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Tolvaptan: Drug information

Tolvaptan: Drug information
(For additional information see "Tolvaptan: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Treatment initiation and monitoring (Samsca):

Tolvaptan (Samsca) should be initiated and reinitiated 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.

Use of tolvaptan for autosomal dominant polycystic kidney disease outside of FDA-approved REMS:

Because of the risk of hepatotoxicity, tolvaptan (Samsca) should not be used for autosomal dominant polycystic kidney disease (ADPKD) outside of the FDA-approved REMS.

Risk of serious liver injury (Jynarque):

Tolvaptan (Jynarque) can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported.

Measure ALT, AST, and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then monthly for the first 18 months and every 3 months thereafter. Prompt action in response to laboratory abnormalities, signs, or symptoms indicative of hepatic injury can mitigate, but not eliminate, the risk of serious hepatotoxicity.

Distribution program (Jynarque):

Because of the risk of serious liver injury, tolvaptan (Jynarque) is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Jynarque REMS Program.

Brand Names: US
  • Jynarque;
  • Samsca
Brand Names: Canada
  • Jinarc;
  • Samsca
Pharmacologic Category
  • Vasopressin Antagonist
Dosing: Adult
Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD): Jynarque, Jinarc [Canadian product]: Oral: Initial: 60 mg/day in divided doses (given as 45 mg upon wakening and 15 mg 8 hours later); titrate per response and tolerability at intervals of at least 7 days between titrations to 90 mg/day in divided doses (given as 60 mg upon wakening and 30 mg 8 hours later) followed by 120 mg/day in divided doses (given as 90 mg upon wakening and 30 mg 8 hours later). Maintain urine osmolality of <300 mOsm/kg if possible; if the maximum dose is not tolerated, administration of a lower dose with the goal of achieving urine osmolarity of 250 to 300 mOsm/kg is reasonable (Ref).

Hyponatremia, euvolemic or hypervolemic

Hyponatremia (chronic), euvolemic or hypervolemic (alternative therapy):

Note: Not recommended for the treatment of acute hyponatremia. Only consider in patients whose serum sodium concentrations cannot be maintained above 120 mEq/L or who have persistent neurologic symptoms despite other therapy (Ref). Monitor serum sodium concentrations more frequently during initiation and titration to avoid too rapid correction and/or overcorrection. Avoid fluid restriction during the first 24 to 48 hours of therapy to help avoid overcorrection (Ref). Goal of initial therapy is to achieve a 24-hour increase in serum sodium concentration by 4 to 6 mEq/L (maximum serum sodium increase: 8 mEq/L in any 24-hour period), which is sufficient to improve most symptoms of hyponatremia. In chronic severe hyponatremia, overcorrection or too rapid correction increases the risk of iatrogenic osmotic demyelination syndrome (Ref).

Maintenance of serum sodium >120 mEq/L in patients who cannot be maintained above this threshold with initial therapy or in patients with persistent neurologic symptoms despite other therapy:

Oral: Initial: 15 mg once daily while the patient is still hospitalized; titrate as needed after initial 24 hours to 30 mg once daily, then after subsequent 24 hours may titrate as needed to a maximum of 60 mg once daily (Ref). In order to avoid hypernatremia, serum sodium concentration should be stable prior to hospital discharge. Do not use for more than 30 days due to the risk of hepatotoxicity. For treatment goals, refer to "Note."

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

ADPKD (Jynarque, Jinarc [Canadian product]): Use is contraindicated in patients who are anuric. Clinical studies included patients with eGFR as low as 25 mL/minute/1.73 m2.

Hypervolemic or euvolemic hyponatremia (Samsca):

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

CrCl <10 mL/minute: Use not recommended (has not been studied and effects of tolvaptan on serum sodium levels is likely lost at very low levels of renal function); contraindicated in anuria.

Dosing: Hepatic Impairment: Adult

ADPKD (Jynarque, Jinarc [Canadian product]): Use is contraindicated in patients with significant hepatic impairment or disease (or a history of). Monitor closely for hepatoxicity developing during use.

Jynarque:

ALT, AST, or bilirubin increase to >2 times ULN or signs/symptoms of hepatotoxicity develop during use: Discontinue immediately, obtain repeat tests promptly within 48 to 72 hours, and continue testing as necessary; if laboratory abnormalities stabilize or resolve, treatment may be reinitiated with increased monitoring as long as ALT and AST <3 times ULN.

ALT or AST >3 times ULN: Do not use or reinitiate therapy.

