Topical therapies have the advantage over their oral counterparts of far fewer interactions when applied to the skin. Occasionally though, there can be risks. I recently received an email from a colleague regarding the use of topical clotrimazole and how they were advised by the pharmacist NOT to supply it to a patient who was taking statins because of potential interactions. Why was that?
What are statins?
3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, or statins as they are more commonly (and easily known as) are one of the most widely prescribed drugs in the UK today due to their cholesterol lowering abilities. In 2023, over 63.5 million were dispensed. Statins prescribed in the UK include atorvastatin (Lipitor®), fluvastatin (Lescol®), pravastatin (Lipostat®), rosuvastatin (Crestor®) and simvastatin (Zocor®).
The drugs are generally well tolerated but the main reported side effect is muscle aches and pains [1]. In exceptional cases, statins have been reported to cause muscle breakdown/necrosis (known as rhabdomyolysis). In a few cases, this can lead to renal failure and death [2, 3].
One of the causes of rhabdomyolysis is high plasma concentration of statins. This may arise as the liver normally metabolises statins (like atorvastatin and simvastatin) with the CYP3A4 enzyme. However, there are other drugs, which a patient may take, which can inhibit this enzyme, effectively causing sharp rises in statin blood levels potentially triggering muscle necrosis. One such group is the imidazole antifungals.
So, what the risks? The main risk appears to be from oral azole antifungals (itraconazole and fluconazole) where systemic levels will be higher. Newer azoles such as isavuconazole and posaconazole (used for systemic fungal infections such as aspergillosis) have a lower risk of interaction but should be still be monitored in patients taking statins [4] but what about topically?
Topical Azoles
Miconazole (Daktarin® [McNeil])
The British National Formulary (BNF) notes that systemic absorption is most likely from an oral gel although mentions this might occur with topical formulations as well. Under atorvastatin, miconazole is listed as a potential interaction. The severity of the reaction is listed as moderate, but the evidence for it is listed as "theoretical". With simvastatin the severity is listed as "severe", but the evidence is recorded as “anecdotal”.
The professional data sheet for Daktarin cream 2% (MacNeil) states that "Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application, clinically relevant interactions are rare".
Also worth mentioning here is the warning that topical miconazole should not be prescribed for patients taking warfarin which I have covered in an earlier blog post
Topical Clotrimazole (Canesten® [Bayer])
The BNF states for clotrimazole that "since systemic absorption can follow topical application, the possibility of interactions with topical clotrimazole should be borne in mind". However, the BNF and electronic medicines compendium, for clotrimazole (Canesten, Bayer) does not list any statin as a specific interaction.
Topical Econazole (Peravyl® [Karo])
For Econazole nitrate, the listing in the BNF does not highlight any interactions with statins. However, the electronic medicine compendium does mention a potential interaction with liver enzymes - "Econazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application, clinically relevant interactions are rare". It goes on to mention potential issues with warfarin but statins are not discussed.
Topical Ketoconazole (Daktarin Intensiv®, Daktarin Gold® [McNeil])
The BNF states "Since systemic absorption can follow topical application, the possibility of interactions with topical ketoconazole should be borne in mind". However, the listing in the BNF of the topical cream and in the data sheet for the topical product does not mention statins.
Avoiding statins and azoles
So what's the bottom line? It is likely many thousands of patients are using these topical antifungals everyday with no problems whatsoever. Saying this, the guidance for each product should be observed (from the BNF & available product data sheets).
Reading the available data, it would appear where there is a potential risk of an interaction, this is likely to be rare and, in some cases, it is even described as "theoretical" and this should be considered before supplying any treatment. Consequently, substitution with alternatives should sought when there is concern.
Authors Note: For regular visitors of the website you may have come across previous articles demonstrating how statins potentially can have antifungal effects. Research has shown this can be the case but particularly with the newer azoles (like isavuconazole and posaconazole) used in combination with statins. This because of their lower interaction rate but work at this time is still exploratory and experimental.
References
1. Selva-O'Callaghan, A., et al., Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. Expert Rev Clin Immunol, 2018. 14(3): p. 215-224.
2. Patel, B.R. and M. Choudhury, Rhabdomyolysis with simvastatin. BMJ Case Rep, 2011. 2011.
3. Dybro, A.M., et al., Statin-associated rhabdomyolysis triggered by drug-drug interaction with itraconazole. BMJ Case Rep, 2016. 2016.
4. Brüggemann, R.J.M., et al., Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents. Clinical Infectious Diseases, 2009. 48(10): p. 1441-1458.