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

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∑ 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.

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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. Documentation of therapies tried and results submitted for review. Other therapies may include but not restricted to fluid restriction, loop diuretics, hypertonic saline.

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3. � Age/Gender/Other restrictions [ALL]

¶ 18 years of age or older ‹ Safety and efficacy not established in pediatric patients.

¶ Confirmation that member does not have underlying liver disease (including cirrhosis) Tolvaptan can cause serious and potentially fatal liver injury. Tolvaptan should be avoided in patients with underlying liver disease, including cirrhosis, because the ability to recover from hepatic injury may be impaired.a-e

¶ Therapy was initiated or re-initiated in a hospital within the past month

4. � Step/Conservative Therapy/Other condition Requirements [ALL: A, B]

¶ Member has been evaluated for drug-induced causes of hyponatremia with suspected offending agents discontinued

¶ Member is NOT concurrently taking ANY of the following: [ANY]

¶ Strong CYP3A inhibitors: e.g., clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, telithromycin)a

5. � Contraindications/Exclusions/Discontinuations Authorization will not be granted if ANY of the following conditions apply [ANY] ¶ Non-FDA approved indications ¶ Hypersensitivity (e.g., anaphylactic shock, generalized rash) to tolvaptan or any component of the formulationa ¶ Urgent need to raise serum sodium acutelya ¶ Inability of the patient to sense or appropriately respond to thirsta ¶ Hypovolemic hyponatremiaa ¶ Anuric patients ¶ Concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin); anuriaa ¶ Renal function impairment: Use in patients with a creatinine clearance less than 10 mL/min is not recommended because drug effects on serum sodium levels are likely lost at very low levels of renal functiona-e ¶ Hepatic function impairment: Avoid use in patients with underlying liver diseasea-e ¶ Autosomal dominant polycystic kidney disease (ADPKD) ‹ Samsca (tolvaptan) is not indicated for use in ADPKD. In a placebo-controlled and open-label extension study of chronically administered tolvaptan in patients with 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.

6. � Labs/Reports/Documentation required [ALL] All documentation for determination of medical necessity must be submitted for review. Prescriber to submit documentation as indicated in the criteria above, including but not limited to chart notes, applicable lab values and/or tests, adverse outcomes, treatment failures, or any other additional clinical information or clinical notes from the member’s medical records supporting the diagnosis. Letters of support and/or explanation are often useful, but are not sufficient documentation unless ALL specific information required by this MCP are included. NOTE: Additional documentation, rationale, and/or supporting evidence may be requested for review as deemed necessary or appropriate by Molina Medical/Pharmacy staff.

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CONTINUATION OF THERAPY

Samsca (tolvaptan) may be authorized for up to a maximum length of therapy of 30 days, or until correction of hyponatremia and improvement in fluid balance and clinical status, whichever is less. The FDA has limited the use of Samsca to no more than 30 days to minimize the risk of liver injury.

***FDA has determined that tolvaptan (Samsca) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver transplant or death. FDA has worked with the manufacturer to revise the Samsca drug label to include new limitations.a-e Reference: FDA Drug Safety Communication 2013 Apr 30, FDA MedWatch 2013 Jan 25

Additional authorization for treatment beyond 30 days is an EXCEPTION and is provided through prior authorization in accord with ALL of the following: [MOLINA MEDICAL DIRECTOR REVIEW REQUIRED]

¶ Member currently meets ALL initial coverage criteria

¶ Member requires continuing/ongoing treatment to prevent clinically significant hypervolemic or euvolemic hyponatremia due to conditions such as heart failure or SIADH

¶ Samsca (tolvaptan) was initiated or re-initiated in a hospital (for close monitoring of serum sodium). Documentation required

¶ Chart notes and medical records supporting the rationale for therapy beyond 30 days, including documentation of improvement in member’s condition as a result of therapy

¶ Acknowledgement from Prescriber that the FDA has limited the use of Samsca to no more than 30 days to minimize the risk of liver injury; however Prescriber is determined to proceed with continuation of therapy. NOTE: At the discretion of the Molina Medical Director, a peer-to-peer consultation may be necessary

¶ Duration of treatment: An additional maximum of 30 days of treatment may be authorized for members who have already received treatment beyond 30 days.

NOTE: All documentation for determination of medical necessity must be submitted for review. Prescriber to submit medical records and specific labs, chart notes, and documentation as indicated in the criteria above. Letters of support and/or explanation are often useful, but are not sufficient documentation unless ALL specific information required by the criteria above is included.