Jinarc [Canadian product]:

ALT or AST increased or signs/symptoms of hepatoxicity: Interrupt therapy, promptly evaluate hepatic function within 48 to 72 hours, and continue testing as necessary; if laboratory abnormalities stabilize or resolve, treatment may be reinitiated with increased monitoring.

ALT or AST >3 times ULN: Permanently discontinue therapy if ALT or AST is >3 times ULN and any of the following occur: persistent symptoms of hepatic injury; total bilirubin >2 times ULN; INR >1.5; ALT or AST >5 times ULN for >2 weeks; ALT or AST >8 times ULN at any time.

Hypervolemic or euvolemic hyponatremia (Samsca): Avoid use in patients with underlying liver disease, including cirrhosis; monitor closely for hepatotoxicity developing during use; discontinue use if signs/symptoms of hepatotoxicity develop (do not use for more than 30 days due to this potential risk).

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.

>10%:

Endocrine & metabolic: Increased thirst (12% to 64%; including polydipsia)

Gastrointestinal: Diarrhea (13%), nausea (21%), xerostomia (7% to 16%)

Nervous system: Dizziness (11%), fatigue (14%)

Renal: Polyuria (≤70%; including nocturia, pollakiuria, and urinary urgency)

1% to 10%:

Cardiovascular: Deep vein thrombosis (<2%), intracardiac thrombus (<2%), palpitations (4%), pulmonary embolism (<2%), ventricular fibrillation (<2%)

Dermatologic: Skin rash (4%), xeroderma (5%)

Endocrine & metabolic: Dehydration (2% to 3%), diabetic ketoacidosis (<2%), hyperglycemia (6%), hypernatremia (≤4%), hyperuricemia (4%), hypovolemia (2%)

Gastrointestinal: Abdominal distention (5%), anorexia (4%), constipation (7%), decreased appetite (7%), dyspepsia (8%), ischemic colitis (<2%)

Genitourinary: Urethral bleeding (<2%), vaginal hemorrhage (<2%)

Hematologic & oncologic: Disseminated intravascular coagulation (<2%), prolonged prothrombin time (<2%)

Hepatic: Increased serum alanine aminotransferase (5%)

Nervous system: Asthenia (9%), cerebrovascular accident (<2%)

Neuromuscular & skeletal: Rhabdomyolysis (<2%)

Respiratory: Respiratory failure (<2%)

Miscellaneous: Fever (4%)

<1%: Hepatic: Hepatotoxicity (including acute hepatotoxicity and increased serum bilirubin)

Postmarketing:

Hepatic: Hepatic failure

Hypersensitivity: Anaphylactic shock, anaphylaxis, hypersensitivity reaction

Nervous system: Osmotic demyelination syndrome

Contraindications

Hypersensitivity (eg, anaphylactic shock, generalized rash) to tolvaptan or any component of the formulation; concurrent use with strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin); use in patients unable to sense or respond to thirst; anuria.

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Samsca: Additional contraindications: Hypovolemic hyponatremia; use in patients with autosomal dominant polycystic kidney disease (ADPKD) outside of the FDA-approved REMS.

Samsca [Canadian product]: Additional contraindications: Hypersensitivity to benzazepine or benzazepine derivatives (eg, mirtazapine); hypovolemic hyponatremia; hypernatremia; urgent need to raise serum sodium acutely; use in patients with ADPKD outside of Health Canada Risk Management Plan (RMP); pregnancy; breastfeeding; galactose intolerance, congenital lactase deficiency; glucose-galactose malabsorption.

Jynarque: Additional contraindications: Patients with a history, signs, or symptoms of significant liver impairment or injury (not applicable to uncomplicated polycystic liver disease); use in patients with uncorrected abnormal blood sodium concentrations; uncorrected urinary outflow obstruction; hypovolemia.

Jinarc [Canadian product]: Additional contraindications: Patients with a history of tolvaptan discontinuation; hypersensitivity to benzazepine or benzazepine derivatives (eg, mirtazapine); hypovolemia; hypernatremia; use in patients who do not have access to fluids; patients with a history, signs, or symptoms of significant liver impairment or injury (not applicable to uncomplicated polycystic liver disease); pregnancy; breastfeeding; galactose intolerance, congenital lactase deficiency; glucose-galactose malabsorption.

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Dizziness, asthenia, and/or syncope have been reported when used for autosomal dominant polycystic kidney disease (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.

