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SAMSCA® (tolvaptan): Effect on fluid balance vs placebo

Significant effect on serum sodium concentrations and fluid balance in patients with hyponatremia on day 1*

  • With SAMSCA, urine output was greater than fluid intake, which results in a net negative fluid balance1

Mean fluid intake, urine output, and fluid balance at day 1 in patients with hyponatremia1*

* Fluid balance was a secondary end point. Primary end point from pivotal clinical trials was average daily AUC for change in serum sodium from baseline to day 4 (SAMSCA, 4.0 mEq/L; placebo, 0.4 mEq/L [P<0.0001]) and baseline to Day 30 (SAMSCA, 6.2 mEq/L; placebo, 1.8 mEq/L [P<0.0001]).2
Fluid balance is equal to total fluid intake (oral or IV) minus urine output. 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.

* Fluid balance was a secondary end point. Primary end point from pivotal clinical trials was average daily AUC for change in serum sodium from baseline to Day 4 (SAMSCA, 4.0 mEq/L; placebo, 0.4 mEq/L [P<0.0001]) and baseline to Day 30 (SAMSCA, 6.2 mEq/L; placebo, 1.8 mEq/L [P<0.0001]).2

Fluid balance is equal to total fluid intake (oral or IV) minus urine output. 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.

  • Greater than 1 L net fluid output in patients treated with SAMSCA® (tolvaptan) vs placebo1

 

Hyponatremic SIADH patients treated with SAMSCA lost significantly more net fluid over the first study day than those on placebo

 

Adapted from Verbalis et al, Eur J Endocrinol, 2011.3

Reduced need for fluid restriction with SAMSCA

With SAMSCA, the percentage of patients needing fluid restriction (<1 L/day) at any time during 30-day treatment period was significantly less (P=0.0017) than with placebo.

Fluid restriction was to be avoided during the first 24 hours of therapy.

Fluid restriction was to be avoided during the first 24 hours of therapy.

Significantly fewer patients required fluid restriction during treatment with SAMSCA in the SALT trials (14% [30/215] vs 25% [51/206] for placebo), P=0.0017.

Fluid restriction during the first 24 hours of therapy may increase the likelihood of overly-rapid correction of serum sodium and should generally be avoided.

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

INDICATION and IMPORTANT SAFETY INFORMATION for SAMSCA® (tolvaptan)

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 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:

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM

  • 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

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

  • Because of the risk of hepatotoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS.

SAMSCA is contraindicated in the following conditions:

  • — Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA-approved REMS
  • — 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
  • — Hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or its components
  • 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. Co-administration of diuretics also increases the risk of too rapid correction of serum sodium and such patients should undergo close monitoring of serum sodium.
  • Liver Injury: Tolvaptan can cause serious and potentially fatal liver injury. In clinical trials, cases of serious liver injury have been attributed to chronically administered tolvaptan in patients with ADPKD. Liver failure requiring transplantation has been reported in postmarketing experience with tolvaptan in ADPKD. Limit duration of therapy with SAMSCA to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover may be impaired.
  • 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

Adverse Reactions: The most common 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%)

Gastrointestinal Bleeding in Patients with Cirrhosis: In patients with cirrhosis in the hyponatremia trials, GI bleeding was reported in 10% of tolvaptan-treated patients vs 2% for placebo

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

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

 

 

References:

1
Data on file. SAM-137. Otsuka America Pharmaceutical, Inc.
2
Schrier RW, Gross P, Gheorghiade M, et al; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. ​N Engl J Med. 2006;355(20):2099-2112.
3
Verbalis JG, Adler S, Schrier RW, Berl T, Zhao Q, Czerwiec FS; SALT Investigators. Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion. Eur J Endocrinol. 2011;164(5):725-732.