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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 or spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with hypoxia, severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials in which SAMSCA was administered in titrated doses starting at 15 mg once daily, 7% of SAMSCA 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 (>12 mEq/L/24 hours), 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.
Hypernatremia (see Warnings): Hemoconcentration associated with rapid diuresis may induce hypernatremia, possibly accompanied by consciousness disturbance. In patients being treated with SAMSCA, fluid intake, urine volume, serum sodium level, and the occurrence of clinical symptoms such as thirst and dehydration should be carefully monitored. If clinical symptoms such as persistent thirst and dehydration are observed, SAMSCA should be discontinued or the dosage reduced and appropriate measures such as fluid replenishment, including fluid therapy, should be taken in accordance with the symptoms. If serum sodium level increases above the normal range, administration of SAMSCA should be discontinued immediately and appropriate measures such as fluid replenishment, including fluid therapy, should be taken.
Liver Injury: SAMSCA 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 liver failure requiring liver transplantation has been reported. SAMSCA should not be used to treat ADPKD [see Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) 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 for treatment of hyponatremia. 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].
For the treatment of volume overload in heart failure, liver function tests should be performed prior to initiation of SAMSCA and frequently at least for the first 2 weeks of treatment. For long term use (i.e. more than 30 days), blood testing for hepatic transaminases and bilirubin is required prior to initiation of SAMSCA and continuing monthly for 18 months and at regular intervals (e.g., 3-6 month) thereafter.
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.
As the aquaretic effect of SAMSCA is most potent within 24 hours after the initial administration, serum sodium concentration should be measured at least at 4 to 6 hours and 8 to 12 hours after administration on the first day of administration. From the second to around the seventh day of administration, serum sodium concentration should be measured every day, and if administration is continued further, serum sodium concentration should be measured at appropriate intervals.
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. If sensation of thirst persists, dose reduction should be considered.
Co-administration with hypertonic saline: Concomitant use with hypertonic saline is not recommended.
Drug Interactions: Other drugs affecting exposure to SAMSCA: CYP 3A Inhibitors: SAMSCA is a substrate of CYP 3A. CYP 3A inhibitors can lead to a marked increase in SAMSCA concentrations [see Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors under Dosage & Administration, Effects of drugs on SAMSCA under Interactions]. Do not use SAMSCA with strong inhibitors of CYP3A and avoid concomitant use with moderate CYP 3A inhibitors [see Concomitant use of strong CYP3A inhibitors under Contraindications].
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 SAMSCA 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 SAMSCA 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 SAMSCA under Interactions].
Hyperkalemia or Drugs that Increase Serum Potassium: Treatment with SAMSCA is associated with an acute reduction of the extracellular fluid volume which could result in increased serum potassium and may lead to ventricular fibrillation and ventricular tachycardia. Serum potassium levels should be monitored after initiation of SAMSCA treatment in patients with a serum potassium >5 mEq/L as well as those who are receiving drugs known to increase serum potassium levels.
Effects on Ability to Drive and Use Machines: There are no controlled trials of the effects of tolvaptan on driving performance. When driving vehicles or using machines it should be taken into account that occasionally dizziness, asthenia or syncope may occur.
Urinary Outflow Obstruction: Urinary output must be secured. Patients with partial obstruction of urinary outflow, for example patients with prostatic hypertrophy or impairment of micturition, have an increased risk of developing acute retention.
Patients with serious coronary artery disease or cerebrovascular disease and elderly patients: Rapid volume decrease or hemoconcentration associated with rapid diuresis may induce thromboembolism.
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, Pharmacology: Pharmacokinetics under Actions].
Use in Patients with Congestive Heart Failure: The exposure to SAMSCA 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 the Elderly: A rapid decrease in circulating plasma volume or hemoconcentration associated with rapid diuresis may induce thromboembolism. SAMSCA should be administered with care and the patient's condition should be closely monitored. Elderly patients generally
have reduced physiological function and are known to be susceptible to dehydration.
Hyponatremia: 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 SAMSCA plasma concentrations.
Adjunct treatment of volume overload in heart failure: Initiation of SAMSCA at half dose (7.5 mg) is recommended in elderly patients with volume overload due to heart failure, because elderly patients were found to be at risk for hypernatremia.