NOTE: Additional documentation, rationale, and/or supporting evidence may be requested for review as deemed necessary or appropriate by Molina Medical Director and/or Pharmacy staff.

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ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD

1. � Recommended Dosage [ALL]

¶ Start at 15mg once daily. May be increased at intervals > 24 hr to 30mg once daily, and to a maximum of 60mg once daily as needed to raise serum sodium. ‹ Monitoring: monitor serum sodium and neurologic status as serious neurologic sequelae can result from rapid correction of sodium. Monitor serum potassium in persons with potassium greater than 5 mEq/L or in individuals administered drugs known to increase potassium (e.g., ACE-Inhibitors)

¶ Dose not to exceed 60mg daily

2. � Authorization Limit [ALL]

¶ Quantity limit: [ONE] û Samsca 15 mg tablet: up to 2 tablets per day (60 tablets per 30 days) û Samsca 30 mg tablet: up to 2 tablets per day (60 tablets per 30 days)

¶ Duration of authorization: [ALL APPLICABLE]

û Duration of treatment: Maximum of 30 days. The FDA has limited the use of Samsca to no more than 30 days to minimize the risk of liver injury.

3. � Route of Administration [ALL]

¶ Tolvaptan is available for oral use only. It should be initiated and re-initiated only in a hospital setting 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

¶ If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider; they must be dispensed through a participating pharmacy.

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COVERAGE EXCLUSIONS

Samsca (tolvaptan) is considered experimental and investigational for all other indications. Therefore, all other uses of Samsca (tolvaptan) that are not an FDA-approved indication or included in ‘Coverage Criteria’ section above are considered experimental/investigational and is not a covered benefit addressed in this policy. This subject to change based on research and medical literature, or at the discretion of Molina Healthcare.

¶ Heart Failure ‹ Samsca (Tolvaptan) is not authorized for the outpatient management of chronic congestive heart failure because published data do not demonstrate a benefit in terms of all-cause mortality, cardiovascular mortality or heart failure hospitalization when compared to placebo. ‹ Additional information addressing’heart failure’ is in the Summary of Evidence’ section.

¶ Autosomal dominant polycystic kidney disease (ADPKD)a,b ‹ Samsca (tolvaptan) can cause serious and potentially fatal liver injury. ‹ Samsca (tolvaptan) is not indicated for use in ADPKD. In a placebo-controlled and open-label extension study of chronically administered tolvaptan in patients with 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. • In a 3-year, double-blind, placebo-controlled trial and its open-label extension in patients with autosomal dominant polycystic kidney disease, severe hepatic injury attributed to tolvaptan was observed in 3 patients receiving chronic therapy with the drug. These patients developed substantial increases in serum ALT concentrations (i.e., exceeding 3 times the upper limit of normal [ULN]) with concomitant, clinically important increases in total serum bilirubin concentrations (i.e., exceeding 2 times the ULN). All 3 patients improved following discontinuance of tolvaptan therapy. In addition, tolvaptan was associated with an increased incidence of ALT concentrations exceeding 3 times the ULN compared with placebo (4.4 versus 1%). enzyme abnormalities generally occurred during the first 18 months of therapy and gradually improved following discontinuance of therapy. Serious hepatic injury occurred 3 months or longer after initiation of tolvaptan therapy; however, ALT elevations occurred within the first 3 months of therapy. In these studies, the maximum daily dosage of tolvaptan administered (90 mg in the morning and 30 mg in the afternoon) exceeded the maximum recommended dosage of tolvaptan (60 mg daily) for the treatment of hyponatremia.

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SUMMARY

Hyponatremia is defined as a serum sodium level of less than 135 mEq/L and is considered severe when the serum level is below 125 mEq/L. Many medical illnesses, such as congestive heart failure, liver failure, renal failure, or pneumonia, may be associated with hyponatremia. 7 Symptoms range from nausea and malaise, with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (if severe) seizures and coma. Overt neurologic symptoms most often are due to very low serum sodium levels (usually < 115 mEq/L), resulting in intracerebral osmotic fluid shifts and brain edema.Hyponatremia is classified according to volume status, as follows: • Hypovolemic hyponatremia: decrease in total body water with greater decrease in total body sodium • Euvolemic hyponatremia: normal body sodium with increase in total body water • Hypervolemic hyponatremia: increase in total body sodium with greater increase in total body water

The condition is associated with significant morbidity and mortality. If left untreated, severe hyponatremia is associated with an increase in mortality. Hyponatremia is associated with neurological symptoms and in severe cases can lead to coma, seizures, respiratory arrest, andeven death. In persons with heart failure, the presence of hyponatremia is associated with increased risk of adverse outcomes. Early identification and appropriate treatment of hyponatremia is essential in improving outcomes.

