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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])
Chart showing the mean serum sodium on day 1 to day 4 in hyponatremia patients taking SAMSCA® and placebo.
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
SALT-1 And SALT-2 Post-Hoc Analysis
 


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

SAMSCA Efficacy Results
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

Tolvaptan Results - SIADH And Malignancy
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).

Limitations of Use:

  • 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.

CONTRAINDICATIONS:

  • Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA-approved REMS
  • Unable to sense or respond to thirst
  • Hypovolemic hyponatremia
  • Taking strong CYP3A inhibitors
  • Anuria
  • Hypersensitivity (e.g., anaphylactic shock, rash generalized) to tolvaptan or any component of the product

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

Drug Interactions – CYP3A Inhibitors: Tolvaptan is a substrate of CYP3A. Moderate to strong CYP3A inhibitors can lead to a marked increase in tolvaptan concentrations. Do not use SAMSCA with strong inhibitors of CYP3A and avoid concomitant use with moderate CYP3A inhibitors. Patients should avoid grapefruit juice beverages while taking SAMSCA

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

Acute Urinary Retention with Outflow Obstruction: Patients with partial obstruction of urinary outflow have an increased risk of developing acute retention. Do not administer tolvaptan in patients with uncorrected urinary outflow obstruction.

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

Other Drug Interactions:

  • Strong CYP3A Inducers: Co-administration of SAMSCA with strong CYP3A inducers reduces exposure to SAMSCA. Avoid concomitant use of SAMSCA with strong CYP3A inducers
  • Angiotensin Receptor Blockers, Angiotensin Converting Enzyme Inhibitors and Potassium Sparing Diuretics: In clinical studies, adverse reactions of hyperkalemia were approximately 1 to 2% higher when tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.
  • V2-Receptor Agonist: Tolvaptan interferes with the V2-agonist activity of desmopressin (dDAVP). Avoid concomitant use of SAMSCA with a V2-agonist

Pregnancy and Lactation: Based on animal data, SAMSCA may cause fetal harm. Advise women not to breastfeed during treatment with SAMSCA.

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.

© 2021 Otsuka America Pharmaceutical, Inc.

May 2021
07US21EBP0001