Pharmacology Update
Tolvaptan Tablets (Samsca™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
The FDA has approved the first oral, selective vasopressin V2-receptor antagonist for the treatment of hypervolemic and euvolemic hyponatremia. Tolvaptan follows conivaptan, a parenteral non-selective vasopressin antagonist. Tolvaptan is marketed by Otsuka America Pharmaceuticals, Inc., as Samsca™.
Indications
Tolvaptan is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (< 125 mEq/L or symptomatic hyponatremia that has not been adequately corrected with fluid restriction). This includes patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan should not be used in hypovolemic hyponatremia and in patients who are unable to autoregulate fluid balance.1
Dosage
The starting dose is 15 mg orally given once daily without regard to meals. The dose should be increased to 30 mg once daily after at least 24 hours to a maximum of 60 mg once daily as required to achieve desired level of serum sodium. Frequent monitoring of serum electrolytes and volume should be done during initiation and titration, and fluid restriction should be avoided during the first 24 hours of therapy. Rapid correction may lead to osmotic demyelination, particularly in patients with severe malnutrition, alcoholism, and advanced liver disease. Dosage reduction is recommended if co-administered with a P-glycoprotein inhibitor (e.g., cyclosporine). No dosage adjustment is required for patients with mild-to-severe renal impairment. Tolvaptan should not be co-administered with a moderate or strong CYP3A inhibitor or CYP 3A4 inducer.1
Tolvaptan is available as 15 mg and 30 mg tablets.
Potential Advantages
Tolvaptan is more effective in treating hyponatremia than fluid restriction alone. It is orally active, more selective than conivaptan, and has about twice the affinity for the receptor than native arginine vasopressin (AVP).
Potential Disadvantages
Tolvaptan should not be used if raising serum sodium is urgently required to treat serious neurological symptoms. The drug may not provide symptomatic benefit.1 The drug may increase the risk of GI bleed in cirrhosis patients compared to placebo (10% vs 2%). Common adverse events include thirst (16%), dry mouth (13%), pollakiuria or polyuria (11%), asthenia (9%), constipation (7%), and hyperglycemia (6%).1
Comments
Tolvaptan causes aquaresis, decreases urine osmolality, and increases sodium levels within 2-4 hours after the first dose. The peak increase in sodium is about 6 mEq between 4-8 hours post administration. The efficacy in hyponatremia (< 135 mEq/L) was based on 2 double-blind, placebo-controlled studies (SALT-1 and SALT-2; n = 424).1,2 Subjects had euvolemic or hypervolemic hyponatremia with a variety of underlying diseases (e.g., heart failure, cirrhosis, SIADH) and were randomized to tolvaptan or placebo for 30 days. They were followed for an additional 7 days after discontinuation of therapy. The primary endpoint was average daily AUC for change in serum sodium from baseline to day 4 and baseline to day 30. The change in serum AUC over placebo was 3.7 mEq/L at day 4 and 4.6 mEq/L at day 30. Subjects with marked hyponatremia showed greater benefit. At day 30, 66% of patients had normal serum levels compared to 25% for placebo.2 The percent with marked hyponatremia was reduced from a baseline value of 50% to 12% in the tolvaptan group compared to 50% to 33% for placebo. Within 7 days after discontinuation of tolvaptan, serum sodium declined to the same levels as the placebo group.1 In an open-label study, patients were able to maintain serum sodium levels for at least 1 year. In patients who were hospitalized with worsening heart failure, tolvaptan improved dyspnea, body weight, and edema. However, all-cause mortality, cardiovascular mortality, cardiovascular death, hospitalization, and worsening heart failure were not statistically different.1,3 Long-term use of tolvaptan is associated with an increase in endogenous AVP and resultant simulation of V1a receptors, resulting in an increase in afterload.4,5 The clinical significance of this effect in not known.
Clinical Implications
Conditions such as heart failure, liver cirrhosis, and SIADH result in excessive release of arginine vasopressin or antidiuretic hormone. This results in hyponatremia and volume overload. Tolvaptan blocks the binding of AVP to the V2 receptor promoting aquaresis and provides an orally effective drug for the treatment of euvolemic or hypervolemic hyponatremia that is more effective than fluid restriction.
References
1. Samsca Product Information. Rockville, MD: Otsuka Pharmaceuticals, Inc.; May 2009.
2. Schrier RW, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099-2112.
3. Konstam MA, 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;297:1319-1331.
4. Udelson JE, et al. Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction. J Am Coll Cardiol 2007;49:2151-2159.
5. Dixon MB, Lien YH. Tolvaptan and its potential in the treatment of hyponatremia. Ther Clin Risk Manag 2008;4:1149-1155.
The FDA has approved the first oral, selective vasopressin V2-receptor antagonist for the treatment of hypervolemic and euvolemic hyponatremia.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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