1INDICATIONS AND USAGE

SAMSCA™ is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

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.

2DOSAGE AND ADMINISTRATION

2.1Usual Dosage in Adults

Patients should be in a hospital for initiation and re-initiation of therapy to eva luate 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 15mg administered once daily without regard to meals. Increase the dose to 30mg once daily, after at least 24hours, to a maximum of 60mg 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 24hours of therapy. Patients receiving SAMSCA should be advised that they can continue ingestion of fluid in response to thirst [see Warnings and Precautions (5.1)].

2.2Drug 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.

2.3Special Populations

There is no need to adjust dose based on age, gender, race, cardiac or hepatic function [see Use In Specific Populations (8) and Clinical Pharmacology (12.3)].

Renal Impairment

There is no need to adjust the dose in patients with mild to severe renal impairment (creatinine clearance 10-79mL/min) as there is no increase in exposure to tolvaptan; tolvaptan has not been eva luated in patients with creatinine clearance <10mL/min or in patients undergoing dialysis. No benefit can be expected in patients who are anuric [see Contraindications (4.5) and Clinical Pharmacology (12.3)].

2.4Co-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 (5.5), Drug Interactions (7.1)].

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 (5.5), Drug Interactions (7.1)].

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 (5.5), Drug Interactions (7.1)].

3DOSAGE FORMS AND STRENGTHS

SAMSCA (tolvaptan) is available in 15mg and 30mg tablets [see How Supplied/Storage and Handling (16)].

4CONTRAINDICATIONS

SAMSCA is contraindicated in the following conditions:

4.1Urgent need to raise serum sodium acutely

SAMSCA has not been studied in a setting of urgent need to raise serum sodium acutely.

4.2Inability of the patient to sense or appropriately respond to thirst

Patients who are unable to auto-regulate fluid balance are at substantially increased risk of incurring an overly rapid correction of serum sodium, hypernatremia and hypovolemia.

4.3Hypovolemic hyponatremia

Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits.

4.4Concomitant use of strong CYP 3A inhibitors

Ketoconazole 200mg administered with tolvaptan increased tolvaptan exposure by 5‑fold. Larger doses would be expected to produce larger increases in tolvaptan exposure. There is not adequate experience to define the dose adjustment that would be needed to allow safe use of tolvaptan with strong CYP 3A inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, and telithromycin.

4.5Anuric patients

In patients unable to make urine, no clinical benefit can be expected.

5WARNINGS AND PRECAUTIONS

5.1Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae

(see BOXED WARNING)

Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (e.g., >12mEq/L/24hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials in which tolvaptan was administered in titrated doses starting at 15mg once daily, 7% of tolvaptan-treated subjects with a serum sodium <130mEq/L had an increase in serum sodium greater than 8mEq/L at approximately 8hours and 2% had an increase greater than 12mEq/L at 24hours. Approximately 1% of placebo-treated subjects with a serum sodium <130mEq/L had a rise greater than 8mEq/L at 8hours and no patient had a rise greater than 12mEq/L/24hours. None of the patients in these studies had evidence of osmotic demyelination syndrome or related neurological sequelae, but such complications have been reported following too-rapid correction of serum sodium. Patients treated with SAMSCA should be monitored to assess serum sodium concentrations and neurologic status, especially during initiation and after titration. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction during the first 24hours of therapy with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided.

5.2Gastrointestinal Bleeding in Patients with Cirrhosis

In patients with cirrhosis treated with tolvaptan in hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo-treated patients. SAMSCA should be used in cirrhotic patients only when the need to treat outweighs this risk.

5.3Dehydration and Hypovolemia

SAMSCA therapy induces copious aquaresis, which is normally partially offset by fluid intake. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In multiple-dose, placebo-controlled trials in which 607 hyponatremic patients were treated with tolvaptan, the incidence of dehydration was 3.3% for tolvaptan and 1.5% for placebo-treated patients. In patients receiving SAMSCA who develop medically significant signs or symptoms of hypovolemia, interrupt or discontinue SAMSCA therapy and provide supportive care with careful management of vital signs, fluid balance and electrolytes. Fluid restriction during therapy with SAMSCA may increase the risk of dehydration and hypovolemia. Patients receiving SAMSCA should continue ingestion of fluid in response to thirst.

5.4Co-administration with Hypertonic Saline

There is no experience with concomitant use of SAMSCA and hypertonic saline. Concomitant use with hypertonic saline is not recommended.

5.5Drug Interactions

Other Drugs Affecting Exposure to Tolvaptan

CYP 3A Inhibitors

Tolvaptan is a substrate of CYP 3A. CYP 3A inhibitors can lead to a marked increase in tolvaptan concentrations [see Dosage and Administration (2.4), Drug Interactions (7.1)]. Do not use SAMSCA with strong inhibitors of CYP 3A [see Contraindications (4.4)] and avoid concomitant use with moderate CYP 3A inhibitors.

CYP 3A Inducers

Avoid co-administration of CYP 3A inducers (e.g., rifampin, rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine, St. John's Wort) with SAMSCA, as this can lead to a reduction in the plasma concentration of tolvaptan and decreased effectiveness of SAMSCA treatment. If co-administered with CYP 3A inducers, the dose of SAMSCA may need to be increased [see Dosage and Administration (2.4), Drug Interactions (7.1)].

P‑gp Inhibitors

The dose of SAMSCA may have to be reduced when SAMSCA is co-administered with P‑gp inhibitors, e.g., cyclosporine [see Dosage and Administration (2.4), Drug Interactions (7.1)].

5.6Hyperkalemia or Drugs that Increase Serum Potassium

Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which could result in increased serum potassium. Serum potassium levels should be monitored after initiation of tolvaptan treatment in patients with a serum potassium >5mEq/L as well as those who are receiving drugs known to increase serum potassium levels.

6ADVERSE REACTIONS

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions 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. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

In multiple-dose, placebo-controlled trials, 607 hyponatremic patients (serum sodium <135mEq/L) were treated with SAMSCA. The mean age of these patients was 62years; 70% of patients were male and 82% were Caucasian. One hundred eighty nine (189) tolvaptan-treated patients had a serum sodium <130mEq/L, and 52 patients had a serum sodium <125mEq/L. Hyponatremia was attributed to cirrhosis in 17% of patients, heart failure in 68% and SIADH/other in 16%. Of these patients, 223 were treated with the recommended dose titration (15mg titrated to 60mg as needed to raise serum sodium).

Overall, over 4,000 patients have been treated with oral doses of tolvaptan in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with tolvaptan for 6 months or more.

The most common adverse reactions (incidence ≥5% more than placebo) seen in two 30‑day, double-blind, placebo-controlled hyponatremia trials in which tolvaptan was administered in titrated doses (15mg to 60mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of tolvaptan-treated patients discontinued treatment because of an adverse event, compared to 12% (26/220) of placebo-treated patients; no adverse reaction resulting in discontinuation of trial medication occurred at an incidence of >1% in tolvaptan-treated patients.

Table 1 lists the adverse reactions reported in tolvaptan-treated