- ADPKD patients: Cases of hepatotoxicity have been reported in patients treated for ADPKD generally during the first 18 months of therapy; liver failure resulting in liver transplantation has also been reported. During use, if signs/symptoms of hepatotoxicity develop or if ALT, AST, or bilirubin increase to >2 times ULN, immediately discontinue use, obtain repeat tests promptly within 48 to 72 hours, and continue testing as necessary; if laboratory abnormalities stabilize or resolve, treatment may be reinitiated with increased monitoring as long as ALT and AST <3 times ULN. Do not reinitiate therapy in patients with signs or symptoms of hepatic injury or ALT or AST >3 times ULN, unless there is another reason for liver injury and the liver injury has resolved. Patients with a stable, low baseline ALT or AST that experience an increase >2 times ULN (or an increase less than 2 times ULN) may be experiencing early liver injury; discontinuation of therapy may be necessary and repeat liver tests prior to reinitiation with increased monitoring.

- Hypervolemic or euvolemic hyponatremia patients: Treatment should be limited to 30 days. Avoid use in patients with liver disease (including cirrhosis) since the ability to recover from further liver injury may be impaired. During use, if signs/symptoms of hepatotoxicity develop, discontinue use.

• 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]: Samsca: Tolvaptan should be initiated and reinitiated 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 death. In susceptible patients (including those with severe malnutrition, alcoholism, or advanced liver disease), slower rates of correction may be advisable. Note: Some experts recommend a correction of hyponatremia no more than 8 mEq/L in any 24-hour period (Sterns 2021). Patients with SIADH, very low baseline, or patients who are fluid restricted during the first 24 hours of therapy may be at greater risk of overly-rapid correction. Avoid fluid restriction during the initial 24 hours of therapy. Discontinue or interrupt therapy if sodium correction is too rapid and consider administration of hypotonic fluids.

Disease-related concerns:

• Hepatic impairment:

- ADPKD patients: Use is contraindicated in patients with significant hepatic impairment or disease (or a history of).

- Hypervolemic or euvolemic hyponatremia patients: 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 is contraindicated in patients who are anuric. In patients with hypervolemic or euvolemic hyponatremia, use is not recommended in patients with CrCl <10 mL/minute; has not been studied and effects of tolvaptan on serum sodium levels is likely lost at very low levels of renal function. In patients with ADPKD, studies have included patients with normal and reduced renal function.

• Urinary obstruction: Avoid use in patients with uncorrected urinary outflow obstruction (eg, partial obstruction including patients with prostatic hypertrophy or impairment of micturition); may have increased risk for developing acute retention.

Other warnings/precautions:

• Appropriate use:

- ADPKD patients: 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.

- Hypervolemic or euvolemic hyponatremia patients: Monitor closely for rate of serum sodium increase and neurological status; rapid serum sodium correction (>8 mEq/L in any 24-hour period) can lead to permanent neurological damage (Sterns 2021). 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.

• 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.

• REMS program [US Boxed Warning]: Jynarque: Because of the risk of serious liver injury, tolvaptan is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Jynarque REMS Program. Prescribers must be certified by enrolling in the REMS program and must inform patients about the risk of hepatotoxicity associated with Jynarque and how to recognize symptoms of hepatotoxicity; patients must be enrolled in the REMS program and follow monitoring requirements; and pharmacies must be certified by enrolling in the REMS program and only dispense to patients authorized to receive Jynarque. Call 1-877-726-7220 or visit http://www.jynarquerems.com for more information.

Dosage Forms: US

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

Tablet, Oral:

Jynarque: 15 mg, 30 mg [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake]

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

Generic: 15 mg, 30 mg

Tablet Therapy Pack, Oral:

Jynarque: 45 & 15 MG (14 ea); 60 & 30 MG (14 ea); 90 & 30 MG (14 ea) [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake]

Generic Equivalent Available: US

May be product dependent

Pricing: US

Tablet Therapy Pack (Jynarque Oral)

45 & 15 mg (per each): $411.42

60 & 30 mg (per each): $411.42

90 & 30 mg (per each): $411.42

Tablets (Jynarque Oral)

15 mg (per each): $411.42

30 mg (per each): $411.42

Tablets (Samsca Oral)

15 mg (per each): $624.24

30 mg (per each): $647.57

Tablets (Tolvaptan Oral)

15 mg (per each): $526.15 - $564.79

30 mg (per each): $546.05 - $585.90

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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 (indigo carm) aluminum lake]

Tablet Therapy Pack, Oral:

