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Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae (see Warnings): Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials in which tolvaptan was administered in titrated doses starting at 15 mg once daily, 7% of tolvaptan-treated subjects with a serum sodium <130 mEq/L had an increase in serum sodium greater than 8 mEq/L at approximately 8 hours and 2% had an increase greater than 12 mEq/L at 24 hours. Approximately 1% of placebo-treated subjects with a serum sodium <130 mEq/L had a rise greater than 8 mEq/L at 8 hours and no patient had a rise greater than 12 mEq/L/24 hours. Osmotic demyelination syndrome has been reported in association with SAMSCA therapy [see Postmarketing Experience under Adverse Reactions]. Patients treated with SAMSCA should be monitored to assess serum sodium concentrations and neurologic status, especially during initiation and after titration. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours of therapy with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided. Co-administration of diuretics also increases the risk of too rapid correction of serum sodium and such patients should undergo close monitoring of serum sodium.
Liver Injury: Tolvaptan can cause serious and potentially fatal liver injury. In placebo-controlled studies and an open-label extension study of chronically administered tolvaptan in patients with ADPKD, cases of serious liver injury attributed to tolvaptan, generally occurring during the first 18 months of therapy, were observed. In postmarketing experience with tolvaptan in ADPKD, acute injury resulting in liver failure requiring liver transplantation has been reported. Tolvaptan should not be used to treat ADPKD outside of the FDA-approved risk evaluation and mitigation strategy (REMS) for ADPKD patients [see Use in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) Outside of FDA-Approved REMS under Contraindications]. Patients with symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice should discontinue treatment with SAMSCA.
Limit duration of therapy with SAMSCA to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired [see Clinical Trials Experience under Adverse Reactions].
Dehydration and Hypovolemia: SAMSCA therapy induces copious aquaresis, which is normally partially offset by fluid intake. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In multiple-dose, placebo-controlled trials in which 607 hyponatremic patients were treated with tolvaptan, the incidence of dehydration was 3.3% for tolvaptan and 1.5% for placebo-treated patients. In patients receiving SAMSCA who develop medically significant signs or symptoms of hypovolemia, interrupt or discontinue SAMSCA therapy and provide supportive care with careful management of vital signs, fluid balance and electrolytes. Fluid restriction during therapy with SAMSCA may increase the risk of dehydration and hypovolemia. Patients receiving SAMSCA should continue ingestion of fluid in response to thirst.
Co-administration with Hypertonic Saline: Concomitant use with hypertonic saline is not recommended.
Drug Interactions: Other Drugs Affecting Exposure to Tolvaptan: CYP 3A Inhibitors: Tolvaptan is a substrate of CYP 3A. CYP 3A inhibitors can lead to a marked increase in tolvaptan concentrations [see Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration, Effects of Drugs on Tolvaptan under Interactions]. Do not use SAMSCA with strong inhibitors of CYP 3A [see Concomitant use of strong CYP 3A inhibitors under Contraindications] and avoid concomitant use with moderate CYP 3A inhibitors.
CYP 3A Inducers: Avoid co-administration of CYP 3A inducers (e.g., rifampin, rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine, St. John's Wort) with SAMSCA, as this can lead to a reduction in the plasma concentration of tolvaptan and decreased effectiveness of SAMSCA treatment. If co-administered with CYP 3A inducers, the dose of SAMSCA may need to be increased [see Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration, Effects of Drugs on Tolvaptan under Interactions].
P-gp Inhibitors: The dose of SAMSCA may have to be reduced when SAMSCA is co-administered with P-gp inhibitors, e.g., cyclosporine [see Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration, Effects of Drugs on Tolvaptan under Interactions].
Hyperkalemia or Drugs that Increase Serum Potassium: Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which could result in increased serum potassium. Serum potassium levels should be monitored after initiation of tolvaptan treatment in patients with a serum potassium >5 mEq/L as well as those who are receiving drugs known to increase serum potassium levels.
Use in Specific Populations: There is no need to adjust dose based on age, gender, race, or cardiac function [see Pharmacology: Pharmacokinetics under Actions].
Use in Patients with Hepatic Impairment: Moderate and severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent. Avoid use of tolvaptan in patients with underlying liver disease.
Use in Patients with Renal Impairment: No dose adjustment is necessary based on renal function. There are no clinical trial data in patients with CrCl <10 mL/min, and, because drug effects on serum sodium levels are likely lost at very low levels of renal function, use in patients with a CrCl <10 mL/min is not recommended. No benefit can be expected in patients who are anuric [see Anuric patients under Contraindications and Pharmacology: Pharmacokinetics under Actions].
Use in Patients with Congestive Heart Failure: The exposure to tolvaptan in patients with congestive heart failure is not clinically relevantly increased. No dose adjustment is necessary.
Use in Children: Safety and effectiveness of SAMSCA in pediatric patients have not been established.
Use in Elderly: Of the total number of hyponatremic subjects treated with SAMSCA in clinical studies, 42% were 65 and over, while 19% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Increasing age has no effect on tolvaptan plasma concentrations.
