 209) for isolates with emergent INSTI-resistance substitutions (n 33). Resistance to one or more background drugs in the dolutegravir twice-daily regimen also emerged in 49% (19 of 39) of subjects in the Week 48 resistance analysis In VIKING-4 (ING116529), 30 subjects with current virological failure on an INSTI-containing regimen and genotypic evidence of INSTI-resistance substitutions at screening were randomized to receive either dolutegravir 50 mg twice daily or placebo with the current failing regimen for days and then all subjects received open-label dolutegravir plus optimized background regimen from Day 8. Virologic responses at Week 48 by baseline genotypic and phenotypic INSTI-resistance categories and the INSTI resistance-associated substitutions that emerged on dolutegravir treatment in VIKING-4 were consistent with those seen in VIKING-3.Cross-ResistanceSite-Directed Integrase Strand Transfer Inhibitor-Resistant Mutant HIV-1 and HIV-2 Strains: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with or more substitutions) and INSTI-resistant site-directed mutant HIV-2 viruses. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively. Reverse Transcriptase Inhibitor- and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent antiviral activity against NNRTI-resistant, NRTI-resistant, and PI-resistant HIV-1 mutant clones compared with the wild-type strain.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisTwo-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14 times higher than those in humans at the maximum recommended dose. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10 times and 15 times higher in males and females, respectively, than those in humans at the maximum recommended dose.MutagenesisDolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.Impairment of FertilityIn study conducted in rats, there were no effects on mating or fertility with dolutegravir up to 1,000 mg per kg per day. This dose is associated with an exposure that is approximately 24 times higher than the exposure in humans at the maximum recommended dose.

OVERDOSAGE SECTION.


10 OVERDOSAGE. There is no known specific treatment for overdose with TIVICAY or TIVICAY PD. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


DRUG: TivicayGENERIC: dolutegravir sodiumDOSAGE: TABLET, FILM COATEDADMINSTRATION: ORALNDC: 70518-1487-0COLOR: yellowSHAPE: ROUNDSCORE: No scoreSIZE: mmIMPRINT: SV;572;50PACKAGING: 30 in BLISTER PACKACTIVE INGREDIENT(S):DOLUTEGRAVIR SODIUM 50mg in 1INULLCTIVE INGREDIENT(S):MANNITOLMICROCRYSTALLINE CELLULOSEPOVIDONE, UNSPECIFIEDSODIUM STARCH GLYCOLATE TYPE CORNSODIUM STEARYL FUMARATEFERRIC OXIDE YELLOWPOLYETHYLENE GLYCOL, UNSPECIFIEDPOLYVINYL ALCOHOL, UNSPECIFIEDTALCTITANIUM DIOXIDE. DOLUTEGRAVIR SODIUM 50mg in 1. MANNITOL. MICROCRYSTALLINE CELLULOSE. POVIDONE, UNSPECIFIED. SODIUM STARCH GLYCOLATE TYPE CORN. SODIUM STEARYL FUMARATE. FERRIC OXIDE YELLOW. POLYETHYLENE GLYCOL, UNSPECIFIED. POLYVINYL ALCOHOL, UNSPECIFIED. TALC. TITANIUM DIOXIDE. RemedyLabel.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. Effects on ElectrocardiogramIn randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3-fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). TIVICAY did not prolong the QTc interval over 24 hours postdose.Effects on Renal FunctionThe effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n 37) who received dolutegravir 50 mg once daily (n 12), dolutegravir 50 mg twice daily (n 13), or placebo once daily (n 12) for 14 days. decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1-infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV-1-infected subjects Table 9) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. Table 9. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1-Infected Adultsa Based on population pharmacokinetic analyses using data from SPRING-1 and SPRING-2. Based on population pharmacokinetic analyses using data from VIKING (ING112961) and VIKING-3. Parameter50 mg Once DailyGeometric Mean (%CV) 50 mg Twice DailyGeometric Mean (%CV) AUC (0-24) (mcg.h/mL) 53.6 (27)75.1 (35)C max (mcg/mL) 3.67 (20)4.15 (29)C min (mcg/mL) 1.11 (46)2.12 (47)TIVICAY tablets and TIVICAY PD tablets for oral suspension are not bioequivalent. The relative bioavailability of TIVICAY PD is approximately 1.6-fold higher than TIVICAY; therefore, the dosage forms are not interchangeable on milligram-per-milligram basis [see Dosage and Administration 2.3)]. AbsorptionFollowing oral administration of dolutegravir, peak plasma concentrations were observed to hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately days with average accumulation ratios for AUC, max, and 24 ranging from 1.2 to 1.5. Dolutegravir plasma concentrations increased in less than dose-proportional manner above 50 mg. Dolutegravir is P-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.Effect of Food: TIVICAY or TIVICAY PD may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir following 50-mg dose of TIVICAY. Low-, moderate-, and high-fat meals increased dolutegravir AUC (0-) by 33%, 41%, and 66%; increased max by 46%, 52%, and 67%; and prolonged max to 3, 4, and hours from hours under fasted conditions, respectively. DistributionDolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 based on population pharmacokinetic analysis.Cerebrospinal Fluid (CSF): In 12 treatment-naive subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per mL (range: 3.74 ng per mL to 18.3 ng per mL) to hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established. EliminationDolutegravir has terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 per hour based on population pharmacokinetic analyses.Metabolism: Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. Polymorphisms in Drug- Metabolizing Enzymes: In meta-analysis of healthy subject trials, subjects with UGT1A1 (n 7) genotypes conferring poor dolutegravir metabolism had 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n 41). Excretion: After single oral dose of 14C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose). Specific PopulationsPediatric Patients: The pharmacokinetics of dolutegravir were evaluated in the IMPAACT P1093 trial and in weight-band-based pharmacokinetic substudies from the ODYSSEY trial. Steady-state plasma exposure at doses by weight band are summarized in Table 10 [see Clinical Studies 14.3)] Mean dolutegravir AUC 0-24h and 24h in HIV-1-infected pediatric subjects were comparable to those in adults after 50 mg once daily or 50 mg twice daily. Mean max is higher in pediatrics, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects [see Use in Specific Populations 8.4)] Table 10. Summary of Pharmacokinetic Parameters in Pediatric HIV-1-Infected Subjects (Pooled Analyses for IMPAACT P1093 and ODYSSEY Trials) Data from weight-band-based pharmacokinetic substudies in the ODYSSEY trial. The bioavailability of TIVICAY PD tablets for oral suspension is ~1.6-fold that of TIVICAY tablets. Weight BandDose of TIVICAY or TIVICAY PD nPharmacokinetic ParameterGeometric Mean (%CV)C max (mcg/mL)AUC 0-24h (mcgh/mL)C 24h (ng/mL)3 kg to <6 kgTIVICAY PD mg once daily 83.80 (34)49.37 (49)962 (98)6 kg to <10 kgTIVICAY PD 15 mg once daily 175.27 (50)57.17 (76)706 (177)10 kg to <14 kgTIVICAY PD 20 mg once daily 135.99 (33)68.75 (48)977 (100)14 kg to <20 kgTIVICAY PD 25 mg once daily 195.97 (42)58.97 (44)725 (75)20 kg to <25 kgTIVICAY PD 30 mg once daily 97.16 (26)71.53 (26)759 (73)>=20 kgTIVICAY 50 mg once daily 494.92 (40)54.98 (43)778 (62)Geriatric Patients: Population pharmacokinetic analysis indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. Patients with Hepatic Impairment: In trial comparing subjects with moderate hepatic impairment (Child-Pugh Score B) with matched healthy controls, exposure of dolutegravir from single 50-mg dose was similar between the groups. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Patients with Renal Impairment: In trial evaluating the pharmacokinetics of single 50-mg tablet of dolutegravir comparing subjects with severe renal impairment (CrCl less than 30 mL per min) with matched healthy controls, AUC, max, and 24 of dolutegravir were lower by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis. HBV or HCV Co-infected Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection. Gender and Race: Population analyses using pooled pharmacokinetic data from adult trials indicated gender and race had no clinically relevant effect on the exposure of dolutegravir. Drug Interaction StudiesDrug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of dolutegravir on the exposure of coadministered drugs are summarized in Table 11 and the effects of coadministered drugs on the exposure of dolutegravir are summarized in Table 12. Dosing or regimen recommendations as result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table [see Dosage and Administration 2.2), Drug Interactions 7.3)] Table 11. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugsa The number of subjects represents the maximum number of subjects that were evaluated. Coadministered Drug(s)and Dose(s)Dose of TIVICAYnGeometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without DolutegravirNo Effect 1.00C max AUCC or 24 Daclatasvir 60 mg once daily 50 mg once daily 121.03 (0.84 to 1.25) 0.98 (0.83 to 1.15) 1.06 (0.88 to 1.29) Elbasvir 50 mg once daily50 mgsingle dose120.97(0.89, 1.05)0.98(0.93, 1.04)0.98(0.93, 1.03)Ethinyl estradiol 0.035 mg 50 mg twice daily 150.99 (0.91 to 1.08) 1.03 (0.96 to 1.11) 1.02 (0.93 to 1.11) Grazoprevir 200 mg once daily50 mgsingle dose120.64(0.44, 0.93)0.81(0.67, 0.97)0.86(0.79, 0.93)Metformin 500 mg twice daily 50 mg once daily 15 1.66 (1.53 to 1.81) 1.79 (1.65 to 1.93) Metformin 500 mg twice daily 50 mg twice daily 15 2.11 (1.91 to 2.33) 2.45 (2.25 to 2.66) Methadone 16 to 150 mg 50 mg twice daily 111.00 (0.94 to 1.06) 0.98 (0.91 to 1.06) 0.99 (0.91 to 1.07) Midazolam mg 25 mg once daily 100.95 (0.79 to 1.15) Norelgestromin 0.25 mg 50 mg twice daily 150.89 (0.82 to 0.97) 0.98 (0.91 to 1.04) 0.93 (0.85 to 1.03) Rilpivirine 25 mg once daily 50 mg once daily 161.10 (0.99 to 1.22) 1.06 (0.98 to 1.16) 1.21 (1.07 to 1.38) Sofosbuvir 400 mg once daily Metabolite (GS-331007)50 mgonce daily240.88(0.80, 0.98)0.92 (0.85, 0.99)NULL1.01(0.93, 1.10)0.99(0.97, 1.01)0.99(0.97, 1.01)Tenofovir disoproxil fumarate 300 mg once daily 50 mg once daily 151.09 (0.97 to 1.23) 1.12 (1.01 to 1.24) 1.19 (1.04 to 1.35) Velpatasvir 100 mg once daily50 mgonce daily240.94 (0.86, 1.02)0.91(0.84, 0.98)0.88(0.82, 0.94)Table 12. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravira Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. The number of subjects represents the maximum number of subjects that were evaluated. Coadministered Drug(s)and Dose(s)Dose of TIVICAYnGeometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered DrugsNo Effect 1.00C max AUCC or 24 Atazanavir 400 mg once daily 30 mg once daily 121.50 (1.40 to 1.59) 1.91 (1.80 to 2.03) 2.80 (2.52 to 3.11) Atazanavir/ritonavir 300/100 mg once daily 30 mg once daily 121.34 (1.25 to 1.42) 1.62 (1.50 to 1.74) 2.21 (1.97 to 2.47) Darunavir/ritonavir 600/100 mg twice daily 30 mg once daily 150.89 (0.83 to 0.97) 0.78 (0.72 to 0.85) 0.62 (0.56 to 0.69) Efavirenz 600 mg once daily 50 mg once daily 120.61 (0.51 to 0.73) 0.43 (0.35 to 0.54) 0.25 (0.18 to 0.34) Elbasvir/grazoprevir 50/200 mg once daily50 mgsingle dose121.22(1.05, 1.40)1.16(1.00, 1.34)1.14(0.95, 1.36)Etravirine 200 mg twice daily 50 mg once daily 160.48 (0.43 to 0.54) 0.29 (0.26 to 0.34) 0.12 (0.09 to 0.16) Etravirine darunavir/ritonavir 200 mg 600/100 mg twice daily 50 mg once daily 90.88 (0.78 to 1.00) 0.75 (0.69 to 0.81) 0.63 (0.52 to 0.76) Etravirine lopinavir/ritonavir 200 mg 400/100 mg twice daily 50 mg once daily 81.07 (1.02 to 1.13) 1.11 (1.02 to 1.20) 1.28 (1.13 to 1.45) Fosamprenavir/ritonavir 700 mg/100 mg twice daily 50 mg once daily 120.76 (0.63 to 0.92) 0.65 (0.54 to 0.78) 0.51 (0.41 to 0.63) Lopinavir/ritonavir 400/100 mg twice daily 30 mg once daily 151.00 (0.94 to 1.07) 0.97 (0.91 to 1.04) 0.94 (0.85 to 1.05) Rilpivirine 25 mg once daily 50 mg once daily 