Hyponatraemia, meaning lower than normal serum sodium concentration, is a common electrolyte imbalance associated with: burns that affect large parts of the body, heart failure, cirrhosis of the liver, advanced renal failure, diarrhoea, sweating, vomiting, use of thiazide diuretics, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

The imbalance of water to salt that occurs in hyponatraemia results from one of three possible causes:

  • Euvolaemic hyponatraemia: an increase in the amount of total body water, with no associated increase in sodium content
  • Hypervolaemic hyponatraemia: an increase in both the amount of water as well as sodium content, with the increase in water being relatively greater, or
  • Hypovolaemic hyponatraemia: a decrease in both water and sodium content in the body, with the loss in sodium being relatively greater.

With the exception of hypovolaemic situations, hyponatraemia is usually treated with fluid restriction.

Tolvaptan (Samsca®) is a new drug for the treatment of hypervolaemic and euvolaemic hyponatraemia that acts as a selective vasopressin V2 receptor antagonist. It blocks the binding of antidiuretic hormone to the V2 receptor, thereby causing an increase in the excretion of water and a rise in the concentration of serum sodium.

Tolvaptan should only be initiated, or re-initiated, in a hospital setting where serum sodium concentrations can be monitored closely. Very rapid correction of serum sodium levels may result in osmotic demyelination causing dysarthria, dysphagia, lethargy, affective changes, seizures, coma or death. In patients suffering severe malnutrition, alcoholism or advanced liver disease, slower rates of correction are generally advisable. Also, patients in whom serum sodium concentration needs to be increased in order to prevent serious neurological symptoms should not be treated with tolvaptan.

The usual initial dose recommended for tolvaptan is 15mg once daily, without regard to meals. The dose may be increased to 30mg once daily after at least 24 hours, and to a maximum of 60mg once daily, depending on the desired serum sodium levels. Tolvaptan should not be administered for more than 30 consecutive days, in order to minimise the risk of liver injury.

It is advisable to frequently monitor serum electrolytes and volume during dose initiation and titration, and to avoid fluid restriction for the first 24 hours of therapy. Patients taking tolvaptan can continue to ingest fluids in response to thirst.

Tolvaptan is primarily metabolised by the cytochrome P450 enzyme, CYP 3A. Co-administration with inhibitors of CYP 3A such as ketoconazole, clarithromycin, itraconazole, sequinavir, nelfinavir, ritonavir, erythromycin, fluconazole, aprepitant, diltiazem, verapamil and nefazodone are likely to significantly increase the levels of tolvaptan and, as such, co-administration of tolvaptan with CYP 3A inhibitors is not recommended.

Co-administration with grapefruit juice is also likely to increase levels of tolvaptan. Grapefruit juice should be avoided in patients taking tolvaptan.

Co-administration of tolvaptan with CYP 3A inducers like rifampicin, barbiturates, phenytoin, carbamazepine and St. John’s wort result in lower than usual levels of tolvaptan and therefore, the dose of tolvaptan may need to be increased when co-administered with CYP 3A inducers.

As tolvaptan is a substrate of the drug transporter permeability glycoprotein (P-gp), the dose may need to be reduced when used concomitantly with P-gp inhibitors such as cyclosporin.

As well as CYP 3A inhibitors, concomitant use with drugs known to increase potassium and hypertonic saline are also not recommended, and patients with potassium > 5mEq/L should be monitored. Tolvaptan is also contraindicated in situations where there is an urgent need to raise serum sodium levels, and in patients who are unable to appropriately sense and respond to thirst, with hypovolaemic hyponatraemia, and with anuria. The use of tolvaptan should be avoided in patients with liver disease, dehydration and hypovolaemia.

The most common adverse reactions associated with tolvaptan are directly related to its antagonism of vasopressin: thirst, dry mouth, asthenia, constipation, polyuria, hyperkalaemia and hyperglycaemia.

While tolvaptan offers a means to correct sodium levels in some cases of hyponatraemia, its contribution towards reducing the average length of hospital stay for patients with heart failure and hyponatraemia is still unclear. It is advisable that due attention should still be paid to the underlying cause of hyponatraemia.


  1. Decaux G, Soupart A, Vassart G. Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet 2008; 371(9624): 1624-32.
  2. New Drugs: Tolvaptan for hyponatraemia. Aust Prescr 2014; 37: 28-35.
  3. Samsca® (tolvaptan) Australian approved product information. St Leonards: Aspen Pharma Pty Ltd. Approved 5 April 2012, amended 24 January 2014.
  4. Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist for hyponatremia. N Engl J Med 2006; 355(20): 2099-112.

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