Tolvaptan (Samsca) is an arginine vasopressin (AVP) receptor antagonist. It primarily inhibits the V2 receptors. V2-receptor inhibitor results in the excretion of free water. This results in an increase in the urine output and a reduced urinary osmolality by the excretion of water without electrolytes.

It is used in the management of the following conditions:

• Autosomal dominant polycystic kidney disease:

  • It slows the progression of declining kidney function in adults who are at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD)

• Hypervolemic or euvolemic hyponatremia:

  • It is used to treat clinically significant euvolemic or hypervolemic hyponatremia (serum sodium of less than 125 mEq/L or symptomatic patients with mild hyponatremia that is resistant to fluid restriction).
  • These patients also include patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).
  • It should not be used in emergency settings to prevent neurological symptoms.
  • Studies have not proven any mortality benefits of raising serum sodium levels with tolvaptan.

Tolvaptan dose in Adults

Tolvaptan dose in the treatment of Autosomal dominant polycystic kidney disease (ADPKD):

• 60 mg/day orally in divided doses.
• It is given as 45 mg upon wakening and 15 mg after 8 hours.
• The dose should be titrated at weekly intervals according to the patient's response and tolerability up to a dose of 90 mg/day in divided doses (given as 60 mg upon wakening and 30 mg after 8 hours).
• If the patient tolerates the 90 mg dose, increase the dose to 120 mg/day in divided doses (given as 90 mg upon wakening and 30 mg after 8 hours) based on tolerability and response.
• Maintain urine osmolality of less than 300 mOsm/kg if possible.
• A urine osmolality of 250 - 300 mOsm/kg is reasonable (if the patient can not tolerate higher doses).

Tolvaptan (Samsca) dose in the treatment of Hypervolemic or euvolemic hyponatremia: 

• 15 mg once a day.
• The dose should be increased incrementally to 30 mg and 60 mg (maximum dose) after 24 hours to the desired serum concentrations.
• For the first 24 hours, restrict free water.
• Avoid using the drug for more than a month because of the risk of hepatotoxicity.

Dosage adjustment with concomitant medication:

• Moderate CYP3A inhibitors (eg, aprepitant, erythromycin, fluconazole, verapamil):

  • Samsca:

    • Avoid its use.

  • Jynarque and Jinarc [Canadian product]:

    • Patients receiving tolvaptan 120 mg/day:

      • Reduce the dose to 60 mg/day (45 mg in the morning and 15 mg after 8 hours).

    • Patients receiving 90 mg/day:

      • Reduce the dose to 45 mg/day (30 mg in the morning and 15 mg after 8 hours).

    • Patients receiving 60 mg/day:

      • Reduce the dose to 30 mg/day (15 mg in the morning and 15 mg after 8 hours).
      • If the dose is not tolerated, further reduction in the dose may be necessary.
      • Treatment may be interrupted temporarily if the reduced doses are not available.

• Strong CYP3A inhibitors (eg, ketoconazole, clarithromycin, ritonavir, saquinavir):

  • Samsca, Jynarque:

    • Use is contraindicated.

• Strong CYP3A inducers (eg, rifampin, barbiturates, phenytoin, carbamazepine, St John's Wort):

  • Jynarque, Jinarc:

    • Avoid use.

  • Samsca:

    • Avoid its use.
    • If the concurrent use of CY3A inducers can not be avoided, monitor the patients' response and increase the dose of tolvaptan as necessary.

• P-GP inhibitors (eg, cyclosporine, quinidine):

  • A reduction in the dose of tolvaptan may be necessary.

Tolvaptan dose in Childrens

It is not approved in children less than 18 years of age.

Pregnancy Risk Factor C

• Animal studies have shown adverse fetal events.

Tolvaptan use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• Manufacturers do not recommend tolvaptan being used during breastfeeding.

Tolvaptan dose in Kidney disease:

• ADPKD (Jynarque, Jinarc):

  • It is contraindicated in anuric patients.

• Hypervolemic or euvolemic hyponatremia:

  • CrCl ≥10 mL/minute:

    • Adjustment in the dose is not necessary.

  • CrCl <10 mL/minute:

    • Use not recommended.
    • It is contraindicated in anuria.

Tolvaptan dose in liver disease:

• ADPKD (Jynarque, Jinarc):

  • It is contraindicated in severe liver disease.
  • Patients should be closely monitored for features of hepatotoxicity during its use.

  • Jynarque:

    • An elevation of ALT, AST, or bilirubin greater than twice the ULN or signs and symptoms of hepatotoxicity during its use:

      • Discontinue immediately.
      • Repeat the tests within 48 - 72 hours and as necessary.
      • if laboratory abnormalities stabilize or resolve, Treatment may be reinitiated if the laboratory abnormalities stabilized and as long as ALT and AST are less than 3 times the ULN with frequent monitoring.

