Fostemsavir Tromethamine

1 INDICATIONS AND USAGE RUKOBIA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations [see Clinical Studies ( 14 )]. RUKOBIA, a human immunodeficiency virus type 1 (HIV-1) gp120-directed attachment inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. ( 1 , 12.4 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of RUKOBIA is one 600-mg tablet taken orally twice daily with or without food [see Clinical Pharmacology ( 12.3 )] . Swallow tablets whole. Do not chew, crush, or split tablets. One tablet taken twice daily with or without food. ( 2 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Immune reconstitution syndrome [see Warnings and Precautions ( 5.1 )] . • QTc prolongation [see Warnings and Precautions ( 5.2 )] . • Elevations in hepatic transaminases in patients with hepatitis B or C virus co-infection [see Warnings and Precautions ( 5.3 )]. The most common adverse reaction (all grades) observed in ≥5% of subjects was nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 620 subjects with HIV-1 infection received at least one dose of RUKOBIA as part of a controlled clinical trial. The primary safety assessment of RUKOBIA is based on 96 weeks of data from a Phase 3 partially randomized, international, multicenter, double-blind, placebo-controlled trial (BRIGHTE) conducted in 371 heavily treatment-experienced adult subjects [see Clinical Studies ( 14 )] . In the randomized cohort, 203 subjects received at least one dose of blinded RUKOBIA 600 mg twice daily and 69 subjects received placebo in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, all randomized subjects except one received open-label RUKOBIA 600 mg twice daily plus an optimized background therapy (OBT). In the nonrandomized cohort, 99 subjects received open-label RUKOBIA 600 mg twice daily plus OBT from Day 1 onward. A total of 370 subjects (271 randomized and 99 nonrandomized) received at least 1 dose of RUKOBIA 600 mg twice daily in the BRIGHTE trial. Overall, most (81%) of the adverse reactions reported with RUKOBIA were mild or moderate in severity. The proportion of subjects who discontinued treatment with RUKOBIA due to an adverse event was 7% at Week 96 (randomized: 5% and nonrandomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of subjects receiving RUKOBIA). Serious drug reactions occurred in 3% of subjects and included 3 cases of severe immune reconstitution inflammatory syndrome. Data from the randomized cohort form the basis of the safety assessment of RUKOBIA because the presence of significant comorbid illness in the nonrandomized cohort (associated with advanced HIV infection) may confound the assessment of causality. Adverse reactions (all grades) reported in ≥2% of subjects in the randomized cohort in the Week 96 analysis are listed in Table 1 . Table 1. Adverse Reactions a (Grades 1 to 4) Reported in ≥2% of Subjects Receiving RUKOBIA plus OBT in the BRIGHTE Trial, Randomized Cohort (Week 96 Analysis) OBT = Optimized background therapy. a Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drug by the investigator. b Of the 272 subjects enrolled in the randomized cohort, 1 subject who received placebo withdrew from the trial prior to receiving RUKOBIA in the open-label phase of the trial. c Includes pooled terms: abdominal discomfort, abdominal pain, and abdominal pain upper. d Includes pooled terms: fatigue and asthenia. e Includes pooled terms: rash, rash generalized, rash maculo-papular, rash pruritic, and dermatitis allergic. f Includes pooled terms: insomnia, sleep deficit, sleep disorder, abnormal dreams. Adverse Reaction RUKOBIA plus OBT (n = 271) b Nausea 10% Diarrhea 4% Headache 4% Abdominal pain c 3% Dyspepsia 3% Fatigue d 3% Rash e 3% Sleep disturbance f 3% Immune Reconstitution Inflammatory Syndrome 2% Somnolence 2% Vomiting 