Treating candidiasis (oral thrush)

First-line: Miconazole oral gel

NICE Clinical Knowledge summaries (CKS) recommend miconazole oral gel first-line for:

• Adults and young people who are not immunocompromised
• Adults taking immunosuppressive treatment (excluding those who are HIV positive)

Second-line: Nystatin oral suspension

If miconazole is unsuitable (e.g. due to clinically significant drug interactions), CKS recommends nystatin oral suspension.

According to the summary of product characteristics (SPC) for nystatin  absorption from the gastro-intestinal tract is negligible. Therefore, nystatin is not expected to interact with statins and may be a suitable alternative to miconazole.

Complications of using miconazole with statins

Miconazole may increase blood levels of some statins, increasing risk of adverse effects such as rhabdomyolysis and myopathy.

Before prescribing miconazole to a person taking a statin consider:

• if an interaction is likely
• the clinical significance of any expected interaction
• licensing (i.e. does the SPC contraindicate use)
• risk mitigation measures
• alternative treatment options (e.g. use of a non-interacting treatment such as nystatin)

Interaction

Mechanism

According to the SPC for miconazole oral gel miconazole, an azole antifungal, is absorbed systemically. It inhibits CYP450 isoenzymes CYP2C9 and CYP3A4, and may increase blood levels of drugs metabolised by these isoenzymes.

Some statins are metabolised, to a greater or lesser extent, by these isoenzymes. Extent of metabolism and associated clinical significance of the interaction varies from statin to statin (see advice for individual statins below).

Potency of CYP3A4 and CYP2C9 inhibition

It is not known how strongly miconazole inhibits CYP450 isoenzymes but it is expected to interact with statins in a similar way to fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4. Whereas itraconazole and ketoconazole are potent inhibitors of CYP3A4.

Interaction case reports

A review of the literature, found no reports describing an interaction between miconazole and any of the statins.

Risk of interaction is theoretical, based on case reports of other azole antifungals and statins.

Licensing

The SPC for miconazole oral gel contraindicates use with some drugs metabolised by CPY3A4; including simvastatin. Combined use of miconazole and simvastatin is considered ‘off-licence’ prescribing.

It makes no specific recommendations for other statins licensed in the UK.

Advice for individual statins

Simvastatin

Do not use miconazole in combination with simvastatin. Instead use a different antifungal, e.g. nystatin.

The SPC for simvastatin states that simvastatin is a substrate of CYP3A4; concomitant use of miconazole oral gel may increase simvastatin levels. Due to risk of myopathy and rhabdomyolysis associated with combined use of miconazole and simvastatin the SPC for miconazole oral gel specifically contra-indicates use. Stockley’s Drug Interactions (subscription required) highlights several cases of rhabdomyolysis and myopathy associated with fluconazole and simvastatin use.

If essential to use miconazole, simvastatin must be temporarily stopped whilst the individual is using miconazole.

Consider involving the individual’s GP in this decision.

Atorvastatin

Do not use miconazole oral gel, if possible. Instead use a different antifungal, e.g. nystatin.

The SPC for atorvastatin states that atorvastatin is metabolised by CYP3A4. Concomitant use with other inhibitors of CYP3A4, such as miconazole, can increase plasma concentrations of atorvastatin and increase risk of myopathy. Combination use with azole antifungals is cautioned, but not contra-indicated.

Stockley’s Drug Interactions (subscription required) highlights cases of rhabdomyolysis and myopathy associated with fluconazole and atorvastatin use. As miconazole has the potential to interact similarly, prescribers should consider benefits of treatment versus the risk of using this combination.

If miconazole oral gel must be used, it may be prudent to:

• temporarily withhold atorvastatin, whilst the individual is using miconazole, to avoid possible adverse effects or,
• use a lower dose of atorvastatin and monitor for toxicity (see counselling advice below).

Consider involving the individual’s GP in this decision.

Fluvastatin

Use miconazole oral gel with caution. Counsel individual regarding possible risk of an interaction and monitor for adverse effects.

As fluvastatin is metabolised by multiple CYP450 pathways, the SPC for fluvastatin highlights its metabolism is relatively insensitive to CYP450 inhibition. Although an interaction is unlikely, a theoretical risk cannot be excluded and the BNF interaction checker  and Stockley’s Drug Interactions (subscription required) suggest caution with this combination.

Rosuvastatin

Use miconazole oral gel. A clinically significant interaction is not expected.

The SPC for rosuvastatin states that drug interactions resulting from CYP450-mediated metabolism are not expected. Rosuvastatin undergoes limited metabolism (~10%, principally by CYP2C9, and by CYP2C19, CYP3A4 and CYP2D6 to a lesser extent).

Whilst there is a small theoretical risk of an increase in rosuvastatin levels, Stockley’s Drug Interactions (subscription required) highlights this is unlikely to be clinically relevant.

Pravastatin

Use miconazole oral gel. A clinically significant interaction is not expected.

The SPC for pravastatin states it is not metabolised, to a clinically significant extent, by the CYP450 isoenzyme system.

Absence of a significant pharmacokinetic interaction with pravastatin has been demonstrated for several azole antifungals including fluconazole, itraconazole and ketoconazole.

Counselling people using miconazole with an interacting statin

If people on an interacting statin need to use miconazole they should be advised to report any possible signs or symptoms of myopathy and rhabdomyolysis, such as:

• unexplained muscle pain
• tenderness
• weakness
• dark coloured urine

If myopathy occurs, Stockley’s Drug Interactions (subscription required) recommends that the statin should be stopped immediately.

Report any adverse effects due to the combination to the MHRA via the Yellow Card Scheme.

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