161.13 (1.06 to 1.21) 1.12 (1.05 to 1.19) 1.22 (1.15 to 1.30) Tenofovir 300 mg once daily 50 mg once daily 150.97 (0.87 to 1.08) 1.01 (0.91 to 1.11) 0.92(0.82 to 1.04)Tipranavir/ritonavir 500/200 mg twice daily 50 mg once daily 140.54 (0.50 to 0.57) 0.41 (0.38 to 0.44) 0.24 (0.21 to 0.27) Antacid (MAALOX) simultaneous administration 50 mg single dose 160.28 (0.23 to 0.33) 0.26 (0.22 to 0.32) 0.26 (0.21 to 0.31) Antacid (MAALOX) h after dolutegravir 50 mg single dose 160.82 (0.69 to 0.98) 0.74 (0.62 to 0.90) 0.70 (0.58 to 0.85) Calcium carbonate 1,200 mg simultaneous administration (fasted) 50 mg single dose 120.63 (0.50 to 0.81) 0.61 (0.47 to 0.80) 0.61 (0.47 to 0.80) Calcium carbonate 1,200 mg simultaneous administration (fed) 50 mg single dose 111.07 (0.83 to 1.38) 1.09 (0.84 to 1.43) 1.08 (0.81 to 1.42) Calcium carbonate 1,200 mg h after dolutegravir 50 mg single dose 111.00 (0.78 to 1.29) 0.94 (0.72 to 1.23) 0.90 (0.68 to 1.19) Carbamazepine 300 mg twice daily 50 mg once daily 16 0.67 (0.61 to 0.73) 0.51 (0.48 to 0.55) 0.27 (0.24 to 0.31) Daclatasvir 60 mg once daily 50 mg once daily 121.29 (1.07 to 1.57) 1.33 (1.11 to 1.59) 1.45 (1.25 to 1.68) Ferrous fumarate 324 mg simultaneous administration (fasted) 50 mg single dose 110.43 (0.35 to 0.52) 0.46 (0.38 to 0.56) 0.44 (0.36 to 0.54) Ferrous fumarate 324 mg simultaneous administration (fed) 50 mg single dose 111.03 (0.84 to 1.26) 0.98 (0.81 to 1.20) 1.00 (0.81 to 1.23) Ferrous fumarate 324 mg h after dolutegravir 50 mg single dose 100.99 (0.81 to 1.21) 0.95 (0.77 to 1.15) 0.92 (0.74 to 1.13) Multivitamin (One-A-Day) simultaneous administration 50 mg single dose 160.65 (0.54 to 0.77) 0.67 (0.55 to 0.81) 0.68 (0.56 to 0.82) Omeprazole 40 mg once daily 50 mg single dose 120.92 (0.75 to 1.11) 0.97 (0.78 to 1.20) 0.95 (0.75 to 1.21) Prednisone 60 mg once daily with taper 50 mg once daily 121.06 (0.99 to 1.14) 1.11 (1.03 to 1.20) 1.17 (1.06 to 1.28) Rifampin 600 mg once daily 50 mg twice daily 110.57 (0.49 to 0.65) 0.46 (0.38 to 0.55) 0.28 (0.23 to 0.34) Rifampin 600 mg once daily 50 mg twice daily 111.18 (1.03 to 1.37) 1.33 (1.15 to 1.53) 1.22 (1.01 to 1.48) Rifabutin 300 mg once daily 50 mg once daily 91.16 (0.98 to 1.37) 0.95 (0.82 to 1.10) 0.70 (0.57 to 0.87).

PREGNULLNCY SECTION.


8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TIVICAY or TIVICAY PD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryData from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first weeks of gestation are at potential risk. Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of TIVICAY and TIVICAY PD. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precautions 5.3)] There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD) of TIVICAY (see Data). DataHuman Data: In birth outcome surveillance study in Botswana, there were cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included cases of myelomeningocele, cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had neural tube defect, compared with infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate. Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir.Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir-containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%.Animal Data: Dolutegravir was administered orally at up to 1,000 mg per kg daily to pregnant rats and rabbits on Gestation Days to 17 and to 18, respectively, and to rats on Gestation Day to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (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/postnatal development study, decreased body weight of the developing offspring was observed during lactation at maternally toxic dose (approximately 27 times human exposure at the MRHD).

RECENT MAJOR CHANGES SECTION.


Indications and Usage 1) 06/2020Dosage and Administration, Pregnancy Testing before Initiation 2.1) 03/2021Dosage and Administration 2.3, 2.4, 2.5, 2.6) 06/2020Warnings and Precautions, Embryo-Fetal Toxicity 5.3) 03/2021Warnings and Precautions, Different Formulations Are Not Interchangeable 5.6) 06/2020.