Jinarc: 15 mg (14 ea); 30 & 15 MG (14 ea) [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake]

Jinarc: 45 & 15 MG (14 ea); 60 & 30 MG (14 ea); 90 & 30 MG (14 ea) [contains fd&c blue #2 (indigo carm) aluminum lake]

Prescribing and Access Restrictions

Jinarc [Canadian product]: Only physicians experienced in the diagnosis and treatment of polycystic kidney disease should prescribe Jinarc. Prior to initiating therapy, a patient-prescriber agreement (PPAF) is required outlining relevant patient selection criteria for consideration, expected benefits and risks of treatment, and the need for mandatory hepatic function monitoring. Jinarc is available only through a hepatic safety monitoring and distribution program conducted and maintained by Otsuka Canada Pharmaceuticals Incorporated. All patients initiating therapy should be offered participation in the Canadian Jinarc patient outcomes registry.

Administration: Adult

Oral: May be administered without regards to meals. Water should be available at all times during use and patients encouraged to drink to avoid thirst and prevent dehydration from occurring. Interrupt therapy if the ability to drink or accessibility to water is limited.

Samsca: Treatment should be initiated or reinitiated in a hospital.

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 (Ref).

Medication Guide and/or Vaccine Information Statement (VIS)

Jynarque: An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204441lbl.pdf, must be dispensed with this medication.

Samsca: An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022275s017lbl.pdf#page=19, must be dispensed with this medication.

Use: Labeled Indications

Autosomal dominant polycystic kidney disease: Jynarque, Jinarc [Canadian product]: Slow the progression of kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD)

Hyponatremia (chronic), euvolemic or hypervolemic: Samsca: 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.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BCRP/ABCG2

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Risk D: Consider therapy modification

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

Angiotensin-Converting Enzyme Inhibitors: Tolvaptan may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

Berotralstat: BCRP/ABCG2 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with BCRP inhibitors. Risk D: Consider therapy modification

Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Risk D: Consider therapy modification

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Tolvaptan. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Tolvaptan. Risk X: Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tolvaptan. Management: Avoid this combination with Samsca brand of tolvaptan. Reduce dose for Jynarque brand: 90 mg AM and 30 mg PM, reduce to 45 mg AM and 15 mg PM; 60 mg AM and 30 mg PM, reduce to 30 mg AM and 15 mg PM; 45 mg AM and 15 mg PM, reduce to 15 mg AM and PM. Risk D: Consider therapy modification

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

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

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

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Grapefruit Juice: May increase the serum concentration of Tolvaptan. Risk X: Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination

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

Rosuvastatin: BCRP/ABCG2 Inhibitors may increase the serum concentration of Rosuvastatin. Risk C: 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. Risk X: Avoid combination

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination

Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a BCRP inhibitor. Risk D: Consider therapy modification

Food Interactions

Tolvaptan exposure may be doubled when taken with grapefruit juice. Management: Avoid grapefruit juice.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies.

Breastfeeding Considerations

It is not known if tolvaptan is present in breast milk.

Due to the potential for adverse events in a breastfed infant, breastfeeding is not recommended by the manufacturer.

Dietary Considerations

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

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; and/or signs of drug-induced hepatotoxicity (eg, anorexia, fatigue, right upper abdominal discomfort, jaundice, dark urine, itching); neurologic status (at initiation and after titration)

Additional monitoring recommendations: Jynarque: Hepatic function (ALT, AST, and bilirubin) prior to initiation, at 2 and 4 weeks after initiation, monthly for 18 months, and every 3 months thereafter

Additional monitoring recommendations: 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. Urine osmolality or specific gravity (trough level prior to morning dose); serum uric acid (prior to initiation and as indicated during therapy

Mechanism of Action

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.

Pharmacokinetics (Adult Data Unless Noted)

Onset of action: Aquaretic and sodium increasing effects (Samsca): 2 to 4 hours

Peak effect: Aquaretic and sodium increasing effects (Samsca): 4 to 8 hours

Duration: Aquaretic and sodium increasing effects (Samsca): 60% peak serum sodium elevation is retained at 24 hours; urinary excretion of free water is no longer elevated

Distribution: Vd: ~3 L/kg

Protein binding: >98%

Metabolism: Almost exclusively via CYP3A4 (none are pharmacodynamically active)

Bioavailability: 56% (range: 42% to 80%)

Half-life elimination: 15 mg doses: 3 hours; ≥120 mg doses: ~12 hours. Note: Half-life increases with higher doses due to a more prolonged absorption.

