Samsca Adverse Reactions

Clinical Trials Experience: Hyponatremia: Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
In multiple-dose, placebo-controlled trials, 607 hyponatremic patients (serum sodium < 135 mEq/L) were treated with SAMSCA. The mean age of these patients was 62 years; 70% of patients were male and 82% were Caucasian. One hundred eighty nine (189) SAMSCA-treated patients had a serum sodium < 130 mEq/L, and 52 patients had a serum sodium < 125 mEq/L. Hyponatremia was attributed to cirrhosis in 17% of patients, heart failure in 68% and SIADH/other in 16%. Of these patients, 223 were treated with the recommended dose titration (15 mg titrated to 60 mg as needed to raise serum sodium).
Overall, over 4,000 patients have been treated with oral doses of SAMSCA in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with SAMSCA for 6 months or more.
The most common adverse reactions (incidence ≥ 5% more than placebo) seen in two 30-day, double-blind, placebo-controlled hyponatremia trials in which SAMSCA was administered in titrated doses (15 mg to 60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of SAMSCA-treated patients discontinued treatment because of an adverse event, compared to 12% (26/220) of placebo-treated patients; no adverse reaction resulting in discontinuation of trial medication occurred at an incidence of > 1% in SAMSCA-treated patients.
Table 4 lists the adverse reactions reported in SAMSCA-treated patients with hyponatremia (serum sodium < 135 mEq/L) and at a rate at least 2% greater than placebo-treated patients in two 30-day, double-blind, placebo-controlled trials. In these studies, 223 patients were exposed to SAMSCA (starting dose 15 mg, titrated to 30 and 60 mg as needed to raise serum sodium). Adverse events resulting in death in these trials were 6% in SAMSCA-treated-patients and 6% in placebo-treated patients. (See Table 4.)

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In a subgroup of patients with hyponatremia (N = 475, serum sodium < 135 mEq/L) enrolled in a double-blind, placebo-controlled trial (mean duration of treatment was 9 months) of patients with worsening heart failure, the following adverse reactions occurred in SAMSCA-treated patients at a rate at least 2% greater than placebo: mortality (42% SAMSCA, 38% placebo), nausea (21% SAMSCA, 16% placebo), thirst (12% SAMSCA, 2% placebo), dry mouth (7% SAMSCA, 2% placebo) and polyuria or pollakiuria (4% SAMSCA, 1% placebo).
Gastrointestinal bleeding in patients with cirrhosis: In patients with cirrhosis treated with SAMSCA in hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) SAMSCA-treated patients and 1 out of 57 (2%) placebo-treated patients.
The following adverse reactions occurred in < 2% of hyponatremic patients treated with SAMSCA and at a rate greater than placebo in double-blind placebo-controlled trials (N = 607 SAMSCA; N = 518 placebo) or in < 2% of patients in an uncontrolled trial of patients with hyponatremia (N = 111) and are not mentioned elsewhere in the label.
Blood and Lymphatic System Disorders: Disseminated intravascular coagulation.
Cardiac Disorders: Intracardiac thrombus, ventricular fibrillation.
Investigations: Prothrombin time prolonged.
Gastrointestinal Disorders: Ischemic colitis.
Metabolism and Nutrition Disorders: Diabetic ketoacidosis.
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.
Nervous System: Cerebrovascular accident.
Renal and Urinary Disorders: Urethral hemorrhage.
Reproductive System and Breast Disorders (female): Vaginal hemorrhage.
Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure.
Vascular disorder: Deep vein thrombosis.
Adjunct treatment of volume overload in heart failure (Japanese data): Table 5 shows the adverse reactions reported in Japanese clinical trials of tolvaptan in patients with volume overload in heart failure (N= 213). Included are adverse events that were reported in ≥2% of patients who received any oral tolvaptan dose and assessed as reasonably associated with tolvaptan use. (See Table 5.)

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Postmarketing Experience: The following adverse reactions have been identified during post-approval use of SAMSCA. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Neurologic: Osmotic demyelination syndrome.
Investigations: Hypernatremia.
Removal of excess free body water increases serum osmolality and serum sodium concentrations. All patients treated with SAMSCA, especially those whose serum sodium levels become normal, should continue to be monitored to ensure serum sodium remains within normal limits. If hypernatremia is observed, management may include dose decreases or interruption of SAMSCA treatment, combined with modification of free-water intake or infusion. During clinical trials of hyponatremia patients, hypernatremia was reported as an adverse event in 0.7% of patients receiving SAMSCA vs. 0.6% of patients receiving placebo; analysis of laboratory values demonstrated an incidence of hypernatremia of 1.7% in patients receiving SAMSCA vs. 0.8% in patients receiving placebo.
Immune system disorders: Hypersensitivity reactions including anaphylactic shock and rash generalized.
In post-marketing experience, anaphylaxis (including anaphylactic shock and rash generalised) has been reported very rarely following administration of SAMSCA. This type of reaction occurred after the first administration of SAMSCA. If an anaphylactic reaction or other serious allergic reactions occur, administration of SAMSCA must be discontinued immediately and appropriate therapy initiated. Since hypersensitivity is a contraindication, treatment must never be restarted after an anaphylactic reaction or other serious allergic reactions.