Metolazone preparation differences and safety considerations

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Healthcare professionals involved in the use of metolazone need to be aware of the differences between licensed and unlicensed products to ensure safe care.


In recent years metolazone has only been available in the UK as an unlicensed (imported) product, a licensed formulation is now available.

Licensed product

The licensed formulation of metolazone is available as Xaqua.

Unlicensed (imported) product

The unlicensed (imported) product is still available.

Product differences


The BNF entry for Xaqua states that it is licensed for oedema in congestive heart failure, oedema in renal disease and hypertension.  In the country of origin, the authorised indications for the unlicensed (imported) metolazone product are oedema and hypertension.


The BNF entry for metolazone states recommended initial doses for both products available.

The initial recommended dose for Xaqua is 2.5mg daily, increased if necessary to 5mg daily.

Patients currently maintained on the unlicensed (imported) product have dosage regimens based on their individual clinical response; doses seen in practice vary.  Daily doses between 1.25mg and 5mg daily are commonly seen, or where smaller doses are required, patients may take their dose on alternate days.

Regimens with daily doses of part tablets or alternate day dosing may be seen in practice for both products.


The Summary of Product Characteristics for the UK-licensed metolazone tablets Xaqua state that there is up to a two-fold difference in bioavailability compared to another brand of metolazone. No comparative bioavailability studies have been conducted with the unlicensed (imported) preparations known to be predominantly used in the UK. A dose adjustment may be necessary and individualised titration based on patient’s response and tolerability is advised if switching from Xaqua tablets to another metolazone product, or vice versa.

The BNF entry for metolazone states that the Xaqua preparation is not interchangeable with other metolazone preparations.


Recommendations from the MHRA in relation to prescribing of unlicensed medications state that if a UK licensed product can meet the clinical need, even if off-label, it should be used in preference of an unlicensed product.


When initiating patients on metolazone the licensed Xaqua preparation should be prescribed.


Consideration should be given to switching patients maintained on the unlicensed (imported) metolazone to the licensed product Xaqua.


Patients unintentionally switched between products may experience toxicity or subtherapeutic effects as a result of the difference in bioavailability.

A high risk scenario would be the inadvertent prescribing of Xaqua rather than unlicensed (imported) product at transfers of care, or vice versa.  Failure to perform adequate medicines reconciliation may contribute to this risk.

There is a risk of confusion where doses result in administration of part tablets; patients or carers may be unclear as to whether the tablets have been supplied in the full tablet form or already split to the dose prescribed.  This may lead to incorrect doses taken by the patient.


Ensure that the prescribing and supply of metolazone is product specific.

Clear documentation of the approved medicinal product name at the point of prescribing and at all transfers of care may limit incorrect formulations inadvertently being chosen.

Rationalise product range used within prescribing systems and local/regional treatment protocols to support product specific prescribing and supply.

Where supply is made in a part tablet form ensure it is clearly documented on the medication label and medication records (where appropriate).  This should also be communicated to the patient and/or carer verbally where possible.

Ensure where possible that patients and/or carers are aware that their brand of metolazone should not be switched, unless advised by their healthcare professional.

Healthcare professionals involved in the prescribing, supply and monitoring of patients taking metolazone should be aware of the difference in bioavailability and take steps to manage the risk.

Switching between products

The MHRA have advised healthcare professionals to exercise caution when switching patients between metolazone preparations.

Switching between products may require dose adjustment depending on the individuals clinical response;  it should be done on a individual patient basis.

Dose and frequency

Any switch between products should take into account the difference in bioavailability.

Switching from the unlicensed (imported) product to Xaqua may require a reduction in dose by half, or for the same dose to be used but adjust the frequency from daily to alternate days.

If a dose reduction is required when switching to Xaqua it may result in a dose which requires the tablet to be split. The tablets have a single score-line allowing them to be halved. Quartering the tablets would be off licence. Shared decision making should be used when deciding the best dosing regimen for the patient.


When switching between products the patient should be closely monitored to assess the clinical impact of the switch.  Arrangements for monitoring should be done on an individual basis after an assessment of the individual clinical risk.

Patients receiving metolazone should be monitored, 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.

Clinical effect

The following monitoring parameters may be used to assess the clinical effect of the switch.

  • Urea and electrolytes (U&Es)
  • Creatinine
  • Blood pressure
  • Weight

Advice for patient

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.


Individual patient factors need to be considered before switching.  These include;

  • how stable the patient is currently
  • the risk of adverse effects from over prescribing or, suboptimal dosing
  • what monitoring arrangements are in place
  • the patient’s understanding of the implication of the switch and when to contact a healthcare professional
  • the patients ability to manage the handling of part tablets (halving or quartering tablets) or alternate day dosing regimens.


Poorly managed switching may result in toxicity or suboptimal therapy.  The patient will be at risk of harm.

Dose regimens with daily doses of part tablets or alternate day dosing may not be suitable for all patients, resulting in poor compliance.

Switching may not be appropriate for unstable patients and those at greater risks of adverse effects.


The decision to switch the product used by the patient should be undertaken on an individual patient basis.

Switching of products should be careful managed with clear documentation of the intended brand to be used, dose, frequency and arrangements for monitoring and follow up.  This information should be communicated at all transfers of care.

Use of a tablet cutter device may support the handling of doses where part tablets are used; consider if this is appropriate for the patient.

Where possible involve the patient and/or carer;

  • ensure they are aware of the intended brand, dose, frequency and arrangements for monitoring.
  • give advice and compliance aids to support the handling of part tablets or alternate day dosing.
  • give advice on the symptoms of excessive or sub optimal dosing and when to contact a healthcare professional

Update history

  1. Additional resources section removed as resources now require individual login to access
  1. Title and URL amended
  1. Added link to MHRA drug safety update advice and additional resources section added.
  1. Bioavailability section updated for clarity
  1. Included information regarding quartering tablets being off license
  1. Minor amendment to wording for clarity
  1. Published

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