SPL PATIENT PACKAGE INSERT SECTION.


PATIENT INFORMATIONTIVICAY (TIV-eh-kay)(dolutegravir)tabletsTIVICAY PD (TIV-eh-kay Pe De)(dolutegravir)tablets for oral suspensionWhat is TIVICAY and TIVICAY PDTIVICAY and TIVICAY PD are prescription medicines used to treat Human Immunodeficiency Virus-1 (HIV-1) infection together with:other HIV-1 medicines in adults who have not received HIV-1 medicines in the past or to replace their current HIV-1 medicines. other HIV-1 medicines in children, aged at least weeks and weighing at least 6.6 pounds (3 kg), who have not received HIV-1 medicines in the past or to replace their current HIV-1 medicines when their healthcare provider determines that they meet certain requirements. TIVICAY is used together with rilpivirine as complete regimen to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults to replace their current HIV-1 medicines when their healthcare provider determines that they meet certain requirements.HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).It is not known if TIVICAY or TIVICAY PD is safe and effective in children who are less than weeks of age and weigh less than 6.6 pounds (3 kg) or in children who have received certain types of medicine for HIV-1 infection.Do not take TIVICAY or TIVICAY PD if you:have ever had an allergic reaction to medicine that contains dolutegravir. take dofetilide. Before you take TIVICAY or TIVICAY PD, tell your healthcare provider about all of your medical conditions, including if you:have or have had liver problems, including hepatitis or infection. are pregnant or plan to become pregnant. TIVICAY or TIVICAY PD may harm your unborn baby. Your healthcare provider may prescribe different medicine than TIVICAY or TIVICAY PD if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy If you can become pregnant, your healthcare provider may perform pregnancy test before you start treatment with TIVICAY or TIVICAY PD. If you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with TIVICAY or TIVICAY PD. Tell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with TIVICAY or TIVICAY PD. Pregnancy Registry. There is pregnancy registry for individuals who take antiretroviral medicines, including TIVICAY and TIVICAY PD, during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.are breastfeeding or plan to breastfeed. Do not breastfeed if you take TIVICAY or TIVICAY PD.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. It is not known if TIVICAY or TIVICAY PD can pass to your baby in your breast milk. Talk with your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Some medicines interact with TIVICAY or TIVICAY PD. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.You can ask your healthcare provider or pharmacist for list of medicines that interact with TIVICAY or TIVICAY PD. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TIVICAY or TIVICAY PD with other medicines. How should take TIVICAY or TIVICAY PDTake TIVICAY or TIVICAY PD exactly as your healthcare provider tells you to take it. Take TIVICAY or TIVICAY PD with or without food. For children who cannot swallow tablets, read the Instructions for Use at the end of this patient information for detailed instructions on how to prepare dose of TIVICAY PD tablets for oral suspension. TIVICAY PD may be swallowed whole or dispersed in drinking water and should not be chewed, cut, or crushed. TIVICAY tablets are not the same as TIVICAY PD tablets for oral suspension and cannot be substituted for each other. Check to make sure you receive the correct form of TIVICAY each time you or your childs prescription is filled to avoid using the wrong medicine. Do not change your dose, switch medicines or stop taking TIVICAY or TIVICAY PD without talking with your healthcare provider first. If you take antacids, laxatives, or other medicines that contain aluminum, magnesium, or buffered medicines, TIVICAY or TIVICAY PD should be taken at least hours before or hours after you take these medicines. If you need to take iron or calcium supplements by mouth during treatment with TIVICAY or TIVICAY PD: If you take TIVICAY with food, you may take these supplements at the same time that you take TIVICAY. If you do not take TIVICAY or TIVICAY PD with food, take TIVICAY or TIVICAY PD at least hours before or hours after you take these supplements. Do not miss dose of TIVICAY or TIVICAY PD. If you miss dose of TIVICAY or TIVICAY PD, take it as soon as you remember. Do not take doses at the same time or take more than your prescribed dose. Stay under the care of healthcare provider during treatment with TIVICAY or TIVICAY PD. Do not run out of TIVICAY or TIVICAY PD. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy. If you take too much TIVICAY or TIVICAY PD, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of TIVICAY or TIVICAY PDTIVICAY or TIVICAY PD can cause serious side effects including: Allergic reactions. Call your healthcare provider right away if you develop rash with TIVICAY or TIVICAY PD. Stop taking TIVICAY or TIVICAY PD and get medical help right away if you develop rash with any of the following signs or symptoms: fever generally ill feeling tiredness muscle or joint aches blisters or sores in mouth blisters or peeling of the skin redness or swelling of the eyes swelling of the mouth, face, lips, or tongue problems breathing Liver problems. People with history of hepatitis or virus may have an increased risk of developing new or worsening changes in certain liver tests during treatment with TIVICAY or TIVICAY PD. Liver problems, including liver failure, have also happened in people without history of liver disease or other risk factors. Your healthcare provider may do blood tests to check your liver. Call your healthcare provider right away if you develop any of the following signs or symptoms of liver problems:your skin or the white part of your eyes turns yellow (jaundice) dark or tea-colored urine light-colored stools (bowel movements) nausea or vomiting loss of appetite pain, aching, or tenderness on the right side of your stomach area Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TIVICAY or TIVICAY PD. The most common side effects of TIVICAY include: trouble sleepingtirednessheadacheThese are not all the possible side effects of TIVICAY or TIVICAY PD. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TIVICAY or TIVICAY PDStore TIVICAY 10-mg, 25-mg, and 50-mg tablets at room temperature between 68F to 77F (20C to 25C). Store TIVICAY 10-mg tablets in the original bottle. Keep the bottle tightly closed and protected from moisture. The bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle. Store TIVICAY PD 5-mg tablets for oral suspension at room temperature below 86F (30C) in the original bottle. Keep the bottle tightly closed and protected from moisture. The bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle. Keep TIVICAY, TIVICAY PD, and all medicines out of the reach of children.General information about the safe and effective use of TIVICAY or TIVICAY PD.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TIVICAY or TIVICAY PD for condition for which it was not prescribed. Do not give TIVICAY or TIVICAY PD to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TIVICAY that is written for health professionals. For more information, go to www.TIVICAY.com or call 1-877-844-8872.What are the ingredients in TIVICAY and TIVICAY PDActive ingredient: dolutegravir.Inactive ingredients:TIVICAY tablets: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients iron oxide yellow (for the 25-mg and 50-mg tablets only), macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.TIVICAY PD tablets for oral suspension: calcium sulfate dihydrate, crospovidone, mannitol, microcrystalline cellulose, povidone K29/32, silicified microcrystalline cellulose, sodium starch glycolate, strawberry cream flavor, sucralose, and sodium stearyl fumarate,. The tablet film-coating contains hypromellose, polyethylene glycol, and titanium dioxide.Repackaged and Distributed By:Remedy Repack, Inc.625 Kolter Dr. Suite Indiana, PA 1-724-465-8762This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 03/2021INSTRUCTIONS FOR USETIVICAY PD (TIV-eh-kay Pe De)(dolutegravir) tablets for oral suspension5 mgRead this Instructions for Use before giving dose of medicine.Follow the steps below, using clean drinking water to prepare and give dose to an infant or child who cannot swallow the tablets.Important informationAlways give this medicine exactly as your healthcare provider tells you. Talk to your healthcare provider if you are not sure.Do not chew, cut, or crush the tablets.If you forget to give dose of medicine, give it as soon as you remember. Do not give doses at the same time or give more than your healthcare provider has prescribed.If your child does not or cannot take the full dose, call your healthcare provider.If you give too much medicine, get emergency medical help right away.If your child is able and prefers to swallow the tablets, then you may skip the following steps.Your pack contains:[Tivicay pack]A bottle containing 60 TIVICAY PD tablets for oral suspension. Dosing kit: Cup: Use this to prepare and give the medicine to children. Syringe: Use this to give the medicine to infants. You will also need:Clean drinking water.Getting ReadyStep 1. Pour water[Figure A]Figure APour clean drinking water into the cup. The Water Volume Guide in Figure shows the amount of water needed for the prescribed dose. See Figure A. Use drinking water only.Do not use any other drink or food to prepare the dose.Step 2. Prepare the medicine[Figure and Figure C]Figure Figure CAdd the prescribed number of tablet(s) to the water. See Figure B. Swirl the cup gently for to minutes to disperse the tablet(s). The medicine will become cloudy. Take care not to spill any of the medicine. See Figure C. Check that the medicine is ready. If there are any lumps of tablet, swirl the cup until they are gone. If you spill any medicine, clean up the spill.Throw away the rest of the prepared medicine and make new dose.You must give the dose of medicine within 30 minutes of preparing the dose. If it has been more than 30 minutes, wash away all the dose in the cup using water and prepare new dose of medicine.Giving the medicineStep 3. Give the medicine[Figure D]Figure DMake sure that the child is upright. Give all the prepared medicine to the child. See Figure D. Add another mL of drinking water to the cup, swirl, and give it all to the child. Repeat if any medicine remains in the cup to make sure the child gets the full dose. [Figure and Figure F]Figure Figure FPlace the tip of the syringe into the prepared medicine and draw up all the medicine into the syringe by pulling up on the plunger. See Figure E. Place the tip of the syringe against the inside of the infants cheek. Gently push down the plunger to give the dose slowly. See Figure F. Add another mL of drinking water to the cup and swirl. Draw up the remaining medicine into the syringe and give it all to the