Brand name: Samsca
Drug class: Vasopressin Antagonists
ATC class: C03XA01
Chemical name: N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methyl-benzamide
Molecular formula: C₂₆H₂₅ClN₂O₃
CAS number: 150683-30-0

Medically reviewed by Drugs.com on May 11, 2023. Written by ASHP.

Introduction

Selective, nonpeptide antagonist of arginine vasopressin (antidiuretic hormone) V₂ receptors; benzazepine derivative.

Uses for Tolvaptan

Euvolemic or Hypervolemic Hyponatremia

Treatment of clinically important euvolemic or hypervolemic hyponatremia (serum sodium concentration of <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including cases in patients with heart failure or SIADH.

Not indicated for the treatment of hypovolemic hyponatremia.

Do not use in patients who require urgent intervention to raise serum sodium concentrations to prevent or treat serious neurologic manifestations.

Use of tolvaptan to increase serum sodium concentrations has not been established to provide symptomatic benefit to patients.

Tolvaptan Dosage and Administration

General

• Avoid fluid restriction during first 24 hours of therapy. Advise patients that they may continue drinking fluids in response to thirst.

• Following discontinuance of drug, advise patients to resume fluid restriction and monitor patients for changes in serum sodium concentration and fluid status.

Administration

Initiate or reinitiate tolvaptan only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely; too rapid a correction of hyponatremia may cause serious neurologic sequelae (e.g., osmotic demyelination syndrome). (See Boxed Warning and see Overly Rapid Correction of Serum Sodium Concentration under Cautions.)

Oral Administration

Administer orally without regard to meals.

Dosage

Adults

Euvolemic or Hypervolemic Hyponatremia

Oral

Initially, 15 mg once daily; dosage may be increased at intervals of ≥24 hours to 30 mg once daily and subsequently up to 60 mg once daily as needed to achieve the desired serum sodium concentration.

Limit therapy to 30 days to minimize risk of hepatic injury. (See Hepatic Injury under Cautions.)

Frequently monitor serum electrolytes and fluid status during initiation and titration of therapy.

Discontinue or interrupt therapy if serum sodium concentrations increase too rapidly or manifestations of hypovolemia occur. (See Overly Rapid Correction of Serum Sodium Concentration and also Dehydration and Hypovolemia under Cautions.)

Prescribing Limits

Adults

Euvolemic or Hypervolemic Hyponatremia

Oral

Maximum: 60 mg once daily. Doses >60 mg do not further increase aquaresis or serum sodium concentrations.

Limit therapy to 30 days to minimize risk of hepatic injury. (See Hepatic Injury under Cautions.)

Special Populations

Dosage adjustment based on gender, race, or cardiac function not necessary.

Hepatic Impairment

Avoid use in patients with underlying liver disease, including cirrhosis. (See Hepatic Injury under Cautions.)

Renal Impairment

Dosage adjustment not necessary based on renal function; use not recommended in patients with Cl_cr <10 mL/minute. (See Renal Impairment under Cautions.)

Anuric patients not expected to benefit from therapy. (See Contraindications under Cautions.)

Geriatric Patients

Dosage adjustment not necessary. (See Geriatric Use under Cautions.)

Cautions for Tolvaptan

Contraindications

• Patients requiring urgent intervention to acutely raise serum sodium concentrations; drug not studied in these patients.

• Patients unable to sense or appropriately respond to thirst. Individuals unable to autoregulate fluid balance at substantially increased risk for overly rapid correction of serum sodium concentrations, hypernatremia, and hypovolemia. (See Overly Rapid Correction of Serum Sodium Concentration and see Dehydration and Hypovolemia, under Cautions.)

• Hypovolemic hyponatremia. Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits of therapy. (See Dehydration and Hypovolemia under Cautions.)

• Concomitant use of potent CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). (See CYP3A Inhibitors under Interactions.)

• Anuria. Anuric patients not expected to obtain clinical benefit from therapy.

Warnings/Precautions

Warnings

Overly Rapid Correction of Serum Sodium Concentration

Initiate or reinitiate tolvaptan only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely. (See Boxed Warning.)

Increases in serum sodium of >12 mEq/L over 24 hours may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease. Patients with SIADH or very low baseline serum sodium concentrations may be at increased risk for too rapid a correction of serum sodium concentration.

Osmotic demyelination syndrome reported.

Monitor serum sodium concentrations and neurologic status, especially during initiation and following titration of therapy; if serum sodium concentrations increase too rapidly, discontinue or interrupt tolvaptan and consider administration of hypotonic fluid.

Avoid fluid restriction during the first 24 hours of therapy; may increase the risk of overly rapid correction of serum sodium concentration.

Other Warnings/Precautions

Hepatic Injury

May cause serious, potentially irreversible and fatal hepatic injury.

Increased incidence of ALT >3 times the ULN and 3 cases of serious hepatic injury (ALT >3 times the ULN with total bilirubin >2 times the ULN) reported during a 3-year placebo-controlled trial and its open-label extension in patients with autosomal dominant polycystic kidney disease^{† [off-label]} receiving chronic tolvaptan therapy (up to 90 mg in the morning and 30 mg in the afternoon).

Hepatic abnormalities generally occurred during first 18 months of therapy and gradually improved following discontinuance. Serious hepatic injury occurred ≥3 months after treatment initiation, but ALT elevations observed during first 3 months of therapy.

Available data not adequate to exclude possibility of increased risk of irreversible and fatal hepatic injury in patients receiving tolvaptan (at lower dosages) for treatment of euvolemic or hypervolemic hyponatremia.

If symptoms suggestive of hepatic injury (e.g., fatigue, anorexia, upper right abdominal discomfort, dark urine, jaundice) occur, promptly discontinue therapy, perform liver function tests, institute appropriate treatment, and determine probable cause. Do not reinitiate therapy unless hepatic injury definitively established to be unrelated to the drug.

Limit duration of therapy to 30 days.

Avoid use in patients with underlying liver disease, including cirrhosis, because ability to recover from hepatic injury may be impaired.

Dehydration and Hypovolemia

Dehydration and hypovolemia may occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted.

If clinically important signs or symptoms of hypovolemia occur, discontinue or interrupt tolvaptan and provide supportive care, including careful management of vital signs, fluid balance, and electrolytes.

Fluid restriction during therapy may increase risk of dehydration and hypovolemia. Patients should continue drinking fluids in response to thirst; use is contraindicated in patients unable to sense or appropriately respond to thirst and in those with hypovolemic hyponatremia. (See Contraindications under Cautions.)

Concomitant Use with Hypertonic Sodium Chloride

Concomitant use with hypertonic sodium chloride not recommended.

Hyperkalemia

Acute reduction of extracellular fluid volume may occur, resulting in increased serum potassium concentrations.

Monitor serum potassium concentrations after initiation of therapy in patients with a serum potassium concentration of >5 mEq/L and in those receiving drugs known to increase serum potassium concentrations (e.g., angiotensin II receptor antagonists, ACE inhibitors, potassium-sparing diuretics). (See Drugs Increasing Serum Potassium Concentration under Interactions.)

Hypernatremia

Hypernatremia reported.

Continue to monitor all patients, especially those who achieve normal serum sodium concentrations, to ensure concentrations remain within normal limits.

Management of hypernatremia may include dosage reduction or interruption of therapy in conjunction with modification of fluid intake or infusion to correct free-water deficit.

Specific Populations

Pregnancy

Category C.

Effect of drug on labor and delivery not known.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. Dosage adjustment based on age not necessary.

Hepatic Impairment

Moderate or severe hepatic impairment does not appear to have clinically important effects on exposure to drug. However, avoid use in patients with underlying liver disease, including cirrhosis. (See Hepatic Injury under Cautions.)

Renal Impairment

Exposure and response to drug similar in individuals with Cl_cr of 10–79 mL/minute and in those with normal renal function. (See Absorption: Special Populations under Pharmacokinetics.)

No dosage adjustment necessary based on renal function; however, use not recommended in patients with Cl_cr <10 mL/minute. Not studied in clinical trials in patients with Cl_cr <10 mL/minute; unlikely to increase serum sodium concentrations in patients with very low levels of renal function.

Anuric patients not expected to benefit from therapy. (See Contraindications under Cautions.)

Common Adverse Effects

Thirst, dry mouth, pollakiuria or polyuria, asthenia, constipation, hyperglycemia, pyrexia, anorexia.

Drug Interactions

Mainly, if not exclusively, metabolized by CYP3A; weak inhibitor of CYP3A. Substrate and inhibitor of P-glycoprotein transport system.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Pharmacokinetic interaction (marked increase in exposure to tolvaptan). Insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use; concomitant use is contraindicated. (See Contraindications under Cautions.)

Moderate CYP3A inhibitors: Effect on tolvaptan exposure not studied; substantial increase in exposure to tolvaptan expected. Avoid concomitant use.

CYP3A inducers: Potential pharmacokinetic interaction (decreased plasma tolvaptan concentrations) with concomitant use of potent CYP3A inducers. Avoid concomitant use with CYP3A inducers. If used concomitantly with CYP3A inducers, expected clinical effects of tolvaptan may not be observed at recommended dosage; monitor patient response and adjust dosage accordingly.

