Jynarque

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)

Recommended dosage 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 )

2.1Recommended 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.

2.2Monitoring 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 .

2.3Missed Doses If a

dose of JYNARQUE is not taken at the scheduled time, take the next dose at its scheduled time.

2.4Co-Administration with CYP3A Inhibitors CYP3A Inhibitors

Concomitant use of strong CYP3A inhibitors is contraindicated . 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 . 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

Hypernatremia, dehydration and hypovolemia: May require intervention

5.1Serious Liver Injury

JYNARQUE can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported in the post-marketing ADPKD experience. Discontinuation in response to laboratory abnormalities or signs or symptoms of liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice) can reduce the risk of severe hepatotoxicity.

In a 3-year placebo-controlled trial and its open-label extension (in which patients' liver tests were monitored every 4 months), evidence of serious hepatocellular injury (elevations of hepatic transaminases of at least 3 times the upper limit of normal [ULN] combined with elevated bilirubin at least 2 times the ULN) occurred in 0.2% (3/1487) of tolvaptan-treated patients compared to none of the placebo-treated patients. To reduce the risk of significant or irreversible liver injury, assess ALT, AST and bilirubin prior to initiation of JYNARQUE, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter. At the onset of signs or symptoms consistent with hepatic injury or if ALT, AST, or bilirubin increase to >2 times ULN, immediately discontinue JYNARQUE, obtain repeat tests as soon as possible (within 48 to 72 hours), and continue testing as appropriate.

If laboratory abnormalities stabilize or resolve, JYNARQUE may be reinitiated with increased frequency of monitoring as long as ALT and AST remain below 3 times the ULN. Do not restart JYNARQUE in patients who experience signs or symptoms consistent with hepatic injury or whose ALT or AST ever exceeds 3 times the ULN during treatment with tolvaptan, unless there is another explanation for liver injury and the injury has resolved. In patients with a stable, low baseline AST or ALT, an increase above 2 times baseline, even if less than 2 times the ULN, may indicate early liver injury. Such elevations may warrant treatment suspension and prompt (48 to 72 hours) re-evaluation of liver test trends prior to reinitiating therapy with more frequent monitoring.

5.2Tolvaptan for

ADPKD Shared System REMS JYNARQUE is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Tolvaptan for ADPKD Shared System REMS, because of the risks of liver injury . Notable requirements of the Tolvaptan for ADPKD Shared System REMS include the following: Prescribers must be certified by enrolling in the REMS program. Prescribers must inform patients receiving JYNARQUE about the risk of hepatotoxicity associated with its use and how to recognize the signs and symptoms of hepatotoxicity and the appropriate actions to take if it occurs. Patients must enroll in the REMS program and comply with ongoing monitoring requirements.

Pharmacies must be certified by enrolling in the REMS program and must only dispense to patients who are authorized to receive JYNARQUE. Further information, including a list of qualified pharmacies/distributors, is available at www.TolvaptanADPKDSharedREMS.com or by telephone at 1-866-244-9446.

5.3Hypernatremia, Dehydration and Hypovolemia

JYNARQUE increases free water clearance and, as a result, may cause dehydration, hypovolemia and hypernatremia. Therefore, ensure abnormalities in sodium concentrations are corrected prior to initiation of therapy. Instruct patients to drink water when thirsty, and throughout the day and night if awake.

Monitor for weight loss, tachycardia and hypotension because they may signal dehydration. In the two double-blind, placebo-controlled trials of patients with ADPKD, hypernatremia (defined as any serum sodium concentration >150 mEq/L) was observed in 4.0% versus 0.6% and 1.4% versus 0% of tolvaptan-treated versus placebo-treated patients, respectively. The rate of dehydration and hypovolemia in the two studies was 2.1% versus 0.7% and 2.3% versus 0.4% for tolvaptan-treated versus placebo-treated patients, respectively.

During JYNARQUE therapy, if serum sodium increases above normal range or the patient becomes hypovolemic or dehydrated and fluid intake cannot be increased, then suspend JYNARQUE until serum sodium, hydration status and volume status is within the normal range.

