A Treatment Option for Dilutional Hyponatremia-Important Considerations

This article was sponsored by Otsuka America Pharmaceutical, Inc.

SAMSCA^® (tolvaptan) is the first and only oral vasopressin V₂-receptor antagonist that increases serum sodium levels through free water clearance.

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.

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.

Please see Important Safety Information below. OVERVIEW

Excess vasopressin is an important physiologic cause of hyponatremia.¹ Tolvaptan antagonizes the effect of vasopressin and causes an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and an increase in serum sodium concentrations.²

Efficacy was evaluated in 2 identical, 30-day, randomized, double-blind, placebo-controlled, multicenter pivotal trials which demonstrated that SAMSCA significantly raised serum sodium levels from baseline versus placebo at day 4 and at day 30 (P <.0001 for both comparisons; primary end points), and in as early as 8 hours.

Safety was evaluated in both open-label and placebo-controlled studies of more than 4000 patients, approximately 650 of whom had hyponatremia. Trial discontinuation rates due to adverse reactions were similar to placebo. The most common adverse reactions observed at an incidence of 5% or more than placebo were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia.

SAMSCA is an oral tablet dosed once-daily with the flexibility to titrate. SAMSCA should be initiated and re-initiated only in a hospital where serum sodium can be monitored closely; however, initiation in the intensive care unit (ICU) is not required. During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Fluid restriction during the first 24 hours of therapy with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided. Do not administer SAMSCA for more than 30 days to minimize the risk of liver injury.

Efficacy

SALT-1 and SALT-2 Trials

The efficacy of SAMSCA was established in 2 identical, 30-day, randomized, double-blind, placebo-controlled, multicenter pivotal trials. The SALT (Study of Ascending Levels of Tolvaptan in hyponatremia) trials, SALT-1 and SALT-2, studied a total of 424 patients with either euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) resulting from a variety of underlying causes (eg, heart failure, SIADH, and cirrhosis). SAMSCA is not indicated for the treatment of patients with cirrhosis. Patients were randomized to 30 days of treatment with either tolvaptan (n = 223) or placebo (n = 220), then followed for an additional 7 days after withdrawal. The primary end point was average daily area under the curve (AUC) for change in serum sodium from baseline to day 4 and baseline to day 30 in patients with serum sodium less than 135 mEq/L. The initial oral dose was 15 mg, which could be increased after at least 24 hours to 30 mg once daily, and then to a maximum of 60 mg once daily as needed to achieve the desired level of serum sodium. Because the ability to recover from liver injury may be impaired, use in patients with underlying liver disease, including cirrhosis, should be avoided.

Serious neurologic sequelae, including osmotic demyelination syndrome, can be caused by too-rapid correction of serum sodium (eg, >12 mEq/L/24 hours).

Sodium Serum Levels

The average daily AUC from baseline for serum sodium was 4.0 mEq/L versus 0.4 mEq/L

(P <.0001) on day 4 and 6.2 mEq/L versus 1.8 mEq/L on day 30 for tolvaptan versus placebo, respectively (P <.0001). A pooled analysis of SALT-1 and SALT-2 data showed a significant treatment effect versus placebo with tolvaptan in as early as 8 hours; increases in serum sodium remained significant to day 30 (Figure 1). Within 7 days of discontinuation, serum sodium concentrations in tolvaptan-treated patients declined to placebo-like levels.¹ A subgroup analyses of data among hyponatremic patients with underlying heart failure (n = 85) or SIADH (n = 61) showed a significant treatment effect at day 4 and day 30 (Figure 2).³

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.

Free Water Clearance

SAMSCA is a selective vasopressin V₂-receptor antagonist with an affinity for the V₂-receptor that is 1.8 times that of native arginine vasopressin. SAMSCA affinity for the V₂-receptor is 29 times greater than for the V_1a-receptor. When taken orally, 15 to 60 mg doses of SAMSCA antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonistic activity for human V₂-receptors compared with tolvaptan.

A secondary end point of the SALT pivotal trials was to evaluate fluid intake and output on day 1 of the study.⁴ Within the first day of SAMSCA use there was a significant effect on urine output in patients with hyponatremia. In a pooled analysis of the 2 studies, the mean urine output for patients who took SAMSCA was 3217 mL, a volume more than 1 L greater than the output (1982 mL) in patients assigned to placebo (Figure 3).³

Renal Function

A pooled analysis of 12 placebo-controlled trials showed no clinically significant change in renal function, as measured by serum creatinine and blood urea nitrogen (BUN). In addition, there was no significant change in urine excretion of sodium and potassium, or in serum potassium. SAMSCA dosing does not need to be adjusted based on renal function; however, SAMSCA is not recommended in patients with a creatinine clearance less than 10 mL/min because drug effects on serum sodium levels are likely lost at very low levels of renal function.

Clinical Safety Profile

The most common adverse reactions observed at an incidence of 5% or more than placebo were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. Table 1 lists adverse reactions that were reported at a rate at least 2% greater in tolvaptan-treated patients than in placebo-treated patients. The safety profile for SAMSCA was evaluated in more than 4000 patients in clinical trials. These include open-label and placebo-controlled studies in approximately 650 patients with hyponatremia. In the pivotal trials, the discontinuation rate due to adverse reactions in the treatment group was similar to placebo (10% and 12%, respectively).

Practical Considerations

Therapy with SAMSCA may be an appropriate choice in patients with clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L) or in patients with less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction, including patients with heart failure and SIADH.

SAMSCA is not an appropriate treatment option in patients who require intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms. SAMSCA has not been shown to provide symptomatic benefit to patients.

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

—

Hypersensitivity (eg, anaphylactic shock, rash generalized) to tolvaptan or its components

Fluid Restriction

Fluid restriction is an effective treatment for hypervolemic and euvolemic hyponatremia⁶; however, hyponatremia may resist correction with fluid restriction.¹ Patients taking SAMSCA should drink in response to their thirst. In addition, fluid restriction should generally be avoided during the first 24 hours of therapy with SAMSCA, as it may increase the likelihood of overly rapid correction of serum sodium, dehydration, and hypovolemia.

Patients taking SAMSCA in the SALT trials demonstrated a reduced need for fluid restriction compared with those taking placebo (Figure 4).

Dosing, Administration, and Ease of Use

SAMSCA is administered via once-daily oral dosing with the flexibility to titrate, and can be taken without regard to meals. Proper administration of SAMSCA involves a starting dose of 15 mg per day, which may be titrated to 30 mg once daily after at least 24 hours, up to a maximum of 60 mg once daily as needed to raise serum sodium. There is no dose adjustment necessary based on age, gender, or race; or on cardiac or renal function. SAMSCA is not recommended in patients with creatinine clearance less than 10 mL/min because drug effects on serum sodium levels are likely lost at very low levels of renal function. SAMSCA does not need to be initiated in the ICU, but should be initiated and re-initiated only in a hospital setting where serum sodium can be monitored closely. Too-rapid correction of serum sodium can cause serious neurologic sequelae, including ODS. During initiation and titration, patients should be monitored frequently for changes in serum electrolytes and volume.

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

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

—

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

• Liver Injury — SAMSCA can cause serious and potentially fatal liver injury. In a placebo-controlled and open-label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD), cases of serious liver injury attributed to tolvaptan were observed. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover may be impaired. Limit duration of therapy with SAMSCA to 30 days. SAMSCA is not approved for use in ADPKD

• 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 inhibitor

—

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 Pgp 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

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

Please see FULL PRESCRIBING INFORMATION, including Boxed WARNING.

References

• Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126:S1-S42.
• Hauptman PJ, Zimmer C, Udelson J, et al. Comparison of two doses and dosing regimens of tolvatan in congestive heart failure. J Cardiovasc Pharmacol. 2005;46(5):609-614.
• Data on file. Integrated Summary of Efficacy of Tolvaptan. Otsuka America Pharmaceutical, Inc; 2007.
• 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.
• Data on file. Protocols 156-02-235 and 156-03-238; Pooled. Otsuka America Pharmaceutical, Inc.
• Ghali JK. Mechanisms, risks, and new treatment options for hyponatremia. Cardiology. 2008;111:147-157.

Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

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SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

©2014 Otsuka America Pharmaceutical, Inc. June 2014 07US13EBP0019