Bioequivalence of Metolazone Preparations

 

For a number of years Metolazone tablets have only been available in the UK on prescription using an imported version from Canada. Recently Renascience Pharma has launched a licensed version of the 5mg tablets called Xaqua®, the 2.5mg strength are still only available as an import.

Comparative bioavailability studies have shown that the bioavailability of Xaqua® 5mg tablets may differ significantly by up to approximately two-fold to other metolazone products. This means that a dose adjustment will be needed when patients are switched between products. The Medicines and Healthcare products Regulatory Agency (MHRA) advises prescribers to initiate new patients on Xaqua® in preference to the unlicensed imported metolazone products.

Numark Information Services team have recently received a number of calls questioning why their usual route of supply has changed as specials companies are directing pharmacies to obtain the licensed version rather than an import.

Although the clinical impact of the difference in bioavailability of the licensed version is unclear, it can be assumed that vulnerable patients such as the elderly or those with renal failure may be at increased risk of adverse effects.

When switching between products the patient will need to be closely monitored to assess the clinical impact of the switch, particularly with high doses and/or long-term use.  Patients should have their serum electrolytes measured at regular intervals and be observed for clinical signs of fluid and/or electrolyte imbalance.

Warning signs of electrolyte imbalance irrespective of cause are: dryness of mouth; thirst; weakness; lethargy; drowsiness; restlessness; muscle pains or cramps; muscular fatigue; hypotension; oliguria; tachycardia; and gastrointestinal disturbances such as nausea and vomiting.

A sub-therapeutic dose on switching may also be an issue for some patients. The signs and symptoms that patients should be made aware of are related to an exacerbation of their underlying illness manifesting as increasing breathlessness, weight gain and worsening peripheral oedema.

Advice to community pharmacy teams

  • Check PMR for any patients taking metolazone and liaise with prescribers to advise them that they will need to assess any necessary dose adjustment when switching between Xaqua® and other metolazone preparations on any future prescriptions
  • Advise any patients who are switched to be aware of the symptoms of fluid and electrolyte imbalance  and the signs and symptoms of under-dosing and to seek advice from their clinician if they experience any of these
  • Dosing with Xaqua® tablets may require the tablet to be split into halves or quarters or taken on alternate days to achieve the required dose adjustment. Patients will need to be advised how this can be managed and may require a tablet cutter device or extra support with compliance aids

Read the full MHRA guidance here: https://www.gov.uk/drug-safety-update/xaqua-metolazone-5mg-tablets-exercise-caution-when-switching-patients-between-metolazone-preparations