Drugs Affecting the P-glycoprotein Transport System

Inhibitors of the P-glycoprotein transport system: Potential pharmacokinetic interaction (increased tolvaptan concentrations); may require reduction of tolvaptan dosage based on clinical response.

Drugs Increasing Serum Potassium Concentration

Potential pharmacologic interaction (increased incidence of hyperkalemia); however, formal drug interaction studies not performed. Monitor serum potassium concentrations during concomitant use with drugs known to increase serum potassium concentrations. (See Hyperkalemia under Cautions.)

Specific Drugs and Foods

Tolvaptan Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability unknown; at least 40% of dose absorbed as tolvaptan or metabolites.

Peak plasma concentrations observed 2–4 hours following a dose.

AUC increases proportionally with dose; however, at doses ≥60 mg, peak plasma concentrations increase less than proportionally with dose.

Onset

Onset of aquaretic and sodium-increasing effects occurs within 2–4 hours following a single 60-mg dose in healthy individuals.

Peak effects (increases in serum sodium concentrations and urinary excretion rate of about 6 mEq/L and 9 mL/minute, respectively) observed 4–8 hours following a 60-mg dose.

Duration

About 60% of peak effect on serum sodium concentrations sustained at 24 hours following a dose; however, urinary excretion rate no longer elevated at this time.

Food

Food does not affect bioavailability.

Special Populations

Increasing age does not affect plasma tolvaptan concentrations.

Exposure to drug similar in individuals with Cl_cr of 10–79 mL/minute and in those with normal renal function. In patients with Cl_cr of 10–124 mL/minute, AUC and peak plasma concentration increased less than twofold in patients with severe renal impairment compared with controls; peak increase in serum sodium concentration was 5–6 mEq/L regardless of renal function, but onset and offset of effect on sodium concentration slower in patients with severe renal impairment. (See Renal Impairment under Cautions.)

Moderate or severe hepatic impairment does not have clinically important effects on exposure to drug.

Patients with CHF do not have a clinically important increase in exposure to drug.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

99%.

Special Populations

Moderate or severe hepatic impairment increases volume of distribution; not considered clinically important.

CHF increases volume of distribution; not considered clinically important.

Elimination

Metabolism

Mainly, if not exclusively, metabolized in the liver by CYP3A. Substrate of the P-glycoprotein transport system. Metabolites have little or no V₂-receptor antagonist activity.

Elimination Route

Following administration of radiolabeled tolvaptan, approximately 40 and 59% of radioactivity recovered in urine and feces, respectively; <1% of tolvaptan dose is excreted unchanged in urine, about 19% is excreted unchanged in feces, and about 80% is metabolized. Tolvaptan eliminated entirely (about 99%) by nonrenal mechanisms.

Half-life

Terminal-phase half-life is approximately 12 hours.

Special Populations

In patients with hyponatremia of any origin, clearance of drug is reduced.

Moderate or severe hepatic impairment decreases clearance; not considered clinically important.

CHF decreases clearance; not considered clinically important.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions

• Selective arginine vasopressin (antidiuretic hormone) V₂ receptor antagonist.

• Affinity for V₂ receptors 29 times that for V_1A receptors.

• Does not appear to have any affinity for V_1B receptors.

• Antagonizes effects of vasopressin at V₂ receptors of distal nephron, resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations.

• Urinary sodium and potassium excretion and plasma potassium concentrations not substantially altered; plasma concentrations of endogenous arginine vasopressin may increase.

• Does not appear to have a clinically important effect on the QT_c interval.

Advice to Patients

• Importance of reviewing the medication guide with every patient. Importance of instructing patients to read the medication guide before initiating therapy and each time the prescription is refilled.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses. Importance of informing clinicians if receiving drugs that are moderate or potent inhibitors of CYP3A or inhibitors of the P-glycoprotein transport system (see Interactions).

• Potential for too rapid an increase in serum sodium concentration, which may result in serious neurologic sequelae. Importance of informing clinicians if any signs or symptoms suggestive of osmotic demyelination syndrome (e.g., difficulty speaking or swallowing, drowsiness, confusion, mood changes, weakness or involuntary movements in the extremities, seizures) occur. Importance of patients not stopping or restarting tolvaptan therapy on their own initiative.

• Potential for hepatic injury, including life-threatening hepatic failure. Importance of not taking tolvaptan for >30 days and of informing clinicians if any signs or symptoms suggestive of hepatic injury (e.g., loss of appetite, nausea, vomiting, fever, feeling unwell, unusual tiredness, pruritus, jaundice, unusual darkening of urine, upper right abdominal pain or discomfort) occur.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Necessity of advising women to avoid breast-feeding during tolvaptan therapy.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Reload page with references included

Frequently asked questions

• What is the difference between Jynarque (tolvaptan) and Samsca (tolvaptan)?

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