Hyponatremia generally occurs due to an excess of extracellular water caused by impaired water excretion. The presence and degree of these symptoms are dependent on the rate of the decrease in sodium as well as the absolute sodium concentration. Hyponatremia is not a primary diagnosis; it is commonly associated with the syndrome of inappropriate antidiuretic hormone (SIADH), excessive hydration during exercise, nephritic syndrome, cirrhosis, heart failure, and the use of certain drugs.A In the United States, the estimated prevalence of hyponatremia ranges from 3.16 million to 6.07 million persons.1

Treatment strategies are targeted at (1) correcting the underlying disease, (2) replacing sodium with normal or hypertonic saline and (3) removing excess fluid using fluid restriction, diuretics or vasopressin receptor antagonists.

Pharmacologic Agents/Conventional Therapy Diuretics and free water restriction have been used to combat this condition, but such strategies may result in electrolyte imbalances, arrhythmias, and renal failure. Desmopressin and lithium have also been used.

Although the etiology of hyponatremia may be diverse, nearly all causes can be related to the hormone arginine vasopressin (AVP). AVP is normally secreted by the anterior hypothalamus in response to an increased plasma osmolality or a decrease in blood volume or blood pressure (BP). After AVP is released, it stimulates several subtypes of AVP receptors throughout the body. Table 1 shows the location and physiological effect of receptor activation. Hyponatremia associated with SIADH results from the incomplete suppression of AVP resulting from a variety of causes, whereas hyponatremia associated with HF results from an increased AVP secretion secondary to decreased effective arterial blood volume that is independent of the sodium concentration.2

At the time of this writing, conivaptan (Vaprisol®) and tolvaptan (Samsca®) are the only FDA-approved vasopressin receptor antagonists. Conivaptan, a non-selective vasopressin receptor antagonist, is available as an injectable formulation only and is approved for short-term treatment (4 days) of hyponatremia in hospitalized patients.

Tolvaptan (Samsca®) was recently approved by the FDA in May 2009 for oral management of the treatment of clinically significant hypervolemic and euvolemic hyponatremia. Tolvaptan blocks the binding of vasopressin to the V2-receptors in the kidney, thus increasing the excretion of free water while not affecting the excretion of sodium and other electrolytes. Tolvaptan is the first orally administered selective vasopressin V2-receptor antagonist for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.

Hayes At the time of this writing, a Hayes Directory report or Hayes Rating is not available addressing tolvaptan for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.

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Pivotal Trials ­

∑ Efficacy in Euvolemic or Hypervolemic Hyponatremia The efficacy of tolvaptan was evaluated in two sets of phase 3 clinical trials: the Study of Ascending Levels of Tolvaptan in Hyponatremia (the SALT trials)2 and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (the EVEREST Program). 3,4,5

Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 [SALT-1 and SALT-2; n =424] 2 Two randomized, placebo-controlled, double-blind trials were conducted in parallel to assess the outpatient use of tolvaptan for hyponatremia secondary to various causes. The drug’s safety and reversibility of effect were also assessed. SALT-1 and SALT-2 were identical in methodology but were run in parallel in order to satisfy regulatory requirements.

SALT-1 and 2 were two identically conducted trials which evaluated a total of 448 euvolemic or hypervolemic patients with a serum sodium <135 mEq/L. The Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT 1 and 2), found that tolvaptan was more effective than placebo in increasing serum sodium concentrations in patients with either euvolemic or hypovolemic hyponatremia. ‹ One study enrolled 205 patients and the other enrolled 243 patients. ‹ Patients were enrolled in the trials if they were 18 years of age or older and had euvolemic or hypervolemic hyponatremia (sodium levels below 135 mEq/L) secondary to HF, cirrhosis, or SIADH. ‹ Patients were excluded from the SALT trials if the following were applicable: • clinically evident hypovolemic hyponatremia • exhibited a reversible cause of hyponatremia • had neurological pathology, including psychogenic polydipsia, progressive or episodic neurological disease (including cerebrovascular accidents), or neurological impairment, accompanied by a serum sodium level below 120 mEq/L • had a cardiopulmonary factor such as hemodynamic instability, myocardial infarction (MI), ventricular tachycardia or fibrillation, severe angina, or severe pulmonary hypertension • had undergone recent surgery • severe renal impairment (serum creatinine >3.5mg/dL), advanced liver disease (Child-Pugh score >10), or urinary tract obstruction • had uncontrolled diabetes mellitus • who may not tolerate sudden shifts in fluid volumes or pressures • little chance of short-term survival ‹ Patients received therapy for 30 days with Samsca or placebo, and were then followed for an additional 7 days after study withdrawal. Patients received tolvaptan 15 mg or placebo once daily for up to 30 days. Tolvaptan dosages could be increased within the first 4 days of the study to 30 mg daily and then to 60 mg daily on the basis of serum sodium concentrations. ‹ The primary study end points were the change in average daily AUC for serum sodium concentration from baseline to day 4 and from baseline to day 30. ‹ Results: In both trials, Samsca therapy led to a greater increase in serum sodium (P < 0.0001) compared with baseline at the measured endpoints at Day 4 and Day 30. The effects of sustained serum sodium were demonstrated for up to 1 year in an open-label study. ‹ 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%).