    • ALT or AST greater than 3 times the ULN:

      • It should not be used or reinitiated.

  • Jinarc:

    • Elevated ALT or AST or features of hepatoxicity:

      • Withhold treatment.
      • Repeat the tests within 48 - 72 hours and as necessary.
      • if laboratory abnormalities stabilize or resolve, Treatment may be reinitiated if the laboratory abnormalities stabilized and as long as ALT and AST are less than 3 times the ULN with frequent monitoring.

    • ALT or AST greater than 3 times the ULN:

      • Treatment should be permanently discontinued if ALT or AST is greater than 3 times the ULN and any of the following occur:
        • Clinical features of hepatic injury.
        • total bilirubin greater than twice the ULN.
        • INR >1.5
        • ALT or AST greater than 5 times the ULN for more than 2 weeks
        • ALT or AST greater than 8 times the ULN at any time.

  • Hypervolemic or euvolemic hyponatremia (Samsca):

    • Patients with cirrhosis and those with underlying liver disease should avoid the use of tolvaptan.
    • The patient should be monitored closely for liver dysfunction.
    • Treatment should not be continued beyond one month and if clinical features of hepatotoxicity develop.

Common Side Effects of Tolvaptan (Samsca) Include:

• Central Nervous System:

  • Fatigue
  • Dizziness

• Endocrine & Metabolic:

  • Increased Thirst

• Gastrointestinal:

  • Nausea
  • Xerostomia
  • Diarrhea

• Renal:

  • Polyuria

Less Common Side Effects of Tolvaptan (Samsca) Include:

• Cardiovascular:

  • Palpitations
  • Cerebrovascular Accident
  • Deep Vein Thrombosis
  • Intracardiac Thrombus
  • Pulmonary Embolism
  • Ventricular Fibrillation

• Dermatologic:

  • Xeroderma
  • Skin Rash

• Endocrine & Metabolic:

  • Increased Serum Sodium
  • Hyperglycemia
  • Hyperuricemia
  • Hypernatremia
  • Dehydration
  • Hypovolemia
  • Diabetic Ketoacidosis

• Gastrointestinal:

  • Gastrointestinal Hemorrhage
  • Dyspepsia
  • Constipation
  • Decreased Appetite
  • Abdominal Distention
  • Anorexia
  • Ischemic Colitis

• Genitourinary:

  • Urethral Bleeding
  • Vaginal Hemorrhage

• Hematologic & Oncologic:

  • Disseminated Intravascular Coagulation
  • Prolonged Prothrombin Time

• Hepatic:

  • Increased Serum Alanine Aminotransferase

• Neuromuscular & Skeletal:

  • Asthenia
  • Rhabdomyolysis

• Respiratory:

  • Respiratory Failure

• Miscellaneous:

  • Fever

Contraindication to Tolvaptan Include:

• • •  

      • •  
      • •  
• Hypersensitivity can manifest as anaphylactic shock, a rash to tolvaptan, or any other component of the formulation.
• concurrent use with strong CYP3A inhibitors like clarithromycin, itraconazole, indinavir, ketoconazole, nefazodone, ritonavir, nelfinavir, saquinavir, and telithromycin.
• Use in patients who are unable to respond appropriately to thirst.
• anuria
• Urgent need to increase serum sodium
• Hypersensitivity to benzazepine or benzazepine derivatives (eg, mirtazapine);
• Hypovolemic hyponatremia
• Hypernatremia
• pregnancy;
• Breastfeeding
• galactose intolerance,
• Lapp lactase deficiency;
• glucose-galactose malabsorption
• Uncorrected urinary output obstruction
• Patients who have had tolvaptan discontinuation in the past;
• Use in patients who don't have fluid access;

Warnings and precautions

• CNS effects

  • It can cause dizziness, asthenia and syncope.
  • Patients with autosomal domin polycystic renal disease (ADPKD), are particularly at risk.
  • The drug should be used with caution by patients who are required to use mental alertness for heavy lifting or other tasks.

• Hepatotoxicity:

  • Hepatotoxicity can be fatal and is a serious side effect to Tolvaptan.

• ADPKD patients:

  • In the first 18 months of treatment, there have been cases of fatal hepatotoxicity and liver failure.
  • If there is an increase in ALT, AST or bilirubin that exceeds twice the ULN, or if you have signs and symptoms related to hepatotoxicity,
    • Stop immediately.
    • You can repeat the tests as many times as you need within 48-72 hours.
    • If laboratory abnormalities are stable or resolve, treatment may be re-initiated if they stabilize and ALT and AST remain below 3 times the ULN. Frequent monitoring is recommended.
  • If the patient is suffering from hepatic injury, or if the ALT or AST exceeds 3 times the ULN, treatment should be stopped.
  • A rise in ALT and AST that exceeds 2x the normal upper limit in symptomatic patients could indicate early liver injury. It may be necessary to discontinue treatment and repeat liver function tests.

