TOLVAR

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.

Lake as colorant.

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).

Mechanism of Action Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP).

Tolvaptan affinity for the

V 2 -receptor is 29 times that for the V 1a -receptor.

Decreased binding of vasopressin to the

V 2 -receptor in the kidney lowers adenylate cyclase activity resulting in a decrease in intracellular adenosine 3′, 5′-cyclic monophosphate (cAMP) concentrations.

Decreased cAMP concentrations prevent aquaporin 2 containing vesicles from fusing with the plasma membrane, which in turn causes an increase in urine water excretion, an increase in free water clearance (aquaresis) and a decrease in urine osmolality.

In human

ADPKD cyst epithelial cells, tolvaptan inhibited AVP-stimulated in vitro cyst growth and chloride-dependent fluid secretion into cysts.

In animal models, decreased cAMP concentrations were associated with decreases in the rate of growth of total kidney volume and the rate of formation and enlargement of kidney cysts.

Tolvaptan metabolites have no or weak antagonist activity for human V 2 -receptors compared with tolvaptan. 12.2 Pharmacodynamics In healthy subjects or patients with eGFRs as low as 10 mL/min/1.73m 2 receiving a single dose of tolvaptan, the onset of the aquaretic effects occurs within to 2 hours post-dose.

In healthy subjects, single doses of 60 mg and 90 mg produce a peak effect of about a 9 mL/min increase in urine excretion rate is observed between and 8 hours post-dose.

Higher doses of tolvaptan do not increase the peak effect in urine excretion rate but sustain the effect for a longer period of time.

Urine excretion rate returns to baseline within 24 hours following the maximum recommended 90 mg dose of tolvaptan.

Changes in free water clearance mirror the changes in urine excretion rate.

Increased free water clearance causes an increase in serum sodium concentration unless fluid intake is increased to match urine output.

Increases in urine excretion rate and free water clearance are positively correlated with baseline glomerular filtration rate with increases in both values observed in patients with creatinine clearance as low as 15 mL/min. With the recommended split-dose regimens, tolvaptan inhibits vasopressin from binding to the V 2 -receptor in the kidney for the entire day, as indicated by increased urine output and decreased urine osmolality.

Following a 90/30 mg split-dose regimen in patients with eGFR >60 mL/min/1.73 m 2, the change in mean daily urine volume was about 4 L for a mean total daily volume of about 7 L. In patients with eGFR <30 mL/min/1.73 m 2, the mean change in daily urine volume was about 2 L for a total daily urine volume of about 5 L. Plasma concentrations of native AVP may increase (avg. 2 to 9 pg/mL) with tolvaptan treatment and return to baseline levels when treatment is stopped.

During tolvaptan treatment, small changes in renal function are expected and the changes are independent of baseline renal function.

Glomerular filtration rate is decreased about 6% to 10% and uric acid clearance is decreased about 20% to 25%.

Percent changes in renal plasma flow are highly correlated to percent changes in GFR.

These changes are reversed upon discontinuation of tolvaptan.

Cardiac Electrophysiology No prolongation of the

QT interval was observed with tolvaptan following multiple doses of 300 mg/day for 5 days. 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.

In healthy subjects, peak concentrations of tolvaptan are observed between 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.

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%.

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.

Age, Gender and Race Age, gender and race have no effect on tolvaptan pharmacokinetics.

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.

In subjects with creatinine clearances ranging from 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.

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.

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.

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%.

Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with tolvaptan has no clinically relevant impact on the exposure to tolvaptan.

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.

Digoxin 0.25 mg was administered once daily for 12 days.

Tolvaptan 60 mg, was co-administered once daily on Days 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.

Co-administration of tolvaptan did not meaningfully alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone).

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.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 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 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.

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 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.

Disorders: Liver failure requiring transplant Immune System.

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%).

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.

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 2.1 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 and 4 weeks after initiation, monthly for 18 months and every 3 months thereafter.

Monitor for concurrent symptoms that may indicate liver injury. 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.

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.

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.

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) .

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) .

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 to 4% and to 20% of clinically recognized pregnancies, respectively.

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.

Safety and effectiveness of

JYNARQUE in pediatric patients have not been established.

Clinical studies of tolvaptan did not include sufficient numbers of subjects aged 65 years old and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.