Samsca Special Precautions

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. None of the patients in these studies had evidence of osmotic demyelination syndrome or related neurological sequelae, but such complications have been reported following too-rapid correction of serum sodium. 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.
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: There is no experience with concomitant use of Samsca and hypertonic saline. Concomitant use with hypertonic saline is not recommended.
Hepatic Impairment: Moderate to severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent. No dose adjustment of tolvaptan plasma concentrations.
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 (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 it is co-administered with P-gp inhibitors eg, cyclosporine (see Dosage & Administration and Interactions).
Hyerkalemia 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.
Renal Impairment: Exposure and response to tolvaptan are similar in patients with CrCl 10-79 mL/min and in patients without renal impairment. No dose adjustment is necessary. Exposure and response to tolvaptan in patients with a CrCl <10 mL/minor in patients on chronic dialysis have not been studied. No benefit can be expected in patients who are anuric (see Contraindications).
Congestive Heart Failure: The exposure to tolvaptan in patients with congestive heart failure is not clinically relevantly increased. No dose adjustment is necessary.
Labor and Delivery: The effect of Samsca on labor and delivery in humans is unknown.
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 embryo-fetal death occurred. Samsca should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryo-fetal 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 embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations (see Toxicology: Nonclinical Toxicology under Actions).
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 the drug, 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.