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Efficacy of SAMSCA® (tolvaptan): Data from the pivotal clinical trials

SAMSCA significantly increased average daily serum sodium from baseline to Day 4 and baseline to Day 30, vs placebo (P<0.0001) in the SALT (Study of Ascending Levels of Tolvaptan in hyponatremia) trials

  • Primary end point was average daily AUC for change in serum sodium from baseline to Day 4 (tolvaptan [n=213], 4.0 mEq/L; placebo [n=203], 0.4 mEq/L [P<0.0001]) and baseline to Day 30 (tolvaptan [n=213], 6.2 mEq/L; placebo [n=203], 1.8 mEq/L [P<0.0001])
In the SALT (Study of Ascending Levels of Tolvaptan in hyponatremia) pivotal trials—two identical, 30-day, randomized, double-blind, placebo-controlled, multicenter studies—424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) were treated for 30 days with tolvaptan or oral placebo, then followed for an additional 7 days after withdrawal. Primary end point from pivotal clinical trials was average daily AUC for change in serum sodium from baseline to Day 4 (tolvaptan, 4.0 mEq/L; placebo, 0.4 mEq/L, P<0.0001) and baseline to Day 30 (tolvaptan, 6.2 mEq/L; placebo, 1.8 mEq/L, P<0.0001). Mean change in serum sodium from baseline to 8 hours for tolvaptan, 2.5 mEq/L; placebo, -0.5 mEq/L, P<0.0001 (secondary end point). Starting dose was 15 mg, and was increased to 30 or 60 mg, if necessary. Within 7 days of discontinuation, serum sodium concentrations in tolvaptan-treated patients declined to placebo-like levels.

In the SALT (Study of Ascending Levels of Tolvaptan in hyponatremia) pivotal trials—two identical, 30-day, randomized, double-blind, placebo-controlled, multicenter studies—424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) were treated for 30 days with tolvaptan or oral placebo, then followed for an additional 7 days after withdrawal. Primary end point from pivotal clinical trials was average daily AUC for change in serum sodium from baseline to Day 4 (tolvaptan, 4.0 mEq/L; placebo, 0.4 mEq/L, P<0.0001) and baseline to Day 30 (tolvaptan, 6.2 mEq/L; placebo, 1.8 mEq/L, P<0.0001). Mean change in serum sodium from baseline to 8 hours for tolvaptan, 2.5 mEq/L; placebo, -0.5 mEq/L, P<0.0001 (secondary end point). Starting dose was 15 mg, and was increased to 30 or 60 mg, if necessary. Within 7 days of discontinuation, serum sodium concentrations in tolvaptan-treated patients declined to placebo-like levels.

SAMSCA provided a statistically significant increase from baseline (P<0.0001) in serum sodium in patients with euvolemic or hypervolemic hyponatremia compared with placebo

  • Significant increase in as early as 8 hours (mean change from baseline, secondary endpoint)
  • Proven in two identical randomized, placebo-controlled, double-blind phase 3 studies (Study of Ascending Levels of Tolvaptan in hyponatremia 1 and 2) [SALT-1 and SALT-2]1
  • The mean increases in serum sodium during treatment initiation (first 24 hours) were 4.06 mEq/L for SAMSCA 15 mg and 0.33 mEq/L for placebo (baseline <135 mEq/L)2
Too-rapid correction of serum sodium (e.g., >12 mEq/L/24 hours) can cause serious neurologic sequelae, including osmotic demyelination syndrome (ODS)

Post hoc analysis

  • Post hoc analysis was done in 2 subgroup populations:
    • Hyponatremia in SIADH subgroup population n=1103
    • Hyponatremia in SIADH in patients with malignancy subgroup population n=284
 


A post hoc analysis of hyponatremic patients with SIADH from the SALT trials

Significant increase in average daily serum sodium from baseline to Day 4 and to Day 30, and in as early as 8 hours for SAMSCA vs placebo3,4

Adapted from Verbalis et al, Eur J Endocrinol, 2011.3
Average daily AUC of change from baseline in serum sodium (last observation carried forward, left) and serum sodium (patients on treatment, right) in the combined hyponatremia in SIADH subgroups of SALT-1 and SALT-2. Results are consistent with those of the overall population in SALT-1 and SALT-2.

