Subject: Samsca (tolvaptan) Original Effective Date: 07/27/15 Policy Number: MCP-252 Revision Date(s): Review Date(s): 12/15/2016; 6/22/2017 DISCLAIMER This Medical Policy is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this Molina Clinical Policy (MCP) document and provide the directive for all Medicare members. SUMMARY OF EVIDENCE/POSITION This policy addresses the coverage of Samsca (tolvaptan) for the treatment of clinically significant hypervolemic and euvolemic hyponatremia when appropriate criteria are met. ∑ The primary treatments used in the management of hyponatremic patients rely on the use of intravenous sodium- containing fluids (normal saline or hypertonic saline) and fluid restriction. Less commonly, loop diuretics (e.g., furosemide) or demeclocycline are used. AVP receptor antagonists [Conivaptan (Vaprisol) and Tolvaptan (Samsca)] treat hyponatremia through V2 antagonism of AVP in the renal collecting ducts. This effect results in aquaresis (excretion of free water). ∑ Tolvaptan (Samsca) is the first U.S. Food and Drug Administration (FDA) approved orally administered selective vasopressin V2-receptor antagonist 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). Tolvaptan causes an increase in urine water excretion and decreased urine osmolality, resulting in an increase in serum sodium concentration. ∑ Therapy Limitations: • Tolvaptan should not be used in members who require urgent intervention to raise serum sodium rapidly in order to prevent or treat serious neurological symptoms. • Initiation, including re-initiation, of therapy should be done in a hospital setting. • Tolvaptan may not provide symptomatic benefit ∑ Tolvaptan has been demonstrated to increase serum sodium in patients with euvolemic or hypervolemic hyponatremia from a variety of underlying causes, including heart failure and syndrome of inappropriate anti-diuretic secretion (SIADH). It has not been established that raising serum sodium with tolvaptan provides a symptomatic benefit to patients. Clinical outcomes were not assessed in the hyponatremia studies.a Page 1 of 12 ∑ Evidence for the efficacy of tolvaptan for other outcomes, such as quality of life measures and mortality, are unclear. Measurements for quality of life were not validated within patients with hyponatremia. ‹ The available literature indicated tolvaptan is effective at increasing urine volume and improving symptoms of dyspnea and pedal edema in persons with acute heart failure and in the treatment of chronic hyponatremia associated with syndrome of SIADH. ‹ Heart failure: In clinical trials in heart failure, tolvaptan use was associated with short-term symptomatic improvement. A clear survival benefit was not demonstrated. Based on the available evidence, tolvaptan cannot be considered a routine therapeutic option in the management of heart failure; furthermore, there is no data available on the use of tolvaptan in acute hyponatremia, and it is not indicated in hypovolemic hyponatremia. • Trials designed to evaluate the effect of tolvaptan use on long-term clinical outcomes such as left ventricular function, worsening heart failure, morbidity, and mortality did not demonstrate an improvement over standard therapy. Additionally, these trials demonstrated a significant incidence of adverse events. • Use of tolvaptan in patients with heart failure has shown efficacy in few clinical parameters, such as a reduction in body weight in the short-term. However, long-term studies have not reported any statistically significant decrease in death or hospitalization compared to placebo. In the therapy of heart failure, tolvaptan has induced short-term clinical improvement in association with its aquaretic effects, but has not demonstrated improvement in long-term outcomes, such as survival, hospitalizations, or clinical worsening. ∑ Tolvaptan offers an oral alternative to conivaptan (Vaprisol®) in the therapy of hyponatremia, particularly patients requiring long-term therapy to correct sodium levels. Although effective in normalizing serum sodium in half of treated patients, it has not been compared with other therapies, such as hypertonic saline or conivaptan. ∑ Guidelines for managing hyponatremia are based primarily on retrospective data and expert opinion, since few prospective studies have been done. The treatment of acute and chronic hyponatremia should be based on the severity of symptoms and taking care not to raise the serum sodium level too rapidly, which can cause neurologic dysfunction. CLASSIFICATION: Endocrine and Metabolic Agents; Selective Vasopressin Antagonist FDA INDICATIONS Hypervolemic and euvolemic hyponatremia: For the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium of less than 125 mEq/L or less marks hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and syndrome of inappropriate secretion of antidiuretic hormone (SIADH).a Limitations: • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with Samsca (tolvaptan). • It has not been established that raising serum sodium with Samsca (tolvaptan) provides a symptomatic benefit to patients. Available as: 15mg and 30mg oral tablets FDA Approved: May 19, 2009 Black Box Warnings: Initiate and reinitiate tolvaptan in patients only in a hospital where serum sodium can be closely monitored. Too rapid correction of hyponatremia (e.g., more than 12 mEq/L per 24 hours) can cause osmotic demyelination, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and/or death. In susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease, slower rates of correction may be advisable. Page 2 of 12 Risk Evaluation and Mitigation Strategy (REMS) � The FDA approved REMS for tolvaptan to ensure that the benefits of a drug outweigh the risks. The REMS may apply to � one or more preparations of tolvaptan and consists of the following: medication guide and communication plan. The � following information will be conveyed: � • The requirement to initiate and re-initiate therapy in a hospital • The risks associated with overly-rapid correction of serum sodium • Reinforcement that a patient Medication Guide should be provided to patients with every prescription of tolvaptan RECOMMENDATIONS/COVERAGE CRITERIA Samsca (tolvaptan) may be authorized for members who meet ALL of the following criteria [ALL] 1. � Prescriber specialty [ONE] ¶ Prescribed by, or in consultation with, a board certified nephrologists, cardiologists, internists, endocrinologist, or has obtained a consult from such a specialist. Submit consultation notes if applicable: Specialist’s consult recommending therapy and/or a discharge summary documenting medical necessity with tolvaptan listed on the discharge summary. 2. � Diagnosis/Indication [ALL] Clinical documented diagnosis of (includes clinical notes from the member’s medical records including any applicable labs and/or tests, supporting the diagnosis): ¶ Diagnosis of ONE of the following [ONE] û Hypervolemic hyponatremia û Euvolemic hyponatremia ¶ Confirmation the member has clinically significant hypervolemic or euvolemic hyponatremia as evidenced by ONE of the following: [ONE] û Clinically significant hypervolemic or euvolemic hyponatremia as evidenced by serum sodium less than 125meq/L û Clinically significant hypervolemic or euvolemic hyponatremia that is symptomatic (e.g., dizziness, gait disturbances, forgetfulness, confusion, lethargy, seizures, impaired mental status) AND has resisted correction with fluid restriction. ‹ For the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium of less than 125 mEq/L or less marks hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and syndrome of inappropriate secretion of antidiuretic hormone (SIADH).a-e ¶ Hyponatremia has resisted correction to other therapy.