2% Adverse reactions in the nonrandomized cohort were similar to those observed in the randomized cohort. The most common adverse reactions reported in nonrandomized subjects were fatigue (7%), nausea (6%), and diarrhea (6%). Less Common Adverse Reactions The following adverse reactions occurred in <2% of subjects receiving RUKOBIA in the randomized cohort of the BRIGHTE trial. These events have been included based on the assessment of potential causal relationship and were also reported in the nonrandomized cohort. Cardiac Disorders: Electrocardiogram QT prolonged. All reports were asymptomatic. Musculoskeletal Disorders: Myalgia. Nervous System Disorders: Dizziness, d ysgeusia, neuropathy peripheral (includes pooled terms: neuropathy peripheral and peripheral sensory neuropathy). Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities Selected laboratory abnormalities (Grades 3 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in ≥2% of subjects in the randomized cohort of the BRIGHTE trial are presented in Table 2 . Table 2. Selected Laboratory Abnormalities (Grades 3 to 4) Reported in ≥2% of Subjects in the Randomized Cohort Receiving RUKOBIA plus OBT in the BRIGHTE Trial (Week 96 Analysis) OBT = Optimized background therapy; ULN = Upper limit of normal. a Percentages were calculated based on the number of subjects with post-baseline toxicity grades for each laboratory parameter (n = 221 for cholesterol and triglycerides, n = 216 for LDL cholesterol, and n = 268 for all other parameters). b Grade 3 only (no Grade 4 values reported). Laboratory Parameter Preferred Term RUKOBIA plus OBT (n = 271 a ) ALT (>5.0 x ULN) 5% AST (>5.0 x ULN) 4% Direct bilirubin (>ULN) b 7% Bilirubin (≥2.6 x ULN) 3% Cholesterol (≥300 mg/dL) b 5% Creatinine (>1.8 x ULN or 1.5 x baseline) 19% Creatine kinase (≥10 x ULN) 2% Hemoglobin (<9.0 g/dL) 6% Hyperglycemia (>250 mg/dL) 4% Lipase (>3.0 x ULN) 5% LDL cholesterol (≥190 mg/dL) 4% Neutrophils (≤599 cells/mm 3 ) 4% Triglycerides (>500 mg/dL) 5% Urate (>12 mg/dL) 3% The incidence of selected laboratory abnormalities (Grades 3 to 4) in the nonrandomized cohort were overall consistent with those of the randomized cohort, with the exception of direct bilirubin (14% versus 7%), bilirubin (6% versus 3%), lipase (10% versus 5%), triglycerides (10% versus 5%), neutrophils (7% versus 4%), and leukocytes (6% versus 1%), respectively. Changes in Serum Creatinine: Clinically relevant increases in serum creatinine have primarily occurred in patients with identifiable risk factors for reduced renal function, including pre-existing medical history of renal disease and/or concomitant medications known to cause increases in creatinine. A causal association between RUKOBIA and elevation in serum creatinine has not been established. Changes in Direct Bilirubin: Increases in direct (conjugated) bilirubin have been observed following treatment with RUKOBIA ( Table 2 ). Cases of clinical significance were uncommon and were confounded by the presence of intercurrent serious comorbid events (e.g., sepsis, cholangiocarcinoma, or other complications of viral hepatitis co-infection). In the remaining cases, elevations in direct bilirubin (without clinical jaundice) were typically transient, occurred without increases in liver transaminases, and resolved on continued RUKOBIA. Changes in ALT and AST in Subjects with Hepatitis B and/or Hepatitis C Virus Co-Infection: A total of 29 subjects with Hepatitis B and/or Hepatitis C co-infection were enrolled in the BRIGHTE trial (randomized and nonrandomized cohorts combined). Grade 3 and 4 elevations in ALT and AST occurred in 14% of these subjects compared with 3% (ALT) and 2% (AST) of subjects without viral hepatitis co-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn [see Warnings and Precautions ( 5.3 )] .

