TOLVAR

Tolvaptan is used to treat low blood sodium levels (hyponatremia) associated with various conditions like congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormones (SIADH).

FDA approved on

May 19, 2009.

Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis.

Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan.

Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours.

The magnitude of serum sodium and osmolality change increases with escalating doses.

Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan.

The affinity for

V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors.

Tmax, Healthy subjects: 2-4 hours Cmax, Healthy subjects, 30 mg: 374 ng/mL Cmax, Healthy subjects, 90 mg: 418 ng/mL Cmax, heart failure patients, 30 mg: 460 ng/mL Cmax, heart failure patients, 90 mg: 723 ng/mL AUC(0-24 hours), 60 mg: 3.71 μg-h/mL AUC(∞), 60 mg: 4.55 μg-h/mL The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3.

The absolute bioavailability of tolvaptan is unknown.

At least 40% of the dose is absorbed as tolvaptan or metabolites.

Food does not impact the bioavailability of tolvaptan.

Healthy subjects: 3 L/kg; slightly higher in heart failure patients.

exclusively by CYP3A4 enzyme in the liver.

Metabolites are inactive.

• very little renal elimination (<1% is excreted unchanged in the urine).

Terminal half life, oral dose = 12 hours.

mL/min/kg (post-oral dosing).

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The oral

LD50 of tolvaptan in rats and dogs is >2000 mg/kg.

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.