infant. Repeat if any medicine remains in the syringe to make sure the infant gets the full dose. Allow time for the medicine to be swallowed .CleaningStep 4. Clean the dosing texts[Figure and Figure H]Figure Figure HWash the cup with water. See Figure G. Pull the plunger out of the syringe and wash the syringe parts separately in water. Allow parts to dry completely before reassembling and storing. See Figure H. All parts will need to be clean before preparing the next dose. Storage InformationStore TIVICAY PD tablets for oral suspension at room temperature below 86F (30C) in the original bottle. Keep the bottle tightly closed and protect from moisture. The bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.Keep TIVICAY PD and all medicines out of the reach of children.Disposal InformationWhen all the tablets in the bottle have been taken or are no longer needed, throw away the bottle, cup, and syringe. Dispose of them using your local household waste guidelines.You will get new cup and syringe in your next pack.Repackaged and Distributed By:Remedy Repack, Inc.625 Kolter Dr. Suite Indiana, PA 1-724-465-8762This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 06/2020.

SPL UNCLASSIFIED SECTION.


2.1 Pregnancy Testing before Initiation. Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential [see Warnings and Precautions 5.3), Use in Specific Populations 8.1, 8.3)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Pregnancy: Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. 2.1, 5.3, 8.1, 8.3) Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. 8.2) Females and males of reproductive potential: Pregnancy testing is recommended in adolescents and adults of childbearing potential. Patients should be counseled on the consistent use of effective contraception. 8.1, 8.3) Pregnancy: Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. 2.1, 5.3, 8.1, 8.3) Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. 8.2) Females and males of reproductive potential: Pregnancy testing is recommended in adolescents and adults of childbearing potential. Patients should be counseled on the consistent use of effective contraception. 8.1, 8.3) 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TIVICAY or TIVICAY PD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryData from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first weeks of gestation are at potential risk. Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of TIVICAY and TIVICAY PD. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precautions 5.3)] There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD) of TIVICAY (see Data). DataHuman Data: In birth outcome surveillance study in Botswana, there were cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included cases of myelomeningocele, cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had neural tube defect, compared with infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate. Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir.Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir-containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%.Animal Data: Dolutegravir was administered orally at up to 1,000 mg per kg daily to pregnant rats and rabbits on Gestation Days to 17 and to 18, respectively, and to rats on Gestation Day to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (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/postnatal development study, decreased body weight of the developing offspring was observed during lactation at maternally toxic dose (approximately 27 times human exposure at the MRHD). 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommends 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 dolutegravir 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), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving dolutegravir.DataAnimal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following 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 hours postdose. 8.3 Females and Males of Reproductive Potential In adolescents and adults of childbearing potential currently on TIVICAY or TIVICAY PD who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TIVICAY or TIVICAY PD and discuss with the patient if an alternative treatment should be considered [see Warnings and Precautions 5.3), Use in Specific Populations 8.1)] Pregnancy TestingPregnancy testing is recommended in adolescents and adults of childbearing potential before initiation of TIVICAY or TIVICAY PD [see Dosage and Administration 2.1)] ContraceptionAdolescents and adults of childbearing potential who are taking TIVICAY or TIVICAY PD should be counseled on the consistent use of effective contraception.. 8.4 Pediatric Use. The safety, pharmacokinetics, and effectiveness of TIVICAY and TIVICAY PD were evaluated in 75 HIV-1-infected, treatment-naive or treatment-experienced, INSTI-naive pediatric and adolescent subjects aged weeks to less than 18 years weighing at least kg in an ongoing, open-label, multicenter, dose-finding clinical trial, IMPAACT P1093 [see Adverse Reactions 6.1), Clinical Pharmacology 12.3), Clinical Studies 14.3)] Additional pharmacokinetics data were evaluated in pharmacokinetic substudies in ODYSSEY, an ongoing open-label, randomized, non-inferiority trial to evaluate the safety, efficacy, and pharmacokinetic parameters of TIVICAY or TIVICAY PD plus two NRTIs compared with standard of care in HIV-1-infected pediatric subjects younger than 18 years [see Clinical Pharmacology 12.3)] Overall, the safety data in pediatric subjects from the IMPAACT P1093 trial were comparable to those observed in adults [see Adverse Reactions 6.1)] The pharmacokinetic parameters of TIVICAY or TIVICAY PD in pediatric subjects from IMPAACT P1093 and ODYSSEY were comparable to those of adults receiving 50 mg once daily or twice daily [see Clinical Pharmacology 12.3)] The effectiveness observed in IMPAACT P1093 is comparable to that of treatment-experienced adult subjects. Safety and effectiveness of TIVICAY or TIVICAY PD have not been established in pediatric patients aged less than weeks or weighing less than kg or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (e.g., raltegravir, elvitegravir).. 