Time to peak, plasma: 2 to 4 hours

Excretion: Feces: 59% (19% as unchanged drug); Urine: 40% (<1% as unchanged drug)

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: AUC and Cmax were increased 90% and 10%, respectively, in patients with CrCl <30 mL/minute compared to patients with CrCl >60 mL/minute.

Hepatic function impairment: Moderate (Child-Pugh class A and B) or severe hepatic impairment (Child-Pugh class C) decreases the clearance and increases the volume of distribution of tolvaptan.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AR) Argentina: Toblaptin | Tolkistan;
  • (AT) Austria: Jinarc | Samsca;
  • (AU) Australia: Jinarc tolvaptan | Samsca;
  • (BE) Belgium: Jinarc;
  • (BG) Bulgaria: Samsca;
  • (CH) Switzerland: Jinarc | Samsca;
  • (CN) China: Su mai ka;
  • (CZ) Czech Republic: Jinarc | Samsca;
  • (DE) Germany: Jinarc | Samsca;
  • (DK) Denmark: Samsca;
  • (EE) Estonia: Samsca;
  • (ES) Spain: Jinarc | Samsca | Tolvaptan teva | Tolvaptan Tevagen;
  • (ET) Ethiopia: Tolvat;
  • (FI) Finland: Jinarc | Samsca;
  • (FR) France: Jinarc | Samsca | Tolvaptan teva;
  • (GB) United Kingdom: Jinarc | Samsca;
  • (GR) Greece: Samsca;
  • (HK) Hong Kong: Jinarc | Samsca;
  • (HU) Hungary: Jinarc | Samsca;
  • (ID) Indonesia: Samsca;
  • (IE) Ireland: Jinarc | Samsca;
  • (IN) India: Hyponat O | Ibtol | Natrise | Shiokem | Tofanta | Tolsama | Tolvagen | Tolvamac | Tolvarise | Tolvasca | Tolvat | Tvaptan | Vaptan | Vaptolva;
  • (IT) Italy: Jinarc | Samsca;
  • (JP) Japan: Samsca;
  • (KE) Kenya: Tolvat;
  • (KR) Korea, Republic of: Myungin tolvaptan | Samsca;
  • (LT) Lithuania: Samsca;
  • (LV) Latvia: Jinarc | Samsca;
  • (MT) Malta: Samsca;
  • (MY) Malaysia: Samsca;
  • (NL) Netherlands: Jinarc | Samsca | Tolvaptan teva;
  • (NO) Norway: Jinarc | Samsca | Tolvaptan teva;
  • (PE) Peru: Tolsama;
  • (PH) Philippines: Samsca;
  • (PL) Poland: Jinarc | Samsca;
  • (PR) Puerto Rico: Jynarque;
  • (PT) Portugal: Jinarc | Samsca;
  • (RO) Romania: Jinarc | Samsca;
  • (SA) Saudi Arabia: Vaprena;
  • (SE) Sweden: Jinarc | Samsca;
  • (SI) Slovenia: Jinarc | Samsca;
  • (SK) Slovakia: Samsca;
  • (TH) Thailand: Samsca;
  • (TR) Turkey: Jinarc | Samsca;
  • (TW) Taiwan: Jinarc;
  • (UG) Uganda: Tolvat
  1. Ali F, Guglin M, Vaitkevicus P, et al. Therapeutic Potential of Vasopressin Receptor Antagonists. Drugs. 2007;67(6):847-858. [PubMed 17428103]
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  6. Jinarc (tolvaptan) [product monograph]. Saint-Laurent, Quebec, Canada: Otsuka Canada Pharmaceutical Inc; October 2019.
  7. Jynarque (tolvaptan) [prescribing information]. Rockville, MD: Otsuka America Pharmaceutical Inc; October 2020.
  8. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of Oral Tolvaptan in Patients Hospitalized for Worsening Heart Failure: The EVEREST Outcome Trial. JAMA. 2007;297(12):1319-1331. [PubMed 17384437]
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  12. Samsca (tolvaptan) [product monograph]. Saint-Laurent, Quebec, Canada: Otsuka Canada Pharmaceuticals Inc; June 2019.
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  16. Spasovski G, Vanholder R, Allolio B, et al; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia [published correction appears in Eur J Endocrinol. 2014;171(1):X1]. Eur J Endocrinol. 2014;170(3):G1-G47. [PubMed 24569125]
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