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Included as part of the PRECAUTIONS section.

Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae (see BOXED WARNING)

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. 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 hours of therapy with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided.

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

There is no experience with concomitant use of SAMSCA and 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 DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS]. Do not use SAMSCA with strong inhibitors of CYP 3A [see 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 coadministered with CYP 3A inducers, the dose of SAMSCA may need to be increased [see DOSAGE AND ADMINISTRATION, DRUG 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 DOSAGE AND ADMINISTRATION, DRUG 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

As a part of patient counseling, healthcare providers must review the SAMSCA Medication Guide with every patient [see FDA-Approved Medication Guide].

Concomitant Medication

Advise patients to inform their 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 CYP 3A inhibitors and Pg-p inhibitors

Advise patients to inform their physician if they use strong (e.g., ketoconazole, itraconazole, clarithromycin, telithromycin, nelfinavir, saquinavir, indinavir, ritonavir) or moderate CYP 3A inhibitors (e.g., aprepitant, erythromycin, diltiazem, verapamil, fluconazol) or P-gp inhibitors (e.g., cyclosporine) [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Nursing

Advise patients not to breastfeed an infant if they are taking SAMSCA [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Up to two years of oral administration of tolvaptan to male and female rats at doses up to 1000 mg/kg/day (162 times the maximum recommended human dose [MRHD] on a body surface area basis), to male mice at doses up to 60 mg/kg/day (5 times the MRHD) and to female mice at doses up to 100 mg/kg/day (8 times the MRHD) did not increase the incidence of tumors.

Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.

In a fertility study in which male and female rats were orally administered tolvaptan at 100, 300 or 1000 mg/kg/day, the highest dose level was associated with significantly fewer corpora lutea and implants than control.

Use In Specific Populations

There is no need to adjust dose based on age, gender, race, or cardiac function [see CLINICAL PHARMACOLOGY].

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 to 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 to 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 Nonclinical Toxicology].

Labor and Delivery

The effect of SAMSCA on labor and delivery in humans is unknown.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness of SAMSCA in pediatric patients have not been established.

Geriatric Use

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.

Use in Patients with Hepatic Impairment

Moderate and severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent. No dose adjustment of tolvaptan is necessary.

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 CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

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.

Last reviewed on RxList: 2/9/2012
This monograph has been modified to include the generic and brand name in many instances.