Tolvaptan is a selective vasopressin V2-receptor antagonist. Tolvaptan affinity for the V2-receptor is 29 times greater than for the V1a-receptor. When taken orally, 15 to 60 mg doses of Tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed.

Tolvaptan is indicated in-

• Hypervolemic or euvolemic hyponatremia.
• Autosomal dominant polycystic kidney disease.

Hypervolemic or euvolemic hyponatremia: The usual starting dose for Tolvaptan is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. Do not use for more than 30 days due to the risk of hepatotoxicity.

Autosomal dominant polycystic kidney disease (ADPKD):

• Initially: 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 osmolality of 250 to 300 mOsm/kg is reasonable.

Hypersensitivity to the active substance or to any of the excipients, anuria, volume depletion, hypovolemic hyponatremia, hypernatremia, Patients who cannot perceive thirst, pregnancy, breast-feeding.

The most common side effects of Tolvaptan are: thirst, dry mouth, weakness, constipation, making large amounts of urine and urinating often & increased blood sugar levels.

Overdose Effects

Single doses up to 480 mg and multiple doses up to 300 mg per day for 5 days have been well tolerated in clinical trials in healthy volunteers. There is no specific antidote for Tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst and dehydration/ hypovolemia (profuse and prolonged aquaresis). In patients with suspected Tolvaptan overdose, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended. Appropriate replacement of water and/or electrolytes must continue until aquaresis abates. Dialysis may not be effective in removing Tolvaptan because of its high binding affinity for human plasma protein (>98%).

Too rapid correction of serum sodium can cause serious neurologic sequelae.

Use in Special Populations

Pediatric Use: Safety and effectiveness of Tolvaptan in pediatric patients have not been established.

Geriatric Use: Of the total number of hyponatremic subjects treated with Tolvaptan in clinical studies, 42% were 65 and over, while 19% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Increasing age has no effect on Tolvaptan plasma concentrations.

Use in Patients with Hepatic Impairment: Moderate and severe hepatic impairment do not affect exposure to Tolvaptan to a clinically relevant extent. Avoid use of Tolvaptan in patients with underlying liver disease.

Use in Patients with Renal Impairment: No dose adjustment is necessary based on renal function. There are no clinical trial data in patients with CrCl<10 ml/min, and, because drug effects on serum sodium levels are likely lost at very low levels of renal function, use in patients with a CrCl<10 ml/min is not recommended. No benefit can be expected in patients who are anuric.

Use in Patients with Congestive Heart Failure: The exposure to Tolvaptan in patients with congestive heart failure is not clinically relevantly increased. No dose adjustment is necessary.

Pregnancy & Lactation

There are no or limited amount of data from the use of Tolvaptan in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Tolvaptan is contraindicated during pregnancy. Women of childbearing potential have to use effective contraception during Tolvaptan treatment. It is unknown whether Tolvaptan is excreted in human milk.