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
Brands: Samsca

Introduction

Selective, nonpeptide antagonist of arginine vasopressin (antidiuretic hormone) V₂ receptors; benzazepine derivative.^{1 2 3 4 5}

Uses for Tolvaptan

Euvolemic or Hypervolemic Hyponatremia

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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, cirrhosis, or SIADH.^{1 2 6 9}

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Not indicated for the treatment of hypovolemic hyponatremia.¹

Do not use in patients who require urgent intervention to raise serum sodium concentrations to prevent or treat serious neurologic manifestations.¹

Use of tolvaptan to increase serum sodium concentrations has not been established to provide symptomatic benefit to patients.¹

Tolvaptan Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Avoid fluid restriction during first 24 hours of therapy.¹ Advise patients that they may continue drinking fluids in response to thirst.¹

• Following discontinuance of drug, advise patients to resume fluid restriction and monitor patients for changes in serum sodium concentration and fluid status.¹

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).¹ (See Boxed Warning and see Overly Rapid Correction of Serum Sodium Concentration under Cautions.)

Oral Administration

Administer orally without regard to meals.¹

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.¹

Frequently monitor serum electrolytes and fluid status during initiation and titration of therapy.¹

Discontinue or interrupt therapy if serum sodium concentrations increase too rapidly or manifestations of hypovolemia occur.¹ (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.¹ Doses >60 mg do not further increase aquaresis or serum sodium concentrations.¹

Special Populations

Dosage adjustment based on gender, race, or cardiac function not necessary.¹

Hepatic Impairment

Dosage adjustment not necessary.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary in patients with mild to severe renal impairment (Cl_cr of 10–79 mL/minute); not studied in patients with Cl_cr of <10 mL/minute or in patients undergoing dialysis.¹ (See Renal Impairment under Cautions.)

Anuric patients not expected to benefit from therapy.¹ (See Contraindications under Cautions.)

Geriatric Patients

Dosage adjustment not necessary.¹ (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.¹

• Patients unable to sense or appropriately respond to thirst.¹ Individuals unable to autoregulate fluid balance at substantially increased risk for overly rapid correction of serum sodium concentrations, hypernatremia, and hypovolemia.¹ (See Overly Rapid Correction of Serum Sodium Concentration and see Dehydration and Hypovolemia under Cautions.)

• Hypovolemic hyponatremia.¹ Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits of therapy.¹ (See Dehydration and Hypovolemia under Cautions.)

• Concomitant use of potent CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin).¹ (See CYP3A Inhibitors under Interactions.)

• Anuria.¹ Anuric patients not expected to obtain clinical benefit from therapy.¹

Warnings/Precautions

Overly Rapid Correction of Serum Sodium Concentration

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Initiate or reinitiate tolvaptan only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely.¹ (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.¹ Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease.¹ Patients with SIADH or very low baseline serum sodium concentrations may be at increased risk for too rapid a correction of serum sodium concentration.¹

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.¹

Avoid fluid restriction during the first 24 hours of therapy; may increase the risk of overly rapid correction of serum sodium concentration.¹

Because of the risk of osmotic demyelination syndrome, FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for tolvaptan.¹² Goals are to educate health-care providers on risk of overly rapid correction of serum sodium concentrations and need for initiating therapy in a hospital and to inform patients of the serious risks associated with the use of the drug, particularly the risk of osmotic demyelination syndrome.¹² (See Advice to Patients.)

GI Bleeding in Patients with Cirrhosis

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

GI bleeding reported in patients with cirrhosis; use tolvaptan in patients with cirrhosis only when the need for treatment outweighs this risk.¹

Dehydration and Hypovolemia

Dehydration and hypovolemia may occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted.¹

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.¹

Fluid restriction during therapy may increase risk of dehydration and hypovolemia.¹ 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.¹ (See Contraindications under Cautions.)

Concomitant Use with Hypertonic Sodium Chloride

No experience with concomitant use of hypertonic sodium chloride injection; concomitant use with hypertonic sodium chloride not recommended.¹

Hyperkalemia

Acute reduction of extracellular fluid volume may occur, resulting in increased serum potassium concentrations.¹

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 inihibitors, potassium-sparing diuretics).^{1 11} (See Drugs Increasing Serum Potassium Concentration under Interactions.)

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 11}

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹ Dosage adjustment based on age not necessary.¹

Hepatic Impairment

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Moderate or severe hepatic impairment does not appear to have clinically important effects on exposure to drug.¹ Dosage adjustment based on hepatic function not necessary.¹

Risk of GI bleeding in patients with cirrhosis; use only when need for treatment outweighs this risk.¹

Renal Impairment

Exposure and response to drug similar in patients with Cl_cr of 10–79 mL/minute and in those without renal impairment; no dosage adjustment necessary in patients with mild to severe renal impairment (Cl_cr of 10–79 mL/minute).¹

Exposure and response to drug not studied in patients with Cl_cr <10 mL/minute or in those undergoing chronic dialysis.¹

Anuric patients not expected to benefit from therapy.¹ (See Contraindications under Cautions.)

Common Adverse Effects

Thirst,^{1 2 3} dry mouth,^{1 2 3} pollakiuria or polyuria,¹ asthenia,¹ constipation,^{1 2} hyperglycemia,^{1 2} pyrexia,¹ anorexia.¹

Interactions for Tolvaptan

Mainly, if not exclusively, metabolized by CYP3A; weak inhibitor of CYP3A.¹ Substrate and inhibitor of P-glycoprotein transport system.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Pharmacokinetic interaction (marked increase in exposure to tolvaptan).^{1 11} Insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use; concomitant use is contraindicated.¹ (See Contraindications under Cautions.)

Moderate CYP3A inhibitors: Effect on tolvaptan exposure not studied; substantial increase in exposure to tolvaptan expected.¹ Avoid concomitant use.¹

CYP3A inducers: Potential pharmacokinetic interaction (decreased plasma tolvaptan concentrations) with concomitant use of potent CYP3A inducers.^{1 11} Avoid concomitant use with CYP3A inducers.^{1 11} 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.^{1 11}

Drugs Affecting the P-glycoprotein Transport System

Inhibitors of the P-glycoprotein transport system: Potential pharmacokinetic interaction (increased tolvaptan concentrations);^{1 11} may require reduction of tolvaptan dosage based on clinical response.¹

Drugs Increasing Serum Potassium Concentration

Potential pharmacologic interaction (increased incidence of hyperkalemia) with concomitant use of angiotensin II receptor antagonists, ACE inihibitors, or potassium-sparing diuretics; however, formal drug interaction studies not performed.¹ Monitor serum potassium concentrations during concomitant use with drugs known to increase serum potassium concentrations.^{1 11} (See Hyperkalemia under Cautions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Amiodarone	No clinically important effects on pharmacokinetics of amiodarone or its active metabolite, desethylamiodarone;1 7 no apparent increase in tolvaptan concentrations7
Angiotensin II receptor antagonists	Possible increased risk of hyperkalemia1 11	Monitor serum potassium concentrations1 11
ACE inihibitors	Possible increased risk of hyperkalemia1 11	Monitor serum potassium concentrations1 11
Anticonvulsants (e.g., barbiturates, carbamazepine, phenytoin)	Decreased plasma tolvaptan concentrations (effects similar to those of rifampin) expected1 11	Avoid concomitant use1 11 If used with barbiturates, carbamazepine, or phenytoin, expected clinical effects of tolvaptan may not be observed at recommended dosage; monitor patient response and adjust dosage accordingly1 11
Antimycobacterials (e.g., rifabutin, rifampin, rifapentine)	Decreased plasma tolvaptan concentrations1 11 Rifampin: Reduced plasma tolvaptan concentrations by 85%1 11	Avoid concomitant use1 11 If used with rifabutin, rifampin, or rifapentine, expected clinical effects of tolvaptan may not be observed at recommended dosage; monitor patient response and adjust dosage accordingly1 11
Aprepitant	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Clarithromycin	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Cyclosporine	Possible increased tolvaptan concentrations1 11	Reduction of tolvaptan dosage may be required based on clinical response1
Digoxin	Increased exposure to digoxin; no clinically important effects on exposure to tolvaptan1
Diltiazem	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Diuretics, potassium-sparing	Possible increased risk of hyperkalemia1 11	Monitor serum potassium concentrations1 11
Erythromycin	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Fluconazole	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Furosemide	No apparent clinically important effects on furosemide pharmacokinetics or tolvaptan exposure1 8 24-hour urine output is greater with tolvaptan than with furosemide, but is not substantially greater with combined tolvaptan/furosemide use than with tolvaptan alone1 8
Grapefruit juice	Increased exposure to tolvaptan1
Hydrochlorothiazide	No apparent clinically important effects on hydrochlorothiazide pharmacokinetics or tolvaptan exposure1 8 24-hour urine output is greater with tolvaptan than with hydrochlorothiazide, but is not substantially greater with combined tolvaptan/hydrochlorothiazide use than with tolvaptan alone1 8
Indinavir	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Itraconazole	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Ketoconazole	Ketoconazole 200 mg daily: Fivefold increase in tolvaptan exposure observed1 Ketoconazole 400 mg daily: Even greater increase in tolvaptan exposure expected1	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Lovastatin	Increased exposure to lovastatin and its active metabolite, lovastatin-β hydroxyacid; not considered clinically important1 No clinically important effects on exposure to tolvaptan1
Nefazodone	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Nelfinavir	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Ritonavir	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
St. John’s wort (Hypericum perforatum)	Decreased plasma tolvaptan concentrations (effects similar to those of rifampin) expected1 11	Avoid concomitant use1 11 If used concomitantly, expected clinical effects of tolvaptan may not be observed at recommended dosage; monitor patient response and adjust dosage accordingly1 11
Saquinavir	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Telithromycin	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Verapamil	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Warfarin	No apparent clinically important effects on pharmacokinetics of warfarin1

Tolvaptan Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability unknown; at least 40% of dose absorbed as tolvaptan or metabolites.¹

Peak plasma concentrations observed 2–4 hours following a dose.¹

AUC increases proportionally with dose; however, at doses ≥60 mg, peak plasma concentrations increase less than proportionally with dose.¹

Onset

Onset of aquaretic and sodium-increasing effects occurs within 2–4 hours following a single 60-mg dose in healthy individuals.¹

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.^{1 11}

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.¹

Food

Food does not affect bioavailability.¹

Special Populations

Increasing age does not affect plasma tolvaptan concentrations.¹

Exposure to drug similar in patients with Cl_cr of 10–79 mL/minute and in those without renal impairment; exposure to drug not studied in patients with Cl_cr of <10 mL/minute or in those undergoing chronic dialysis.¹

Moderate or severe hepatic impairment does not have clinically important effects on exposure to drug.¹

Patients with CHF do not have a clinically important increase in exposure to drug.¹

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

99%.¹

Special Populations

Moderate or severe hepatic impairment increases volume of distribution; not considered clinically important.¹

CHF increases volume of distribution; not considered clinically important.¹

Elimination

Metabolism

Mainly, if not exclusively, metabolized in the liver by CYP3A.^{1 6} Substrate of the P-glycoprotein transport system.¹ Metabolites have little or no V₂-receptor antagonist activity.¹

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.¹¹ Tolvaptan eliminated entirely (about 99%) by nonrenal mechanisms.^{1 11}

Half-life

Terminal-phase half-life is approximately 12 hours.¹

Special Populations

In patients with hyponatremia of any origin, clearance of drug is reduced.¹

Moderate or severe hepatic impairment decreases clearance; not considered clinically important.¹

CHF decreases clearance; not considered clinically important.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

• Selective arginine vasopressin (antidiuretic hormone) V₂ receptor antagonist.^{1 2 3 4 5}

• Affinity for V₂ receptors 29 times that for V_1A receptors.^{1 4 5}

• Does not appear to have any affinity for V_1B receptors.⁵

• Antagonizes effects of vasopressin at V₂ receptors of distal nephron, resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations.^{1 2 4}

• Urinary sodium and potassium excretion and plasma potassium concentrations not substantially altered; plasma concentrations of endogenous arginine vasopressin may increase.^{1 2 4}

• Does not appear to have a clinically important effect on the QT_c interval.¹

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Under the REMS program approved by FDA, medication guide must be dispensed with every prescription for the drug.¹² (See Overly Rapid Correction of Serum Sodium Concentration under Cautions.) Importance of reviewing this information with the patient.¹ Importance of reading the medication guide before initiating therapy and each time the prescription is refilled.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.¹ 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).¹

• Potential for too rapid an increase in serum sodium concentration, which may result in serious neurologic sequelae.¹ Importance of informing clinician 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.¹ Importance of patients not stopping or restarting tolvaptan therapy on their own initiative.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Necessity of advising women to avoid breast-feeding during tolvaptan therapy.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

Tolvaptan

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	15 mg	Samsca	Otsuka
		30 mg	Samsca	Otsuka