SAMSCA™ (tolvaptan) tablets

SAMSCA tablets for oral use contain 15 mg or 30 mg of tolvaptan. 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.

Mechanism of Action
Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times greater than for the V1a-receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V2-receptors compared with tolvaptan.

Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan administration

Important Limitations
Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA.

It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients.

 
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm.
Nursing mothers: Discontinue drug or nursing taking into consideration importance of drug to mother.
Pediatric Use: There are no studies.

• Monitor serum sodium and neurologic status as serious neurologic sequelae can result from over rapid correction of sodium
• Because of the potential increased risk of gastrointestinal bleeding in patients with cirrhosis, use in patients with cirrhosis only when the need to treat outweighs this risk
• Dehydration and hypovolemia may require intervention
• Avoid use with hypertonic saline
• Avoid use with CYP 3A inducers and moderate CYP 3A inhibitors
• Consider dose reduction if co-administered with P-gp inhibitors
• Monitor serum potassium in patients with potassium >5 mEq/L or on drugs known to increase potassium

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka at 1-877-726-7220 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Usual Dosage in Adults
Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.

The usual starting dose for SAMSCA is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hours of therapy. Patients receiving SAMSCA should be advised that they can continue ingestion of fluid in response to thirst [see Warnings and Precautions].

Drug Withdrawal
Following discontinuation from SAMSCA, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.

Special Populations
There is no need to adjust dose based on age, gender, race, cardiac or hepatic function [see Use In Specific Populations  and Clinical Pharmacology].

Renal Impairment
There is no need to adjust the dose in patients with mild to severe renal impairment (creatinine clearance 10-79 mL/min) as there is no increase in exposure to tolvaptan; tolvaptan has not been evaluated in patients with creatinine clearance <10 mL/min or in patients undergoing dialysis. No benefit can be expected in patients who are anuric.

Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors--------

CYP 3A Inhibitors
Tolvaptan is metabolized by CYP 3A, and use with strong CYP 3A inhibitors causes a marked (5-fold) increase in exposure [see Contraindications (4.4)]. The effect of moderate CYP 3A inhibitors on tolvaptan exposure has not been assessed. Avoid co-administration of SAMSCA and moderate CYP 3A inhibitors [see Warnings and Precautions, Drug Interactions].

CYP 3A Inducers
Co-administration of SAMSCA with potent CYP 3A inducers (e.g., rifampin) reduces tolvaptan plasma concentrations by 85%. Therefore, the expected clinical effects of SAMSCA may not be observed at the recommended dose. Patient response should be monitored and the dose adjusted accordingly [see Warnings and Precautions, Drug Interactions].

P-gp Inhibitors
Tolvaptan is a substrate of P-gp. Co-administration of SAMSCA with inhibitors of P-gp (e.g., cyclosporine) may necessitate a decrease in SAMSCA dose [see Warnings and Precautions, Drug Interactions].

HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
SAMSCA™ (tolvaptan) tablets are available in the following strengths and packages.

SAMSCA 15 mg tablets are non-scored, blue, triangular, shallow-convex, debossed with "OTSUKA" and "15" on one side.
Blister of 10 NDC 59148-020-50

SAMSCA 30 mg tablets are non-scored, blue, round, shallow-convex, debossed with "OTSUKA" and "30" on one side.
Blister of 10 NDC 59148-021-50

Storage and Handling
Store at 25°C (77°F), excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP controlled Room Temperature].

Keep out of reach of children

This Medication Guide has been approved by the U.S. Food and Drug Administration.
©2009 Otsuka Pharmaceutical Co., Ltd.

PRINCIPAL DISPLAY PANEL - 15 mg Tablet Carton
10 Tablets
NDC 59148-020-50

Carton contains 1 strip with 10 tablets.
Samsca™
(tolvaptan)
tablets
15 mg