∑ Another long-term analysis (the Safety and sodium Assessment of Long-term Tolvaptan With hyponatremia: A year- long, open-label Trial to gain Experience under Real-world conditions [SALTWATER]) showed that in 111 patients who received Samsca for approximately 1.9 years, increases in serum sodium were maintained with reasonable safety.2

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∑ Heart failure: No significant effect of tolvaptan (favorable or unfavorable) was established for all-cause mortality or a composite of cardiovascular mortality or subsequent hospitalization for worsening heart failure during long-term use in patients with heart failure.a,c

In clinical trials in heart failure, tolvaptan use was associated with short-term symptomatic improvement. 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. A clear survival benefit was not demonstrated.

Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan [EVEREST]3,4,5 In a phase 3, double-blind, placebo-controlled study (EVEREST), 4133 patients with reduced left ventricular ejection fraction (40% or less), signs of volume expansion, and New York Heart Association (NYHA) class III or IV symptoms, who had been hospitalized for exacerbation of chronic heart failure within the previous 48 hours, were randomized to receive tolvaptan 30 mg once daily or placebo as an adjunct to standard care for heart failure (e.g., diuretics, digoxin, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, b-adrenergic blocking agents, aldosterone blockers, hydralazine, nitrates). The median duration of treatment was 9.9 months. All- cause mortality rates (25.9 versus 26.3%) and occurrences of the combined outcome of cardiovascular death or hospitalization for heart failure (42 versus 40.2%) were similar for patients who received tolvaptan and those who received placebo.4 ‹ Mean patient age was 66 years; approximately 75% were men and 85% were white; almost 80% had previously been hospitalized for heart failure. Patients received tolvaptan 30 mg once daily (2,072 patients) or placebo (2,061 patients) for a minimum of 60 days. ‹ Therapy was initiated within 48 hours of hospitalization. ‹ All patients continued to receive standard therapy for heart failure, including diuretics, digoxin, ACE inhibitors, ARBs, hydralazine, nitrates, or beta-blockers, at the discretion of the treating health care provider. ‹ Co-primary end points were 1) the time to all-cause mortality, and 2) time to cardiovascular mortality or heart failure hospitalization. ‹ The study was designed to be terminated after 1,065 deaths and a minimum of 60 days of therapy for all current subjects. The first subject was enrolled in October 2003; the study was completed in February 2006 after a total of 1,080 deaths. ‹ Results: No differences were observed between the tolvaptan and placebo groups in any of the prespecified primary or secondary end points. • During a median follow-up of 9.9 months, 537 patients in the tolvaptan group (25.9%) and 543 patients in the placebo group (26.3%) died (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.68). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan-treated patients (42%) and 829 placebo recipients (40.2%; HR, 1.04; 95% CI, 0.95 to 1.14; P = 0.55). • Differences between tolvaptan and placebo also were not observed for the secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, or worsening heart failure.3.4 • Two prospective embedded subgroup studies were conducted as components of the larger study with a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier, serving as the primary end point of each. These studies included 2,048 and 2,085 patients. Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan than placebo (trial A, 1.06 vs 0.99; trial B, 1.07 vs 0.97; both P < 0.001). Mean body weight reduction was greater with tolvaptan at day 1 (trial A, 1.71 kg vs 0.99 kg; trial B, 1.82 kg vs 0.95 kg; both P < 0.001) and day 7 or discharge (trial A, 3.35 kg vs 2.73 kg; trial B, 3.77 vs 2.79; both P < 0.001). Improvement in dyspnea at day 1 was observed in both trials with tolvaptan compared with placebo (trial A, 76.7% with improvement on tolvaptan vs 70.6% with placebo; trial B, 72.1% vs 65.3%; both P < 0.001). Improvement in edema scores were reported in 1 substudy, but not the other.5