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 or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY and TIVICAY PD are 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-naive or treatment-experienced and INSTI-naive 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, TIVICAY PD, or other coadministered antiretroviral agents [see Clinical Pharmacology 12.3)] There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported. Discontinue TIVICAY or TIVICAY PD and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop, as delay in stopping treatment may result in life-threatening reaction. 5.1) Hepatotoxicity has been reported in patients receiving dolutegravir-containing regimens. Patients with underlying hepatitis or may be at increased risk for worsening or development of transaminase elevations. Monitoring for hepatotoxicity is recommended. 5.2) Embryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception. 2.1, 5.3, 8.1, 8.3) Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. 5.5) TIVICAY tablets and TIVICAY PD tablets for oral suspension are not interchangeable. 2.3, 5.6) Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported. Discontinue TIVICAY or TIVICAY PD and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop, as delay in stopping treatment may result in life-threatening reaction. 5.1) Hepatotoxicity has been reported in patients receiving dolutegravir-containing regimens. Patients with underlying hepatitis or may be at increased risk for worsening or development of transaminase elevations. Monitoring for hepatotoxicity is recommended. 5.2) Embryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception. 2.1, 5.3, 8.1, 8.3) Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. 5.5) TIVICAY tablets and TIVICAY PD tablets for oral suspension are not interchangeable. 2.3, 5.6) 5.1 Hypersensitivity Reactions. Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase clinical trials. Discontinue TIVICAY or TIVICAY PD and other suspect agents immediately if signs or symptoms of 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, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TIVICAY or TIVICAY PD or other suspect agents after the onset of hypersensitivity may result in life-threatening reaction. TIVICAY and TIVICAY PD are contraindicated in patients who have experienced previous hypersensitivity reaction to dolutegravir.. 5.2 Hepatotoxicity. Hepatic adverse events have been reported in patients receiving dolutegravir-containing regimen. Patients with underlying hepatitis or may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY or TIVICAY PD [see Adverse Reactions 6.1)] In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended. 5.3 Embryo-Fetal Toxicity. An ongoing observational study showed an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform adolescents and adults of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with TIVICAY and TIVICAY PD. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester [see Use in Specific Populations 8.1, 8.3)] Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential [see Dosage and Administration 2.1)] Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception [see Use in Specific Populations 8.1, 8.3)] TIVICAY or TIVICAY PD may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus.. 5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions. The concomitant use of TIVICAY or TIVICAY PD and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications 4), Drug Interactions 7.3)] Loss of therapeutic effect of TIVICAY or TIVICAY PD and possible development of resistance. Possible clinically significant adverse reactions from greater exposures of concomitant drugs. For concomitant drugs for which the interaction can be mitigated, please see Table 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 TIVICAY or TIVICAY PD; review concomitant medications during therapy with TIVICAY or TIVICAY PD; and monitor for the adverse reactions associated with the concomitant drugs. Loss of therapeutic effect of TIVICAY or TIVICAY PD and possible development of resistance. Possible clinically significant adverse reactions from greater exposures of concomitant drugs. 5.5 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY or TIVICAY PD. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.. 5.6 Different Formulations Are Not Interchangeable TIVICAY and TIVICAY PD are not bioequivalent and are not interchangeable on milligram-per-milligram basis [see Clinical Pharmacology 12.3)] If pediatric patient switches from one formulation to the other, the dose must be adjusted for the new dosage formulation [see Dosage and Administration 2.3)] Incorrect dosing of given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure of dolutegravir.