Adapted from Verbalis et al, Eur J Endocrinol, 2011.3

Average daily AUC of change from baseline in serum sodium (last observation carried forward, left) and serum sodium (patients on treatment, right) in the combined hyponatremia in SIADH subgroups of SALT-1 and SALT-2. Results are consistent with those of the overall population in SALT-1 and SALT-2.

Results from a post hoc analysis of 110 patients (n=52, SAMSCA; n=58, placebo) from the SALT-1 and SALT-2 trials with investigator-diagnosed SIADH3

  • Primary end point: Significant change in average daily AUC for serum sodium from baseline to Day 4 (SAMSCA 5.28 mEq/L vs placebo 0.47 mEq/L; P<0.0001) and from baseline to Day 30 (SAMSCA 8.07 mEq/L vs placebo 1.89 mEq/L; P<0.0001)3
  • Secondary end point: Significant change in mean serum sodium concentration from baseline to 8 hours (SAMSCA 4.0 mEq/L vs placebo -0.7 mEq/L; P<0.0001; n=102)4

A post hoc analysis of hyponatremic patients with SIADH and malignancy from the SALT trials

Significant increase in average daily serum sodium from baseline to Day 4 and to Day 30, and in as early as 8 hours, for SAMSCA vs placebo4

Last observation carried forward data shown. Similar results were shown for the subgroup of hyponatremic patients with SIADH and for the full population of patients included in SALT-1 and SALT-2.
This separate post hoc analysis in 28 hyponatremic patients with SIADH and malignancy (n=12, SAMSCA; n=16, placebo) from the SALT trials was conducted to determine the efficacy of SAMSCA in this group relative to the overall hyponatremia in SIADH population.

Last observation carried forward data shown. Similar results were shown for the subgroup of hyponatremic patients with SIADH and for the full population of patients included in SALT-1 and SALT-2. This separate post hoc analysis in 28 hyponatremic patients with SIADH and malignancy (n=12, SAMSCA; n=16, placebo) from the SALT trials was conducted to determine the efficacy of SAMSCA in this group relative to the overall hyponatremia in SIADH population.

Average daily AUC of change from baseline in serum sodium in hyponatremic patients with SIADH and malignancy from SALT-1 and SALT-2. Results are consistent with those of the overall population in SALT-1 and SALT-2.

The post hoc analysis of patients in the trial was not powered to analyze the hyponatremic patients with SIADH and malignancy separately.

Results from a post hoc analysis of 28 patients (n=12, SAMSCA; n=16, placebo) from the SALT-1 and SALT-2 trials with investigator-diagnosed SIADH and malignancy4

  • Primary end point: Significant change in average daily AUC for serum sodium from baseline to Day 4 (SAMSCA 5.32 mEq/L vs placebo -0.49 mEq/L; P<0.0001) and from baseline to Day 30 (SAMSCA 7.66 mEq/L vs placebo 0.50 mEq/L; P<0.0001).4
  • Secondary end point: Significant change in mean serum sodium from baseline to 8 hours (SAMSCA 4.6 mEq/L vs placebo -1.6 mEq/L; P<0.0001; n=25).4

In a separate small clinical trial that studied SAMSCA in hospitalized cancer patients with nonhypovolemic hyponatremia, efficacy and safety results were consistent with SALT-1 and SALT-2 results5

  • This prospective, randomized, placebo-controlled, double-blind trial studied SAMSCA use in adult patients with cancer who were admitted to The University of Texas MD Anderson Cancer Center with nonhypovolemic hyponatremia (125-130 mEq/L; N=48).
    • Subjects were randomized to receive either SAMSCA or placebo. Both groups received the standard of care for hyponatremia, except that patients were allowed to drink in response to thirst
  • 94% of patients (16/17) treated with SAMSCA achieved the primary end point of serum sodium correction (≥136 mEq/L) on day 14, vs 8% (1/13) on placebo (P<0.001)
  • Efficacy and safety results were consistent with SALT-1 and SALT-2 results

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
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.
2
Data on file. SAM-136. Otsuka America Pharmaceutical, Inc.
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.
4
Data on file. SAM-126. Otsuka America Pharmaceutical, Inc.