IMPORTANT SAFETY INFORMATIONU.S. FULL PRESCRIBING INFORMATION, including Boxed WARNING and Medication Guide

SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. SAFETY INFORMATION CONTINUED BELOW

Samsca

Hyponatremia in Cirrhosis

Hyponatremia in Cirrhosis
– Patient Case Video
Sam Sigal, MD

Use the following links to explore this section in further detail:

Hyponatremia in cirrhosis
SAMSCA: Increases serum sodium levels
Fluid balance
Clinical case

Hyponatremia in cirrhosis

Patients with hyponatremia and cirrhosis are at risk in the hospital

Hyponatremia in cirrhosis

Pathogenic properties of patients with cirrhosis

Vasopressin secretion stimulated:
— By arterial underfilling as a result of arterial vasodilation³
— Despite low plasma osmolality
Nonosmotic release of vasopressin contributes to:
— Water retention²
— Hyponatremia²

SAMSCA: Increases Serum Sodium Levels

In the SALT trials, on Day 4 SAMSCA increased serum sodium concentration by 3.5 mEq/L vs 0.4 mEq/L for placebo. On Day 30, SAMSCA increased serum sodium concentration by 4.2 mEq/L vs 1.5 mEq/L for placebo⁴

SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.

Too rapid correction of serum sodium (e.g., >12 mEq/L/24 hours) can cause serious neurologic sequelae, including osmotic demyelination syndrome (ODS).

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 the risk.

Pooled SALT studies

*Data on file. Protocols 156-02-235 and 156-03-238; pooled.

In the SALT trials, SAMSCA was effective in increasing average daily serum [Na+] AUC at Day 4 and Day 30 both in patients with euvolemic hyponatremia (SIADH) and in patients with hypervolemic hyponatremia (HF and cirrhosis). In two identical, 30‑day, randomized, double-blind, placebo-controlled, multicenter studies, 424 patients with euvolemic (SIADH) or hypervolemic (HF and cirrhosis) hyponatremia were treated for 30 days with tolvaptan or placebo, then followed for an additional 7 days after withdrawal. The primary endpoint for these studies was the average daily AUC for change in serum sodium from baseline to Day 4 (tolvaptan, 4.0 mEq/L vs placebo, 0.4 mEq/L) and baseline to Day 30 (tolvaptan, 6.2 mEq/L vs placebo, 1.8 mEq/L). In cirrhosis patients, the mean change from baseline to Day 4 was 3.5 mEq/L in the SAMSCA group (n=63) and 0.4 mEq/L in the placebo group (n=54) (estimated treatment effect: 3.15, 95% Cl: 2.32-3.99, P<0.0001). The mean change from baseline to Day 30 was 4.2 mEq/L and 2.4 mEq/L, respectively (estimated treatment effect: 2.83, 95% Cl: 1.65-4.01, P<0.0001). Patients received either tolvaptan or placebo, at a starting dose of 15 mg. The dosage of tolvaptan or placebo was increased to 30 mg or 60 mg, if necessary.

SAMSCA: Significant effect on fluid balance

With SAMSCA, urine output is greater than fluid intake. Thus there is a net negative fluid balance.⁴

Samsca effect on fluid balance

*Data on file. Protocols 156-02-235 and 156-03-238; pooled.

Only subjects whose time spans in both urine collection and fluid intake were no less than 22 hours and no more than 26 hours are included. P values were derived from ANOVA model. ^† Fluid balance is equal to total fluid intake (oral or IV) minus urine output.

Clinical case by Sam Sigal, MD, Hepatologist

Insight on hyponatremia in cirrhosis

Patient presentation at hospitalization

42-year old male

Hyponatremia
Cirrhosis with ascites
Encephalopathy
Muscle cramps
Serum sodium 118 mEq/L

Results*

Free water clearance
Increased serum sodium

*Individual results may vary.

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.

Hyponatremia in Cirrhosis
– Patient Case Video
Sam Sigal, MD

“[One of the main benefits] of SAMSCA is the free water clearance. In fact, we saw a significant improvement in serum sodium levels within one day with this patient. He was able to drink fluids.... And because we saw a good response with SAMSCA, we were able to discharge the patient.”

Dr. Sigal

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References:

Angeli P, Wong F, Watson H, Ginès P, CAPPS Investigators. Hyponatremia in cirrhosis: results of a patient population survey. Hepatology. 2006;44(6):1535-1542.
Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11, suppl 1):S1-S21.
Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. 2006;17(7):1820-1832.
Data on file: Protocols 156-02-235 and 156-03-238; pooled.

INDICATION

SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/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

IMPORTANT SAFETY INFORMATION

SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too-rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.

SAMSCA is contraindicated in the following conditions:

— Urgent need to raise serum sodium acutely
— Inability of the patient to sense or appropriately respond to thirst
— Hypovolemic hyponatremia
— Concomitant use of strong CYP 3A inhibitors
— Anuric patients

Too-Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae – During initiation and after titration monitor patients to assess serum sodium concentrations and neurologic status. 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 24 hours with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided.
Gastrointestinal Bleeding in Patients With Cirrhosis – Use in cirrhotic patients only when need to treat outweighs this risk
Dehydration and Hypovolemia – In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted
Co-administration With Hypertonic Saline – Not recommended
Other Drugs Affecting Exposure to SAMSCA

— CYP 3A Inhibitors – Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors
— CYP 3A Inducers – Avoid concomitant use with CYP 3A inducers. If co-administered, the dose of SAMSCA may need to be increased
— P-gp Inhibitors – The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors

Hyperkalemia or Drugs that Increase Serum Potassium – Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels

Pregnancy and Nursing Mothers – SAMSCA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother.

Commonly observed adverse reactions – (SAMSCA incidence ≥5% more than placebo, respectively): thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%).

Please see U.S. FULL PRESCRIBING INFORMATION, including Boxed WARNING, and Medication Guide.

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.
Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850.
SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

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Hyponatremia in Cirrhosis

Use the following links to explore this section in further detail:

Hyponatremia in cirrhosis

Pathogenic properties of patients with cirrhosis

SAMSCA: Increases Serum Sodium Levels

SAMSCA: Significant effect on fluid balance

Clinical case by Sam Sigal, MD, Hepatologist

Insight on hyponatremia in cirrhosis

Patient presentation at hospitalization

Results*

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.

Click the following links to explore the site further:

References:

INDICATION

Important Limitations

IMPORTANT SAFETY INFORMATION

SAMSCA is contraindicated in the following conditions: