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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 (eg, >12 mEq/L/24 hrs). 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 >8 mEq/L at approximately 8 hrs and 2% had an increase >12 mEq/L at 24 hrs. Approximately 1% of placebo-treated subjects with a serum sodium <130 mEq/L had a rise >8 mEq/L at 8 hrs and no patient had a rise >12 mEq/L/24 hrs. Osmotic demyelination syndrome has been reported in association with Samsca therapy (see 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 hrs of therapy with Samsca may increase the likelihood of overly-rapid correction of serum sodium and should generally be avoided.
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 eg, thirst and dehydration should be carefully monitored. If clinical symptoms eg, persistent thirst and dehydration are observed, Samsca should be discontinued or the dosage reduced and appropriate measures eg, fluid replenishment, including fluid therapy, should be taken in accordance with the symptoms. If serum sodium level is increased above the normal range, administration of Samsca should be discontinued immediately and appropriate measures eg, fluid replenishment, including fluid therapy, should be taken.
Liver Injury: Drug-induced liver injury has been observed in clinical trials investigating a different indication with long-term use of Samsca at higher doses than for the approved indication. In these clinical trials, clinically significant increases [>3 x upper limit of normal (ULN)] in serum alanine aminotransferase (ALT), along with clinically significant increases (>2 x ULN) in serum total bilirubin were observed in 3 patients treated with Samsca. In addition, an increased incidence of significant elevations of ALT was observed in patients treated with Samsca [4.4% (42/958)] compared to those receiving placebo [1% (5/484)]. Most of the liver enzyme abnormalities were observed during the first 18 months of treatment. The elevations gradually improved after discontinuation of Samsca. These findings may suggest that Samsca has the potential to cause irreversible and potentially fatal liver injury.
In other clinical trials of Samsca, including the trials supporting the approved indications, an increased incidence of liver injury relative to placebo has not been observed. However, these data are not adequate to exclude the possibility that patients receiving Samsca for its indicated use are at a potential of a similar risk for liver injury.
To mitigate the risk of significant or irreversible liver injury, blood testing for hepatic transaminases and bilirubin is required prior to initiation of Samsca. For short-term use (ie, <30 days) of Samsca for the treatment of volume overload in heart failure, liver function test should be performed prior to initiation and frequently at least for the first 2 weeks while the patient is on Samsca treatment. (See Adverse Reactions.) After completion of treatment, liver function test is not required, however, if the patient reports symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice, liver function test should be promptly initiated.
For long-term use (ie, >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 (eg, 3-6 months), thereafter. Liver function tests should be promptly performed in patients taking Samsca who report symptoms of liver injury. If liver injury is suspected, Samsca should be promptly discontinued, appropriate treatment should be instituted and investigations should be performed to determine the probable cause. Samsca should not be re-initiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with Samsca.
Gastrointestinal Bleeding in Patients with Cirrhosis: In patients with cirrhosis treated with tolvaptan in hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo-treated patients. Samsca should be used in cirrhotic patients only when the need to treat outweighs this risk.
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 Interaction: Other Drugs Affecting Exposure to Tolvaptan: CYP3A Inhibitors: Tolvaptan is a substrate of CYP3A. CYP3A inhibitors can lead to a marked increase in tolvaptan concentrations (see Dosage & Administration and Interactions). Do not use Samsca with strong inhibitors of CYP3A (see Contraindications) and avoid concomitant use with moderate CYP3A inhibitors.
CYP3A Inducers: Avoid co-administration of CYP3A inducers (eg, 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 CYP3A inducers, the dose of Samsca may need to be increased (see Dosage & Administration and Interactions).
P-gp Inhibitors: The dose of Samsca may have to be reduced when Samsca is co-administered with P-gp inhibitors eg, cyclosporine (see Dosage & Administration and 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.
Patient Counseling Information: Concomitant Medication: Advise patients to inform the physician if they are taking or plan to take any prescription or over-the-counter drugs since there is a potential for interactions.
Strong and Moderate CYP3A Inhibitors and P-gp Inhibitors: Advise patients to inform the physician if they use strong (eg, ketoconazole, itraconazole, clarithromycin, telithromycin, nelfinavir, saquinavir, indinavir, ritonavir) or moderate CYP3A inhibitors (eg, aprepitant, erythromycin, diltiazem, verapamil, fluconazole) or P-gp inhibitors (eg, cyclosporine) (see Dosage & Administration, Contraindications, Warnings and Interactions).
Nursing: Advise patients not to breastfeed an infant if they are taking Samsca (see Use in lactation).
Use in pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies of Samsca use in pregnant women. In animal studies, cleft palate, brachymelia, microphthalmia, skeletal malformations, decreased fetal weight, delayed fetal ossification and embryofetal death occurred. Samsca should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryofetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. Rats received 2-162 times the maximum recommended human dose (MRHD) of tolvaptan (on a body surface area basis). Reduced fetal weights and delayed fetal ossification occurred at 162 times the MRHD. Signs of maternal toxicity (reduction in body weight gain and food consumption) occurred at 16 and 162 times the MRHD. When pregnant rabbits received oral tolvaptan at 32-324 times the MRHD (on a body surface area basis), there were reductions in maternal body weight gain and food consumption at all doses and increased abortions at the mid- and high-doses (about 97 and 324 times the MRHD). At 324 times the MRHD, there were increased rates of embryofetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations (see Toxicology: Nonclinical Toxicology under Actions).
Labor and Delivery: The effect of Samsca on labor and delivery in humans is unknown.
Use in lactation: It is not known whether Samsca is excreted into human milk. Tolvaptan is excreted into the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Samsca, a decision should be made to discontinue nursing or Samsca, taking into consideration the importance of Samsca to the mother.
Use in children: Safety and effectiveness of Samsca in pediatric patients have not been established.
Use in the elderly: Of the total number of hyponatremic subjects treated with Samsca in clinical studies, 42% were ≥65, while 19% were ≥75. 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.