• Patients with hyponatremia, hypervolemic or euvolemic:

  • Avoid treatment that lasts more than 30 days.
  • Patients suffering from liver cirrhosis or liver disease should not use it as the liver could be further damaged.
  • If hepatotoxicity is present, the treatment should be stopped immediately.

• Hypovolemia and hypohydration

  • Patients should be encouraged to drink plenty of fluids when they feel thirsty.
  • Hypovolemia patients should be withheld from treatment.

• Start the treatment in a hospital setting to monitor the serum sodium levels. [US Boxed Warning]

  • Only hospital staff should initiate or reinitiate treatment. This is to ensure that the serum sodium levels are regularly monitored.
  • Osmotic demyelination may be caused by rapid correction of sodium levels greater than 12 mEq/L per daily. This can manifest as dysarthria or dysphagia, mutism and lethargy, affective change, spastic quadriparesis and seizures.
  • Patients at high risk for demyelination, such as those who are severely malnourished, addicted to alcohol, or have advanced liver disease, should start on a lower dose. Slow correction is recommended in these cases.
  • Patients who have SIADH, low sodium levels at baseline or are on fluid restriction longer than 24 hours may be at greater risk for rapid correction.
  • Fluid restriction should not be allowed to occur within the first 24 hours after treatment begins.
  • In the event of rapid sodium correction, treatment discontinuation and hypotonic liquids can be given.

• ADPKD patients:

  • Patients with severe liver disease should avoid it.

• Patients with hyponatremia, hypervolemic, or euvolemic:

  • Patients with liver disease and patients with cirrhosis should avoid its use. Further liver injury can be fatal, and there is a high risk of gastrointestinal bleeding.

• Hyperkalemia:

  • Hyperkalemia can be caused by a decrease in extracellular fluid volume.
  • Patients with serum potassium levels greater than 5 mEq/l or those taking medications that can increase serum potassium should be closely monitored.

• Renal impairment

  • It should be avoided by patients with uremia.
  • It should not be used in patients suffering from advanced kidney disease, such as those who have a GFR less than 10 ml/min.
  • Its effects on serum sodium are also lost.

Tolvaptan: Drug Interaction

Monitor:

• Sodium concentration,
• the rate of increase in the serum sodium,
• serum potassium concentration (if >5 mEq/L before the administration of tolvaptan or the patient is receiving medications that may elevate the serum potassium levels).
• volume status of the patient, and/or
• Features of drug-induced hepatotoxicity like anorexia, jaundice, right upper abdominal discomfort, fatigue, dark urine, and itching).
  • Liver function tests should be monitored and tested before the initiation of treatment, at 2 - 4 weeks of therapy, monthly for 18 months, and every three months thereafter.
• neurologic status at the start of treatment and after dose titration.
• Urine osmolality or specific gravity one hour prior to the morning dose (trough level)
• serum uric acid before starting the treatment and as indicated during therapy.

How to administer Tolvaptan (Samsca)?

• It may be administered with or without meals.
• Treatment should be initiated (or reinitiated if withheld) within a hospital setting.
• The patient should be encouraged to drink, avoid thirst, and prevent dehydration.
• Discontinue the treatment if the patient is drowsy or if the thirst mechanism is impaired.

Mechanism of action of Tolvaptan (Samsca):

• Tolvaptan (Samsca), is an antagonist of the arginine vasopressin receptor (AVP). 
• It binds specifically to the V-2 and V-1a subtypes of AVP receptors in a ratio 29:1.
• V2-receptor inhibitor results are the excrettion of water free. 
• This causes an increase in urine output and decreases urinary osmolality due to the excretion water without electrolytes. It causes an increase in serum sodium.

The onset of action is 2 - 4 hours. 

The peak aquaretic and sodium increasing effects of Samsca are seen in 4 - 8 hours.

Duration: 60% or more of the water excreting and sodium increasing effects of Samsca lasts for about 24 hours.

Distribution: V : ~3 L/kg

Protein binding: more than 98%

Metabolism: It is almost exclusively metabolized via CYP3A4, however, the metabolites are inactive.

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

Half-life elimination: It is dependent on the dose because of a prolonged absorption. When administered in low doses such as 15 mg, its half-life is about 3 hours. Doses greater than 120 mg have a half-life of about 12 hours.

Time to reach the peak plasma concentration is 2 - 4 hours.

Excretion: 59% (19% as unchanged drug) of the drug is excreted in feces while 40% (<1% as unchanged drug) is excreted in urine.

International Brands of Tolvaptan:

• Jinarc
• Natrise
• Normonat
• Samsca
• Tolvat

Tolvaptan Brands in Pakistan:

Tolvaptan is not available in Pakistan.