Tolvaptan Drug Information

JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).

Recommended Dosage

The initial dosage for JYNARQUE is 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.

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.

Missed Doses If a dose of JYNARQUE is not taken at the scheduled time, take the next dose at its scheduled time.

Co-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

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.

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.

Aquaretic effects were the most common reasons for discontinuation of JYNARQUE. 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 ≥ 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.

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% versus 1.1%, respectively) within the first 18 months after initiating treatment and increases usually resolved within 1 to 4 months after discontinuing the drug.

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

Larger doses of the strong CYP3A inhibitor would be expected to produce larger increases in tolvaptan exposure. Concomitant use of tolvaptan with strong CYP3A inhibitors is contraindicated. Dose reduction of JYNARQUE is recommended for patients while taking moderate CYP3A inhibitors.

Patients should avoid grapefruit juice beverages while taking JYNARQUE. Strong CYP3A Inducers Co-administration of JYNARQUE with strong CYP3A inducers reduces exposure to JYNARQUE. Avoid concomitant use of JYNARQUE with a V 2 -agonist.

Pregnancy 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 (see Data ).

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 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. 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.

Pediatric Use Safety and effectiveness of JYNARQUE in pediatric patients have not been established.

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 Unable to sense or respond to thirst Hypovolemia Hypersensitivity to tolvaptan or any of its components Uncorrected urinary outflow obstruction Anuria

Single oral doses up to 480 mg (4 times the maximum recommended daily dose) and multiple doses up to 300 mg once daily for 5 days have been well tolerated in trials in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia.

No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose). A single oral dose of 2000 mg/kg was lethal in mice, and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia. In patients with suspected JYNARQUE overdosage, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended.

Continue replacement of water and electrolytes until aquaresis abates. Dialysis may not be effective in removing JYNARQUE because of its high binding affinity for human plasma protein (>98%).