Tolvaptan

1 INDICATIONS AND USAGE JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). JYNARQUE is a selective vasopressin V 2 -receptor antagonist indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD) ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dosage ( 2.1 ) Initial Dosage Titration Step Target Dosage 1st Dose 45 mg 1st Dose 60 mg 1st Dose 90 mg 2nd Dose (8 hours later) 15 mg 2nd Dose (8 hours later) 30 mg 2nd Dose (8 hours later) 30 mg Total Daily Dose 60 mg Total Daily Dose 90 mg Total Daily Dose 120 mg Dose adjustment is recommended for patients taking moderate CYP3A inhibitors ( 2.4 , 5.4 , 7.1 ) 2.1 Recommended Dosage The initial dosage for JYNARQUE is 60 mg orally per day as 45 mg taken on waking and 15 mg taken 8 hours later. Titrate to 60 mg plus 30 mg then to 90 mg plus 30 mg per day if tolerated with at least weekly intervals between titrations. Patients may down-titrate based on tolerability. Encourage patients to drink enough water to avoid thirst or dehydration. 2.2 Monitoring To mitigate the risk of significant or irreversible liver injury, perform blood testing for ALT, AST and bilirubin prior to initiation of JYNARQUE, at 2 and 4 weeks after initiation, monthly for 18 months and every 3 months thereafter . Monitor for concurrent symptoms that may indicate liver injury [see Warnings and Precautions (5.1) ] . 2.3 Missed Doses If a dose of JYNARQUE is not taken at the scheduled time, take the next dose at its scheduled time. 2.4 Co-Administration with CYP3A Inhibitors CYP3A Inhibitors Concomitant use of strong CYP3A inhibitors is contraindicated [see Contraindications (4) and Warnings and Precautions (5.4) ] . In patients taking concomitant moderate CYP3A inhibitors, reduce the dose of JYNARQUE per Table 1. Consider further reductions if patients cannot tolerate the reduced dose [see Warnings and Precautions (5.4) and Drug Interactions (7.1) ] . Interrupt JYNARQUE temporarily for short term therapy with moderate CYP3A inhibitors if the recommended reduced doses are not available. Table 1: Dose adjustment for patients taking moderate CYP3A inhibitors Standard Morning and Afternoon Dose (mg) Dose (mg) with Moderate CYP3A Inhibitors 90 mg and 30 mg 45 mg and 15 mg 60 mg and 30 mg 30 mg and 15 mg 45 mg and 15 mg 15 mg and 15 mg

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Serious Liver Injury [see Boxed Warning and Warnings and Precautions (5.1) ] Hypernatremia, Dehydration and Hypovolemia [see Warnings and Precautions (5.3) ] Drug Interactions with Inhibitors of CYP3A [see Warnings and Precautions (5.4) ] Most common observed adverse reactions with JYNARQUE (incidence >10% and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria and polydipsia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. JYNARQUE has been studied in over 3000 patients with ADPKD. Long-term, placebo-controlled safety information of JYNARQUE in ADPKD is principally derived from two trials where 1,413 subjects received tolvaptan and 1,098 received placebo for at least 12 months across both studies. TEMPO 3:4: A Phase 3, Double-Blind, Placebo-Controlled, Randomized Trial in Early, Rapidly-Progressing ADPKD The TEMPO 3:4 (NCT00428948) trial employed a two-arm, 2:1 randomization to tolvaptan or placebo, titrated to a maximally-tolerated total daily dose of 60 to 120 mg. A total of 961 subjects with rapidly progressing ADPKD were randomized to JYNARQUE. Of these, 742 (77%) subjects who were treated with JYNARQUE remained on treatment for at least 3 years. The average daily dose in these subjects was 96 mg daily. Adverse events that led to discontinuation were reported for 15.4% (148/961) of subjects in the JYNARQUE group and 5.0% (24/483) of subjects in the placebo group. Aquaretic effects were the most common reasons for discontinuation of JYNARQUE. These included pollakiuria, polyuria, or nocturia