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Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations. A panel of United States experts on hyponatremia issued guidelines on the diagnosis, evaluation, and treatment of hyponatremia in 2007; the guidelines were updated in 2013.A ‹ For treatment of symptomatic patients with acute hyponatremia (i.e., with a known duration of <24-48 hours), the panel recommended urgent correction by 4-6 mmol/L to prevent brain herniation and neurological damage from cerebral ischemia. Recommended treatment of acute hyponatremia varies by symptom severity, as follows: • Severe symptoms: 100 mL of 3% NaCl infused intravenously over 10 minutes × 3 as needed • Mild to moderate symptoms, in patients at low risk for herniation: 3% NaCl infused at 0.5–2 mL/kg/h ‹ For patients with inappropriate antidiuretic hormone secretion (SIADH), fluid restriction (with a goal of 500 mL/d below the 24-hour urine volume) is generally first-line therapy, however pharmacologic treatment should be strongly considered if the patient's urinary parameters indicate low renal electrolyte-free water excretion or if the serum sodium concentration does not correct after 24-48 hours of fluid restriction. Pharmacologic options include demeclocycline (off-label use), urea, and vasopressin receptor antagonists (vaptans). Vaptans should not be used in hypovolemic hyponatremia, or in conjunction with other treatments for hyponatremia.A

DEFINITIONS

Hyponatremia is a condition in which there is an excess of body water relative to body sodium. Often defined as serum sodium concentration < 135 mEq/L. Reference: Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006;73(suppl 3):S4- S12.

APPENDIX

N/A �

CODING INFORMATION: THE CODES LISTED IN THIS POLICY ARE FOR REFERENCE PURPOSES ONLY. LISTING OF A SERVICE OR DEVICE CODE IN THIS POLICY DOES NOT IMPLY THAT THE SERVICE DESCRIBED BY THIS CODE IS A COVERED OR NON-COVERED. COVERAGE IS DETERMINED BY THE BENEFIT DOCUMENT. THIS LIST OF CODES MAY NOT BE ALL INCLUSIVE. CPT Description NA HCPCS Description J8499 Prescription drug, oral, non-chemotherapeutic, Not Otherwise Specified ICD-9 Description: [For dates of service prior to 10/01/2015] 276.1 Hyposmolality and/or hyponatremia ICD-10 Description: [For dates of service on or after 10/01/2015] E78.1 Hypo-osmolality and hyponatremia

REFERENCES

Package Insert, FDA, Drug Compendia � a. Samsca [package insert]. Rockville, MD: Otsuka America Pharmaceutical Inc; February 2014. Accessed July 2015. b. American Hospital Formulary Service (AHFS). Drug Information 2015. [STAT!Ref Web site]. 05/02/14. Available at: http://online.statref.com. [via subscription only]. c. Micromedex Healthcare Series. DrugDex. [Micromedex Web site]. Available at: http://www.thomsonhc.com/micromedex2/librarian [via subscription only]. d. Drug Facts and Comparisons. Drug Facts and Comparisons 4.0 [online]. 2015. Available from Wolters Kluwer Health, Inc.

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e. � Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2015. URL: http://www.clinicalpharmacology.com.

Clinical Trials, Definitions, Peer-Reviewed Publications 1. � Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Eff Resource Alloc. 2006;4:10. 2. � Schrier RW, Gross P, Gheorghiade M, et al, for the SALT Investigators. Tolvaptan, a Selective Oral Vasopressin V2- Receptor Antagonist, for Hyponatremia. N Engl J Med. 2006;355(20):2099-2112. 3. � Gheorghiade M, Orlandi C, Burnett JC, et al. Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of vasopressin antagonism in heart failure: outcome study with tolvaptan (EVEREST). J Card Fail. 2005;11(4):260-269. PubMed 4. � Konstam MA, Gheorghiade M, Burnett JC Jr, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA. 2007;297(12):1319-1331. 5. � Gheorghiade M, Konstam MA, Burnett JC Jr, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials. JAMA. 2007;297(12):1332- 1343. 6. � Josiassen RC, Goldman M, Jessani M, et al. Double-blind, placebo-controlled, multicenter trial of a vasopressin V2- receptor antagonist in patients with schizophrenia and hyponatremia. Biol Psychiatry. 2008;64(12):1097-1100. 7. � Coyle JD, Joy MS, "Chapter 52. Disorders of sodium and water homeostasis" (Chapter). DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/content.aspx?aID=3183025.

Government Agencies, Professional Societies, and Other Authoritative Publications A. � Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013 Oct;126(10 Suppl 1):S1-42.

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