12.3 Pharmacokinetics Fostemsavir is a prodrug of temsavir, its active moiety. Fostemsavir was generally not detectable in plasma following oral administration. However, temsavir was readily absorbed ( Table 4 ). Following oral administration, increases in plasma temsavir exposure (C max and AUC tau ) appeared dose proportional or slightly greater than dose proportional, over the range of 600 mg to 1,800 mg of RUKOBIA. The pharmacokinetics of temsavir following administration of RUKOBIA are similar between healthy and HIV-1–infected subjects. Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic properties of temsavir following administration of RUKOBIA are provided in Table 4 . The multiple-dose pharmacokinetic parameters are provided in Table 5 . Table 4. Pharmacokinetic Properties of Temsavir HSA = Human serum albumin; UGT = Uridine diphosphate glucuronosyl transferases. a Dosing in absolute bioavailability study: single-dose administration of fostemsavir extended-release tablet 600 mg followed by single IV infusion of [ 13 C] temsavir 100 mcg. b Geometric mean ratio (fed/fasted) in pharmacokinetic parameters and (90% confidence interval). Standard meal = ~423 kcal, 36% fat, 47% carbohydrates, and 17% protein. High-calorie/high-fat meal = ~985 kcal, 60% fat, 28% carbohydrates, and 12% protein. c Volume of distribution at steady state (Vss) following IV administration. d Apparent clearance. e In vitro studies have shown that temsavir is biotransformed into 2 predominant circulating inactive metabolites: BMS-646915 (hydrolysis metabolite) and BMS-930644 (N-dealkylated metabolite). f Dosing in mass balance study: single-dose administration of [ 14 C] fostemsavir oral solution 300 mg containing 100 microCi (3.7 MBq) of total radioactivity. Absorption % Absolute bioavailability a 26.9 T max (h) 2.0 Effect of standard meal (relative to fasting) b AUC ratio =1.10 (0.95, 1.26) Effect of high-fat meal (relative to fasting) b AUC ratio =1.81 (1.54, 2.12) Distribution % Plasma protein binding 88.4 (primarily to HSA) Blood-to-plasma ratio 0.74 Steady-state volume of distribution (Vss, L) c 29.5 Elimination Major route of elimination Metabolism Clearance (CL and CL/F d , L/h) 17.9 and 66.4 Half-life (h) 11 Metabolism Metabolic pathways e Hydrolysis (esterases) [36.1% of oral dose] Oxidation (CYP3A4) [21.2% of oral dose] UGT [<1% of oral dose] Excretion % of dose excreted in urine (unchanged drug) f 51 (<2) % of dose excreted in feces (unchanged drug) f 33 (1.1) Table 5. Multiple-Dose Pharmacokinetic Parameters of Temsavir CV = Coefficient of variation; C max = Maximum concentration; AUC = Area under the time concentration curve; C 12 = Concentration at 12 hours. a Based on population pharmacokinetic analyses in heavily treatment-experienced adult subjects with HIV-1 infection receiving 600 mg of RUKOBIA twice daily with or without food in combination with other antiretroviral drugs. Parameter Mean (CV%) Temsavir a C max (ng/mL) 1,770 (39.9) AUC tau (ng.h/mL) 12,900 (46.4) C trough or C 12 (ng/mL) 478 (81.5) Specific Populations No clinically significant differences in the pharmacokinetics of temsavir were observed based on age, sex, race/ethnicity (White, Black/African American, Asian, or other). The effect of hepatitis B and/or C virus co-infection on the pharmacokinetics of temsavir is unknown. The pharmacokinetics of temsavir has not been studied in pediatric subjects and data are limited in subjects aged 65 years or older. Population pharmacokinetic analyses of subjects with HIV-1 infection aged up to 73 years from studies with RUKOBIA indicated age had no clinically relevant effect on the pharmacokinetics of temsavir [see Use in Specific Populations ( 8.4 , 8.5 )] . Patients with Renal Impairment: No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe renal impairment. No clinically relevant differences in temsavir pharmacokinetics were observed in patients with end-stage renal disease (ESRD) on hemodialysis compared with the same patients with ESRD off hemodialysis. Temsavir was not readily cleared by hemodialysis with approximately 12.3% of the administered dose removed during the 4-hour hemodialysis session [see Use in Specific Populations ( 8.6 )] . Patients with Hepatic Impairment: No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C) [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies Temsavir is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Drugs that induce or inhibit CYP3A, P-gp, and BCRP may affect temsavir plasma concentrations. Coadministration of fostemsavir with drugs that are strong CYP3A inducers result in decreased concentrations of temsavir. Coadministration of fostemsavir with drugs that are moderate CYP3A inducers and/or strong CYP3A, P-gp and/or BCRP inhibitors are not likely to have a clinically relevant effect on the plasma concentrations of temsavir. Temsavir is an inhibitor of OATP1B1 and OATP1B3. Additionally, temsavir and 2 metabolites ( Table 4 ) are inhibitors of BCRP. Thus, temsavir is expected to affect the pharmacokinetics of drugs that are substrates of OATP1B1/3 and/or BCRP [see Drug Interactions ( 7.3 )] . At clinically relevant concentrations, significant interactions are not expected when RUKOBIA is coadministered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1, 1A4, 1A6, 1A9, 2B7; P-gp; multidrug resistance protein (MRP)2; bile salt export pump (BSEP); sodium taurocholate co-transporting polypeptide (NTCP); multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2 based on in vitro and clinical drug interaction results ( Table 6 ). Drug interaction studies were performed with RUKOBIA and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of temsavir on the pharmacokinetics of coadministered drugs are summarized in Table 6 and the effects of coadministration of other drugs on the pharmacokinetics of temsavir are summarized in Table 7 . Dosing recommendations as a result of established and other potentially significant drug-drug interactions with RUKOBIA are provided in Table 3 [see Drug Interactions ( 7.3 )] . Table 6. Effect of Fostemsavir a on the Pharmacokinetics of Coadministered Drugs CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available. AUC = AUC tau for repeat-dose studies and AUC (0-inf) for single-dose study. a Temsavir is the active moiety. Coadministered Drug(s) and Dose(s) Dose of RUKOBIA n Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drugs with/without RUKOBIA No Effect = 1.00 C max AUC C tau Atazanavir + 300 mg once daily/ 600 mg twice daily 18 1.03 (0.96, 1.10) 1.09 (1.03, 1.15) 1.19 (1.10, 1.30) Ritonavir 100 mg once daily 1.02 (0.96, 1.09) 1.07 (1.03, 1.10) 1.22 (1.12, 1.32) Darunavir + 600 mg twice daily/ 600 mg twice daily 13 0.98 (0.93, 1.04) 0.94 (0.89, 1.00) 0.95 (0.87, 1.04) Ritonavir 100 mg twice daily 1.00 (0.86, 1.16) 1.15 (0.99, 1.33) 1.19 (1.06, 1.35) Darunavir + 600 mg twice daily/ 600 mg twice daily 13 0.95 (0.90, 1.01) 0.94 (0.89, 0.99) 0.88 (0.77, 1.01) Ritonavir + 100 mg twice daily/ 1.14 (0.96, 1.35) 1.09 (0.98, 1.22) 1.07 (0.97, 1.17) Etravirine 200 mg twice daily 1.18 (1.10, 1.27) 1.28 (1.20, 1.36) 1.28 (1.18, 1.39) Etravirine 200 mg twice daily 600 mg twice daily 14 1.11 (1.04, 1.19) 1.11 (1.05, 1.17) 1.14 (1.08, 1.21) Tenofovir disoproxil fumarate 300 mg once daily 600 mg twice daily 18 1.18 (1.12, 1.25) 1.19 (1.12, 1.25) 1.28 (1.20, 1.38) Rosuvastatin 10-mg single dose 600 mg twice daily 18 1.78 (1.52, 2.09) 1.69 (1.44, 1.99) NA Ethinyl estradiol/ 0.030 mg once daily/ 600 mg twice daily 26 1.39 (1.28, 1.51) 1.40 (1.29, 1.51) NA Norethindrone 1.5 mg once daily 1.08 (1.01, 1.16) 1.08 (1.03, 1.14) NA Maraviroc 300 mg twice daily 600 mg twice daily 13 1.01 (0.84, 1.20) 1.25 (1.08, 1.44) 1.37 (1.26, 1.48) Methadone 40 to 120 mg 600 mg 16 R(-) Methadone once daily twice daily 1.15 (1.11, 1.20) 1.13 (1.07, 1.19) 1.09 (1.01, 1.17) S(+) Methadone 1.15 (1.10, 1.19) 1.15 (1.09, 1.21) 1.10 (1.02, 1.19) Total Methadone 1.15 (1.11, 1.19) 1.14 (1.09, 1.20) 1.10 (1.02, 1.18) Buprenorphine/ Naloxone 8/2 to 24/6 mg once daily 600 mg twice daily 16 Buprenorphine 1.24 (1.06, 1.46) 1.30 (1.17, 1.45) 1.39 (1.18, 1.63) Norbuprenorph- ine 1.24 (1.03, 1.51) 1.39 (1.16, 1.67) 1.36 (1.10, 1.69) Table 7. Effect of Coadministered Drugs on the Pharmacokinetics of Temsavir a following Coadministration with Fostemsavir CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available. AUC = AUC tau for repeat-dose studies and AUC (0-inf) for single-dose study. C tau = C 12 for single-dose study. a Temsavir is the active moiety. Coadministered Drug(s) and Dose(s) Dose of RUKOBIA n Geometric Mean Ratio (90% CI) of Temsavir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 C max AUC C tau Atazanavir + 300 mg once daily/ 600 mg twice daily 36 1.68 (1.58, 1.79) 1.54 (1.44, 1.65) 1.57 (1.28, 1.91) Ritonavir 100 mg once daily Darunavir + 600 mg twice daily/ 600 mg twice daily 14 1.52 (1.28, 1.82) 1.63 (1.42, 1.88) 1.88 (1.09, 3.22) Ritonavir 100 mg twice daily Darunavir + 600 mg twice daily/ 600 mg twice daily 18 1.53 (1.32, 1.77) 1.34 (1.17, 1.53) 1.33 (0.98, 1.81) Ritonavir + 100 mg twice daily/ Etravirine 200 mg twice daily Etravirine 200 mg twice daily 600 mg twice daily 14 0.52 (0.45, 0.59) 0.50 (0.44, 0.57) 0.48 (0.32, 0.72) Ritonavir 100 mg once daily 600 mg twice daily 18 1.53 (1.31, 1.79) 1.45 (1.29, 1.61) 1.44 (1.00, 2.08) Raltegravir + 400 mg twice daily/ 1,200 mg once daily 17 1.23 (0.92, 1.64) 1.07 (0.84, 1.34) 1.17 (0.59, 2.32) Tenofovir disoproxil fumarate 300 mg once daily Rifabutin + 150 mg once daily/ 600 mg twice daily 23 1.50 (1.38, 1.64) 1.66 (1.52, 1.81) 2.58 (1.95, 3.42) Ritonavir 100 mg once daily Rifabutin 300 mg once daily 600 mg twice daily 22 0.73 (0.65, 0.83) 0.70 (0.64, 0.76) 0.59 (0.46, 0.77) Rifampin 600 mg once daily 1,200-mg single dose 15 0.24 (0.21, 0.28) 0.18 (0.16, 0.2) NA Cobicistat 150 mg once daily 600 mg twice daily 16 1.71 (1.54, 1.90) 1.93 (1.75, 2.12) 2.36 (2.03, 2.75) Darunavir + 800 mg once daily/ 600 mg twice daily 15 1.79 (1.62, 1.98) 1.97 (1.78, 2.18) 2.24 (1.75, 2.88) Cobicistat 150 mg once daily Tenofovir disoproxil fumarate 300 mg once daily 600 mg twice daily 18 0.99 (0.86, 1.13) 1.00 (0.91, 1.11) 1.13 (0.77, 1.66) Maraviroc 300 mg twice daily 600 mg twice daily 14 1.13 (0.96, 1.32) 1.10 (0.99, 1.23) 0.90 (0.69, 1.17) Famotidine 40-mg single dose 600-mg single dose 24 1.01 (0.85, 1.21) 1.04 (0.87, 1.25) 0.90 (0.64, 1.28)