in 63 (6.6%) subjects treated with JYNARQUE compared to 1 subject (0.2%) treated with placebo. Table 2 lists the adverse reactions that occurred in at least 3% of ADPKD subjects treated with JYNARQUE and at least 1.5% more than on placebo. Table 2: TEMPO 3:4, Treatment Emergent Adverse Reactions in ≥3% of JYNARQUE Treated Subjects with Risk Difference ≥1.5%, Randomized Period Adverse Reaction Tolvaptan (N=961) Placebo (N=483) Number of Subjects Proportion (%) 100× (Number of subjects with an adverse event/N) Annualized Rate 100× (Number of subjects with an adverse event/Total subject years of drug exposure) Number of Subjects Proportion (%) Annualized Rate Increased urination Increased urination includes micturition urgency, nocturia, pollakiuria, polyuria 668 69.5 28.6 135 28.0 10.3 Thirst Thirst includes polydipsia and thirst 612 63.7 26.2 113 23.4 8.7 Dry mouth 154 16.0 6.6 60 12.4 4.6 Fatigue 131 13.6 5.6 47 9.7 3.6 Diarrhea 128 13.3 5.5 53 11.0 4.1 Dizziness 109 11.3 4.7 42 8.7 3.2 Dyspepsia 76 7.9 3.3 16 3.3 1.2 Decreased appetite 69 7.2 3.0 5 1.0 0.4 Abdominal distension 47 4.9 2.0 16 3.3 1.2 Dry skin 47 4.9 2.0 8 1.7 0.6 Rash 40 4.2 1.7 9 1.9 0.7 Hyperuricemia 37 3.9 1.6 9 1.9 0.7 Palpitations 34 3.5 1.5 6 1.2 0.5 REPRISE: A Phase 3, Randomized-Withdrawal, Placebo-Controlled, Double-Blind, Trial in Late Stage 2 to Early Stage 4 ADPKD The REPRISE (NCT02160145) trial employed a 5-week single-blind titration and run-in period for JYNARQUE prior to the randomized double-blind period. During the JYNARQUE titration and run-in period, 126 (8.4%) of the 1496 subjects discontinued the study, 52 (3.5%) were due to aquaretic effects and 10 (0.7%) were due to liver test findings. Because of this run-in design, the adverse reaction rates observed during the randomized period are not described. Liver Injury In the two double-blind, placebo-controlled trials, ALT elevations >3 times ULN were observed at an increased frequency with JYNARQUE compared with placebo (4.9% [80/1637] versus 1.1% [13/1166], respectively) within the first 18 months after initiating treatment and increases usually resolved within 1 to 4 months after discontinuing the drug. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tolvaptan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary Disorders: Liver failure requiring transplant Immune System Disorders: Anaphylaxis

12.3 Pharmacokinetics In healthy subjects, the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been studied. In ADPKD patients, single doses up to 120 mg and multiple split-doses up to 90/30 mg have been studied. Absorption In healthy subjects, peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Peak concentrations increase less than dose proportionally with doses greater than 240 mg. The absolute bioavailability of tolvaptan decreases with increasing doses. The absolute bioavailability of tolvaptan following an oral dose of 30 mg is 56% (range 42% to 80%). Co-administration of 90 mg JYNARQUE with a high-fat meal (~1000 calories, of which 50% are from fat) doubles peak concentrations but has no effect on the AUC of tolvaptan; tolvaptan may be administered with or without food. Distribution Tolvaptan binds to both albumin and α1-acid glycoprotein and the overall protein binding is >98%; binding is not affected by disease state. The volume of distribution of tolvaptan is about 3 L/kg. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. When administered as multiple once-daily 300 mg doses to healthy subjects or as split-dose regimens to patients with ADPKD, tolvaptan's accumulation factor is <1.2. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30% and 60%. Metabolism and Elimination Tolvaptan is metabolized almost exclusively by CYP3A. Fourteen metabolites have been identified in plasma, urine and feces; all but one were also metabolized by CYP3A and none are pharmacodynamically active. After oral administration of radiolabeled tolvaptan, tolvaptan was a minor component in plasma representing 3% of total plasma radioactivity; the oxobutyric acid metabolite was present at 52.5% of total plasma radioactivity with all other metabolites present at lower concentrations than tolvaptan. The oxobutyric acid metabolite shows a plasma half-life of ~180 h. About 40% of radioactivity was recovered in urine (<1% as unchanged tolvaptan) and 59% in feces (19% as unchanged tolvaptan). Following intravenous infusion, tolvaptan half-life is approximately 3 hours. Following single oral doses to healthy subjects, the estimated half-life of tolvaptan increases from 3 hours for a 15 mg dose to approximately 12 hours for 120 mg and higher doses due to more prolonged absorption of tolvaptan at higher doses; apparent clearance is approximately 4 mL/min/kg and does not appear to change with increasing dose. Specific Populations Age, Gender and Race Age, gender and race have no effect on tolvaptan pharmacokinetics. Hepatic Impairment In studies involving patients with hepatic impairment (Child-Pugh class A-C), but without ADPKD; moderate (class A, B) or severe (class C) hepatic impairment decreases the clearance and increases the volume of distribution of tolvaptan. Renal Impairment In subjects with creatinine clearances ranging from 10 to 124 mL/min administered a single dose of 60 mg tolvaptan, the AUC and C max of plasma tolvaptan was increased 90% and 10%, respectively, for subjects with clearances of <30 mL/min compared to subjects with clearances >60 mL/min [see Use in Special Populations (8.7) ]. In ADPKD patients with estimated creatinine clearance >60 mL/min, pharmacokinetics were similar to healthy subjects. Drug Interaction Studies Impact of Other Drugs on Tolvaptan Strong CYP3A Inhibitors Tolvaptan's Cmax and AUC were, respectively, 3.5 times and 5.4 times as high following ketoconazole 200 mg given one day prior to and concomitantly with 30 mg tolvaptan. Moderate CYP3A4 Inhibitors Fluconazole: Fluconazole 400 mg given one day prior and 200 mg given concomitantly produced an 80% and 200% increase in tolvaptan C max and AUC, respectively. Grapefruit Juice: When 60 mg tolvaptan was taken with 240 mL regular strength grapefruit juice, tolvaptan C max and AUC increased 90% and 60%, respectively. CYP3A Inducers Rifampin: Rifampin 600 mg once daily for 7 days followed by a single 240 mg dose of tolvaptan decreased both tolvaptan C max and AUC about 85%. Other Drugs Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with tolvaptan has no clinically relevant impact on the exposure to tolvaptan. Impact of Tolvaptan on Other Drugs CYP3A Substrates Co-administration of lovastatin and tolvaptan increases the AUC of lovastatin and its active metabolite lovastatin-β hydroxy acid by 40% and 30%, respectively. These are non-clinically significant increases in exposure. P-gp Substrates Digoxin: Digoxin 0.25 mg was administered once daily for 12 days. Tolvaptan 60 mg, was co-administered once daily on Days 8 to 12. Digoxin C max and AUC were increased 30% and 20%, respectively. Transporter Substrates Tolvaptan is a substrate of P-gp and an inhibitor of P-gp and BCRP. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1 and OAT3. Co-administration of tolvaptan with rosuvastatin (BCRP substrate) did not have a clinically significant effect on rosuvastatin exposure. Rosuvastatin C max and AUC t increased 54% and 69%, respectively. Administration of rosuvastatin (OATP1B1 substrate) or furosemide (OAT3 substrate) to healthy subjects with elevated oxobutyric acid metabolite plasma concentrations did not meaningfully alter the pharmacokinetics of rosuvastatin or furosemide. Other Drugs Co-administration of tolvaptan did not meaningfully alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone).