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Tolvaptan

Pronunciation

Pronunciation

(tol VAP tan)

Index Terms

  • OPC-41061

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Samsca: 15 mg, 30 mg [contains fd&c blue #2 aluminum lake]

Brand Names: U.S.

  • Samsca

Pharmacologic Category

  • Vasopressin Antagonist

Pharmacology

An arginine vasopressin (AVP) receptor antagonist with affinity for AVP receptor subtypes V2 and V1a in a ratio of 29:1. Antagonism of the V2 receptor by tolvaptan promotes the excretion of free water (without loss of serum electrolytes) resulting in net fluid loss, increased urine output, decreased urine osmolality, and subsequent restoration of normal serum sodium levels.

Distribution

Vd: 3 L/kg

Metabolism

Hepatic via CYP3A4

Excretion

Feces (19% as unchanged drug)

Onset of Action

2 to 4 hour; Peak effect: 4 to 8 hours

Time to Peak

Plasma: 2 to 4 hours

Duration of Action

60% peak serum sodium elevation is retained at 24 hours; urinary excretion of free water is no longer elevated

Half-Life Elimination

~12 hours; dominant half-life <12 hours

Protein Binding

99%

Use: Labeled Indications

Samsca:

Hypervolemic and euvolemic hyponatremia: Treatment of clinically significant hypervolemic or euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and resistant to fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

Limitations of use: Not indicated for use when urgent treatment of hyponatremia is required to prevent or treat serious neurological symptoms. It has not been established that raising serum sodium with tolvaptan provides symptomatic benefit.

Jinarc [Canadian product]:

Autosomal dominant polycystic kidney disease (ADPKD): Slow the progression of kidney enlargement in patients with ADPKD.

Limitations of use: Clinical trials evaluated ADPKD patients having a total kidney volume ≥750 mL with relatively preserved renal function (eg, estimated creatinine clearance ≥60 mL/minute, generally corresponding to a CKD-EPI eGFR ≥30 mL/minute/1.73 m2 at the time of therapy initiation).

Contraindications

Samsca: Hypersensitivity (eg, anaphylactic shock, generalized rash) to tolvaptan or any component of the formulation; hypovolemic hyponatremia; urgent need to raise serum sodium acutely; use in patients unable to sense or appropriately respond to thirst; anuria; concurrent use with strong CYP3A inhibitors (eg, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, telithromycin, clarithromycin)

Jinarc [Canadian product]: Hypersensitivity to tolvaptan or any component of the formulation; hypovolemia; hypernatremia; use in patients unable to sense or appropriately respond to thirst; clinically relevant hepatic impairment; anuria; pregnancy; breastfeeding

Dosing: Adult

Hyponatremia: Oral:

Samsca: Initial: 15 mg once daily; after at least 24 hours, may increase to 30 mg once daily to a maximum of 60 mg once daily titrating at 24-hour intervals to desired serum sodium concentration. Avoid fluid restriction during the first 24 hours of therapy. Do not use for more than 30 days due to the risk of hepatotoxicity.

Canadian labeling: Note: Based on serum sodium concentrations following an initial dose of 15 mg the following dose titration is recommended (at 24-hour intervals):

Change <5 mEq/L in 24 hours and serum sodium <130 mEq/L:

Day 2: Consider titration to 30 mg once daily.

Day 3 through discontinuation: Consider titration to 60 mg once daily.

Change ≥5 mEq/L in 24 hours:

Day 2: Consider maintenance dose of 15 mg once daily.

Day 3 through discontinuation: Consider maintenance of prior current dose.

Change >8 mEq/L in 8 hours or >12 mEq/L in 24 hours: Day 2 through discontinuation: Consider withholding dose and/or increase hypotonic fluid intake; monitor sodium closely.

Serum sodium ≥140 mEq/L at any time: Discontinue therapy and consider increasing hypotonic fluid intake.

Autosomal dominant polycystic kidney disease (ADPKD): Jinarc [Canadian product]: Oral: Note:Prior to initiating therapy, restrict overnight fluid intake for 10 to 14 hours to assess ability to concentrate urine using urine osmolality or specific gravity (less accurate). Upon initiation of therapy fluid intake should not be restricted.

Initial: 60 mg/day in divided doses (45 mg upon wakening and 15 mg approximately 8 hours later); titrate per response and tolerability at intervals of at least 7 days to 90 mg/day (60 mg upon wakening and 30 mg approximately 8 hours later) and then to 120 mg/day (90 mg upon wakening and 30 mg approximately 8 hours later). Downward titration may be necessary based on tolerability.

Maintenance: Maintain patient on highest tolerated dose to decrease urine osmolality 200 to 300 mOsm/kg (preferable in most cases) from baseline. Urine osmolality or specific gravity should be measured before morning dose. Urine osmolality <300 mOsm/kg (corresponds to a specific gravity of 1.005) should be maintained at all times if possible. Avoid unnecessary interruptions in therapy; however if the ability to drink or accessibility to water is limited therapy should be interrupted.

Dosage adjustment with concomitant medication: Jinarc [Canadian product]:

Strong CYP3A inhibitors (eg, ketoconazole, clarithromycin, ritonavir, saquinavir): Patients receiving tolvaptan 120 mg/day or 90 mg/day: Reduce dose to 30 mg/day administered upon wakening. Patients receiving tolvaptan 60 mg/day: Reduce dose to 15 mg/day administered upon wakening. Titrate cautiously per response and tolerability. Further downward titration or discontinuation of concurrent therapy may be necessary based on tolerability.

Moderate CYP3A inhibitors (eg, erythromycin, fluconazole, verapamil): Decrease daily dose by 50% administered as split regimen with first dose upon wakening and second dose ~8 hours later (eg, 120 mg/day [90 mg + 30 mg/day] is reduced to 60 mg/day [45 mg + 15 mg/day]). When adjusting the dose reduce the first daily dose as needed and maintain the second daily dose at 15 mg.

Dosing: Geriatric

Refer to adult dosing. Note: Jinarc [Canadian product] has not been studied in patients >65 years.

Dosing: Renal Impairment

CrCl ≥10 mL/minute: No dosage adjustment necessary.

CrCl <10 mL/minute: Use not recommended (has not been studied); contraindicated in anuria (no benefit expected).

Dosing: Hepatic Impairment

US labeling: Avoid use in patients with underlying liver disease, including cirrhosis.

Canadian labeling:

Jinarc:

Preexisting hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor closely. Avoid initiation of therapy if AST/ALT >3 times ULN. Use is contraindicated in patients with clinically relevant impairment.

Dosage adjustment for toxicity (during therapy): Interrupt therapy if hepatotoxicity is suspected and promptly evaluate hepatic function; upon resolution may consider reinitiating therapy cautiously.

ALT or AST <3 times ULN: Continue therapy cautiously and monitor frequently.

Permanently discontinue for any the following: ALT or AST >8 times ULN, ALT or AST >5 times ULN for >2 weeks, ALT or AST >3 times ULN and total bilirubin >2 times ULN or INR >1.5, ALT or AST >3 times ULN with persistent symptoms of hepatic injury.

Samsca: No dosage adjustment is necessary. Use with caution and monitor closely due to risks of hepatotoxicity; discontinue use promptly if hepatotoxicity is suspected.

Administration

Samsca: Treatment should be initiated or reinitiated in a hospital. May be administered without regards to meals.

Nasogastric (NG) tube: Administration via NG tube resulted in an ~25% reduction in AUC and a modest reduction in Cmax in one study; 24-hour urine output was reduced by only 2.8%. Therefore, until further studies are done to determine a bioequivalent dose when administering via NG tube, NG tube administration of a crushed 15 mg tablet appears to be a viable alternative method of administration (McNeely, 2012).

Jinarc [Canadian product]: May be administered without regards to meals. Interrupt therapy if the ability to drink or accessibility to water is limited.

Dietary Considerations

Grapefruit juice may increase tolvaptan serum concentrations. Management: Avoid concurrent use with grapefruit juice.

Storage

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

ACE Inhibitors: Tolvaptan may enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Angiotensin II Receptor Blockers: Tolvaptan may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tolvaptan. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tolvaptan. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Desmopressin: Tolvaptan may diminish the therapeutic effect of Desmopressin. Avoid combination

Digoxin: Tolvaptan may increase the serum concentration of Digoxin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Potassium-Sparing Diuretics: Tolvaptan may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Chloride: May enhance the adverse/toxic effect of Tolvaptan. Specifically, Hypertonic Saline may increase the risk for too rapid of an increase in serum sodium concentrations. Management: This interaction is specific to Hypertonic Saline. Avoid concurrent use of Hypertonic Saline with Tolvaptan. Avoid combination

St John's Wort: May decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

>10%:

Endocrine & metabolic: Increased thirst (12% to 16%)

Gastrointestinal: Nausea (21%), xerostomia (7% to 13%)

Renal: Polyuria (including pollakiuria, 4% to 11%)

2% to 10%:

Endocrine & metabolic: Hyperglycemia (6%), hypernatremia (<2%)

Gastrointestinal: Gastrointestinal hemorrhage (cirrhosis patients 10%), constipation (7%), anorexia (4%)

Hepatic: Hepatotoxicity (≤4%)

Neuromuscular & skeletal: Weakness (9%)

Miscellaneous: Fever (4%)

<2% (Limited to important or life-threatening): Anaphylactic shock, cerebrovascular accident, deep vein thrombosis, diabetic ketoacidosis, disseminated intravascular coagulation, hypersensitivity reaction, increased serum ALT, intracardiac thrombus, ischemic colitis, osmotic demyelination syndrome, prolonged prothrombin time, pulmonary embolism, respiratory failure, rhabdomyolysis, skin rash, urethral bleeding, vaginal hemorrhage, ventricular fibrillation

ALERT: U.S. Boxed Warning

Treatment initiation and monitoring:

Initiate and reinitiate tolvaptan in patients only in a hospital where serum sodium can be closely monitored.

Too rapid correction of hyponatremia (eg, more than 12 mEq/L per 24 hours) can cause osmotic demyelination, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and/or death. In susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease, slower rates of correction may be advisable.

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Dizziness, asthenia, and/or syncope have been reported when used for ADPKD; advise patients to use caution when performing dangerous tasks (eg, driving, operating machinery).

• Hepatotoxicity: Tolvaptan may increase the risk of serious hepatotoxicity, including fatal hepatotoxicity. Cases of hepatotoxicity have been reported in patients treated for ADPKD and have usually occurred after 3 months of therapy although some cases occurred prior to 3 months. Therefore, treatment with Samsca should be limited to 30 days. If hepatotoxicity is suspected, discontinue use. Avoid use in patients with liver disease (including cirrhosis) since the ability to recover from further liver injury may be impaired. In the treatment of ADPKD, use of Jinarc [Canadian product] is not limited to 30 days however close monitoring of hepatic function is recommended. Interrupt therapy for signs/symptoms of hepatotoxicity (eg, anorexia, dark urine, jaundice, itching, fatigue, nausea, right upper abdominal pain) and evaluate hepatic function promptly (ie, within 48 to 72 hours) then increase the frequency of hepatic function testing; upon resolution may consider cautious reinitiation of therapy.

• Hyperuricemia/Gout: Hyperuricemia and gout have been observed; in the treatment of ADPKD, monitoring of serum uric acid is recommended (Jinarc Canadian product monograph, 2015).

• Hypovolemia/dehydration: Patients should ingest fluids in response to thirst during therapy. Interrupt or discontinue therapy in patients who develop significant signs or symptoms of hypovolemia.

• Serum sodium monitoring/initiating in hospital: [US Boxed Warning]: Tolvaptan should be initiated and reinitiated in patients only in a hospital where serum sodium can be closely monitored. Too rapid correction of hyponatremia (ie, >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death. In susceptible patients (including those with severe malnutrition, alcoholism, or advanced liver disease), slower rates of correction may be advisable. Patients with SIADH, very low baseline, or patients who are fluid restricted during the first 24 hours of Samsca therapy may be at greater risk of overly-rapid correction. Avoid fluid restriction during the initial 24 hours of Samsca therapy. Discontinue or interrupt therapy if sodium correction is too rapid and consider administration of hypotonic fluids.

Disease-related concerns:

• Hepatic impairment: Avoid use in patients with liver disease, including those with cirrhosis, since the ability to recover from further liver injury may be impaired. In addition, patients with cirrhosis have a higher risk of gastrointestinal bleeding.

• Hyperkalemia: Reductions in extracellular fluid volumes may cause hyperkalemia. Patients using concomitant medications that may increase potassium levels or with a pretreatment serum potassium >5 mEq/L should be monitored after initiation of therapy.

• Renal impairment: Use in patients with creatinine clearance <10 mL/minute is not recommended; has not been studied. Use is contraindicated in patients who are anuric.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Monitor closely for rate of serum sodium increase and neurological status; rapid serum sodium correction (>12 mEq/L/24 hours) can lead to permanent neurological damage. Discontinue use if rate of serum sodium increase is undesirable; fluid restriction during the first 24 hours of sodium correction can increase the risk of overly-rapid correction and should generally be avoided; not intended for urgent correction of serum sodium to prevent or treat serious neurologic symptoms; it has not been demonstrated that raising serum sodium with tolvaptan provides a symptomatic benefit. . In the treatment of ADPKD, patients most likely to benefit from therapy are those with rapidly progressive disease or those who are developing progressive disease but lack extensive renal damage. Factors associated with rapid progression include large total renal cyst mass for a given age (measured by total kidney volume), chronic kidney disease stage 2 to 3, rapid deterioration of renal function, systemic hypertension or albuminuria.

• Limitations of use: SIADH: Limitations to the use of tolvaptan in SIADH may exist due to concerns about safety, such as overly rapid correction of hyponatremia and potential for hepatotoxicity (Spasovski, 2014). Based on available evidence, European clinical practice guidelines recommend against the use of vasopressin receptor antagonists in the treatment of hyponatremia in patients with SIADH (Spasovski, 2014). Additional data may be necessary to define the appropriate clinical role of tolvaptan in this condition.

Monitoring Parameters

Serum sodium concentration, rate of serum sodium increase, serum potassium concentration (if >5 mEq/L prior to administration or receiving medications known to elevate serum potassium); volume status; signs of drug induced hepatotoxicity (eg, anorexia, fatigue, right upper abdominal discomfort, jaundice, dark urine, itching).

Additional monitoring recommendations:

Samsca (Canadian labeling): Hepatic function testing prior to therapy initiation, at any time during therapy with signs/symptoms of hepatotoxicity, monthly for 18 months, and then at regular intervals.

Jinarc [Canadian product]:Hepatic function testing prior to therapy initiation, monthly for the first 18 months, then every 3 months for 12 months, and then every 3 to 6 months during therapy. If signs/symptoms of hepatotoxicity, obtain ALT/AST, total bilirubin, alkaline phosphatase promptly (ie, within 48 to 72 hours) and increase frequency of testing until clinical/laboratory signs of resolution; urine osmolality or specific gravity (trough level prior to morning dose); serum uric acid (prior to initiation and as indicated during therapy.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Jinarc [Canadian product] is contraindicated in pregnant women and the manufacturer recommends women of childbearing potential use reliable contraception during therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience more thirst, loss of strength and energy, constipation, dry mouth, polyuria, or nausea. Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, nausea, or vomiting); signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit); signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities); difficulty speaking; dysphagia; abnormal movements; bruising; bleeding; diarrhea; black, tarry, bloody stools; angina; coughing up blood; behavioral changes; shortness of breath; vision changes; vomiting blood; or signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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