5.4Co-Administration with Inhibitors of CYP3A Concomitant

use of JYNARQUE with drugs that are moderate or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, ritonavir, and conivaptan) increases tolvaptan exposure . Use with strong CYP3A inhibitors is contraindicated; dose reduction of JYNARQUE is recommended for patients while taking moderate CYP3A inhibitors .

4 CONTRAINDICATIONS JYNARQUE is contraindicated in patients: With a history, signs or symptoms of significant liver impairment or injury. This contraindication does not apply to uncomplicated polycystic liver disease Taking strong CYP3A inhibitors With uncorrected abnormal blood sodium concentrations Unable to sense or respond to thirst Hypovolemia Hypersensitivity (e.g., anaphylaxis, rash) to tolvaptan or any component of the product Uncorrected urinary outflow obstruction Anuria History of signs or symptoms of significant liver impairment or injury, does not include uncomplicated polycystic liver disease Concomitant use of strong CYP3A inhibitors is contraindicated Uncorrected abnormal blood sodium concentrations ( 4 , 5.3 ) Unable to sense or respond to thirst Hypovolemia Hypersensitivity to tolvaptan or any of its components Uncorrected urinary outflow obstruction Anuria

8.1Pregnancy Risk Summary Available

data with JYNARQUE use in pregnant women are insufficient to determine if there is a drug associated risk of adverse developmental outcomes. In embryo-fetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. At maternally non-toxic doses, tolvaptan did not cause any developmental toxicity in rats or in rabbits at exposures approximately 4- and 1-times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 90/30 mg.

However, effects on embryo-fetal development occurred in both species at maternally toxic doses. In rats, reduced fetal weights and delayed fetal ossification occurred at 17 times the human exposure. In rabbits, increased abortions, embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations occurred at approximately 3 times the human exposure . Advise pregnant women of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.

Data Animal Data Oral administration of tolvaptan during the period of organogenesis in Sprague-Dawley rats produced no evidence of teratogenesis at doses up to 100 mg/kg/day. Lower body weights and delayed ossification were seen at 1000 mg/kg, which is approximately 17 times the human exposure at the 90/30 mg dose (AUC 24h 6570 h∙ng/mL). The fetal effects are likely secondary to maternal toxicity (decreased food intake and low body weights).

In a prenatal and postnatal study in rats, tolvaptan had no effect on physical development, reflex function, learning ability or reproductive performance at doses up to 1000 mg/kg/day. In New Zealand White rabbits, placental transfer was demonstrated with C max values in the yolk sac fluid approximating 22.7% of the value in maternal rabbit serum. In embryo-fetal studies, teratogenicity (microphthalmia, embryo-fetal mortality, cleft palate, brachymelia and fused phalanx) was evident in rabbits at 1000 mg/kg (approximately 3 times the exposure at the 90/30 mg dose).

Body weights and food consumption were lower in dams at all doses, equivalent to 0.6 to 3 times the human exposure at the 90/30 mg dose.

The following adverse reactions are discussed in more detail in other sections of the labeling: Serious Liver Injury Hypernatremia, Dehydration and Hypovolemia Drug Interactions with Inhibitors of CYP3A Most common observed adverse reactions with JYNARQUE (incidence >10% and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria and polydipsia 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 .

6.1Clinical 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

10.3Thirst Thirst

includes polydipsia and thirst 612 63.7 26.2 113 23.4

8.7Dry

mouth 154 16.0 6.6 60 12.4

4.6Fatigue

131 13.6 5.6 47 9.7

3.6Diarrhea

128 13.3 5.5 53 11.0

4.1Dizziness

109 11.3 4.7 42 8.7

3.2Dyspepsia

76 7.9 3.3 16 3.3

1.2Decreased

appetite 69 7.2 3.0 5 1.0

0.4Abdominal

distension 47 4.9 2.0 16 3.3

1.2Dry

skin 47 4.9 2.0 8 1.7

0.6Rash

40 4.2 1.7 9 1.9

0.7Hyperuricemia

37 3.9 1.6 9 1.9

0.7Palpitations

34 3.5 1.5 6 1.2

0.5REPRISE: 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.

6.2Postmarketing 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