Tolvaptan

FDA Drug Information • Also known as: Jynarque, Samsca, Tolvaptan

Brand Names: Jynarque, Samsca, Tolvaptan
Dosage Form: POWDER
Product Type: BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: RISK OF SERIOUS LIVER INJURY JYNARQUE (tolvaptan) can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported [see Warnings and Precautions (5.1) ] . Measure ALT, AST and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then monthly for the first 18 months and every 3 months thereafter [see Warnings and Precautions (5.1) ] . Prompt action in response to laboratory abnormalities, signs, or symptoms indicative of hepatic injury can mitigate, but not eliminate, the risk of serious hepatotoxicity. Because of the risks of serious liver injury, 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 [see Warnings and Precautions (5.2) ] . WARNING: RISK OF SERIOUS LIVER INJURY See full prescribing information for complete boxed warning . JYNARQUE (tolvaptan) can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported ( 5.1 ) Measure transaminases and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then continuing monthly for the first 18 months and every 3 months thereafter ( 5.1 ) JYNARQUE is available only through a restricted distribution program called the Tolvaptan for ADPKD Shared System REMS ( 5.2 )

Description

11 DESCRIPTION JYNARQUE contains tolvaptan, a selective vasopressin V2-receptor antagonist in immediate release tablets for oral administration available in 15 mg, 30 mg, 45 mg, 60 mg and 90 mg strengths. Tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1 H -1-benzazepin-1-yl) carbonyl]- o -tolu- m -toluidide. The empirical formula is C 26 H 25 ClN 2 O 3 . Molecular weight is 448.94. The chemical structure is: Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant. Chemical Structure

What Is Tolvaptan Used For?

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 )

Dosage and Administration

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

Side Effects (Adverse Reactions)

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...

Drug Interactions

7 DRUG INTERACTIONS Avoid concomitant use with: Strong CYP3A Inducers ( 7.1 ) V 2 -Receptor Agonists ( 7.2 ) 7.1 CYP3A Inhibitors and Inducers CYP3A Inhibitors Tolvaptan's AUC was 5.4 times as large and Cmax was 3.5 times as large after co-administration of tolvaptan and 200 mg ketoconazole [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] . 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 [see Contraindications (4) ]. Dose reduction of JYNARQUE is recommended for patients while taking moderate CYP3A inhibitors [see Dosage and Administration (2.4) ]. Patients should avoid grapefruit juice beverages while taking JYNARQUE. Strong CYP3A Inducers Co-administration of JYNARQUE with strong CYP3A inducers reduces exposure to JYNARQUE [see Clinical Pharmacology (12.3) ]. Avoid concomitant use of JYNARQUE with strong CYP3A inducers [see Dosage and Administration (2.4) ]. 7.2 V 2 -Receptor Agonist As a V 2 -receptor antagonist, tolvaptan will interfere with the V 2 -agonist activity of desmopressin (dDAVP). Avoid concomitant use of JYNARQUE with a V 2 -agonist.

Contraindications

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 [see Warnings and Precautions (5.1) ] Taking strong CYP3A inhibitors With uncorrected abnormal blood sodium concentrations [see Warnings and Precautions (5.3) ] Unable to sense or respond to thirst [see Warnings and Precautions (5.3) ] Hypovolemia [see Warnings and Precautions (5.3) ] Hypersensitivity (e.g., anaphylaxis, rash) to tolvaptan or any component of the product [see Adverse Reactions (6) ] Uncorrected urinary outflow obstruction Anuria History of signs or symptoms of significant liver impairment or injury, does not include uncomplicated polycystic liver disease ( 4 ) Concomitant use of strong CYP3A inhibitors is contraindicated ( 4 ) Uncorrected abnormal blood sodium concentrations ( 4 , 5.3 ) Unable to sense or respond to thirst ( 4 ) Hypovolemia ( 4 ) Hypersensitivity to tolvaptan or any of its components ( 4 ) Uncorrected urinary outflow obstruction ( 4 ) Anuria ( 4 )

Pregnancy and Breastfeeding

8.1 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 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...

Overdosage

10 OVERDOSAGE 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%).

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied All JYNARQUE (tolvaptan) tablets are non-scored, blue, shallow-convex, debossed with "OTSUKA" and the tablet strength (mg) on one side and supplied as follows: 15 mg tablets are triangular, 30 mg tablets are round, 45 mg tablets are square, 60 mg tablets are rectangular, and 90 mg tablets are pentagonal. Morning and Afternoon Doses NDC 7‑Day Blister Card (Containing 14 Tablets) 28‑Day Carton (4 Blister Cards Containing a Total of 56 Tablets) 15 mg and 15 mg 59148-079-07 59148-079-28 30 mg and 15 mg 59148-080-07 59148-080-28 45 mg and 15 mg 59148-087-07 59148-087-28 60 mg and 30 mg 59148-088-07 59148-088-28 90 mg and 30 mg 59148-089-07 59148-089-28 30 Count Bottles NDC 15 mg 59148-082-13 30 mg 59148-083-13 Storage and Handling Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP controlled Room Temperature].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.