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) tolvaptan-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 4000 patients have been treated with oral doses of tolvaptan in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with tolvaptan for ≥6 months.
The most common adverse reactions (incidence ≥5% more than placebo) seen in two 30-day, double-blind, placebo-controlled hyponatremia trials in which tolvaptan was administered in titrated doses (15-60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of tolvaptan-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 tolvaptan-treated patients.
Table 3 lists the adverse reactions reported in tolvaptan-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 tolvaptan (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 tolvaptan-treated patients and 6% in placebo-treated patients. (See Table 3.)

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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 tolvaptan-treated patients at a rate at least 2% greater than placebo: Mortality (42% tolvaptan, 38% placebo), nausea (21% tolvaptan, 16% placebo), thirst (12% tolvaptan, 2% placebo), dry mouth (7% tolvaptan, 2% placebo) and polyuria or pollakiuria (4% tolvaptan, 1% placebo).
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 tolvaptan; 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: Prolonged prothrombin time.
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): Of 213 patients included in safety evaluations in Japanese clinical trials for volume overload in heart failure, 143 patients (67.1%) had adverse drug reactions, including abnormal laboratory values. The most common adverse drug reactions were 65 cases of thirst (30.5%), 28 cases of increased blood urea nitrogen (BUN) (13.1%) and 20 cases of increased blood uric acid (9.4%).
Clinically Significant Adverse Reactions: Renal Failure (0.1% to <5%): Since severe renal impairment, including renal failure, may occur in patients being treated with Samsca, patients should be carefully monitored during treatment. If any abnormalities are observed, the drug should be discontinued and appropriate measures should be taken.
Thromboembolism (0.1% to <5%): Hemoconcentration associated with rapid diuresis may induce thrombosis or thromboembolism. Patients should be carefully monitored during treatment. If any abnormalities are observed, Samsca should be discontinued and appropriate measures should be taken.
Other adverse reactions.
(See Table 4.)

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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.
Immune system disorders: Anaphylactic shock, Rash generalized.
Removal of excess free body water increases serum osmolality and serum sodium concentrations. All patients treated with tolvaptan, 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 tolvaptan treatment, combined with modification of free-water intake or infusion. During clinical trials of hyponatremic patients, hypernatremia was reported as an adverse event in 0.7% of patients receiving tolvaptan vs. 0.6% of patients receiving placebo; analysis of laboratory values demonstrated an incidence of hypernatremia of 1.7% in patients receiving tolvaptan vs. 0.8% in patients receiving placebo.
In post-marketing experience, anaphylaxis (including anaphylactic shock and rash generalized) has been reported very rarely following administration of tolvaptan. This type of reaction occurred after the first administration of tolvaptan. If an anaphylactic reaction or other serious allergic reactions occur, administration of tolvaptan should be discontinued immediately and appropriate therapy initiated.