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Medicines Q&As
Q&A 240.3
Can miconazole oral gel be used by patients taking a statin?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: April 2014
Summary
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Miconazole is an azole antifungal which inhibits cytochrome P450 isoenzymes CYP2C9 and
CYP3A4. It is absorbed systemically from the oral gel preparation and has the potential to raise
plasma levels of drugs metabolised by these isoenzymes, increasing the risk of adverse effects.
The Summary of Product Characteristics for miconazole oral gel (Daktarin) contraindicates the
coadministration of miconazole with drugs that are metabolised by CYP3A4, including some of the
statins.
There are no reports describing interactions between miconazole and any of the statins.
Patients taking pravastatin can use miconazole oral gel. Pravastatin is not metabolised by
CYP450 isoenzymes and therefore will not interact with miconazole.
As metabolism via CYP3A4 is limited for fluvastatin and rosuvastatin, a clinically significant
interaction is unlikely. Miconazole oral gel could be used with caution in patients taking fluvastatin
or rosuvastatin, provided they are monitored for adverse effects.
For patients taking atorvastatin or simvastatin, the lack of reports of an interaction with miconazole
oral gel suggests that the antifungal may be used with caution if considered essential and there is
no suitable alternative. However, cases of rhabdomyolysis have been reported with concomitant
use of fluconazole and atorvastatin or simvastatin, and as miconazole has the potential to interact
similarly, prescribers should consider the benefits of treatment versus the risk of using the
combination.
Prescribers should be aware that prescribing the combination of atorvastatin, simvastatin,
fluvastatin or rosuvastatin and Daktarin is outside of the product licence.
Any patient taking a statin (other than pravastatin) who is given miconazole oral gel should be
warned to watch for signs of myopathy (i.e. unexplained muscle pain, tenderness or weakness or
dark coloured urine). If myopathy does occur the statin should be stopped immediately.
Background
Miconazole is an azole antifungal used for the treatment and prevention of oral and gastrointestinal
fungal infections [1]. It is available as an oral gel which can be applied topically to lesions or ingested
at a dose of 5 to 10ml four times daily for gastrointestinal infections [1, 2]. The Summary of Product
Characteristics (SmPC) for miconazole oral gel (Daktarin) contraindicates coadministration of
miconazole with drugs that are metabolised by the cytochrome P450 isoenzyme CYP3A4 including
HMG-CoA reductase inhibitors (statins), such as simvastatin [1].
This Medicines Q&A explores the evidence for the interaction between miconazole oral gel and the
statins.
Answer
When miconazole oral gel is applied locally, a large proportion may be swallowed or absorbed through
inflamed oral mucosa and therefore absorbed systemically [3]. Miconazole oral gel has been reported
to increase the INR in patients taking warfarin [4,5], indicating that it is absorbed systemically in
sufficient amounts to result in clinically significant drug interactions.
The ability of azole antifungals to inhibit cytochrome P450 isoenzymes is variable. Miconazole and
fluconazole inhibit CYP3A4 and CYP2C9. Itraconazole and ketoconazole are potent inhibitors of
CYP3A4 (but not CYP2C9).
Of the statins, atorvastatin and simvastatin are metabolised by CYP3A4 [6,7]. Fluvastatin is
substantially metabolised by CYP2C9 and a small amount is metabolised by CYP3A4 [2], whilst
Available through NICE Evidence Search at www.evidence.nhs.uk
rosuvastatin undergoes limited metabolism by CYP2C9 and by CYP3A4 to a lesser extent [8].
Pravastatin is not metabolised to a clinically significant extent by the CYP450 system [9].
The Medicines and Healthcare products Regulatory Agency (MHRA) acknowledges the potential for
interaction between some of the statins and azole antifungals. It issued guidance in January 2008
advising that prescribing of potent inhibitors of CYP3A4, such as itraconazole and ketoconazole,
should be avoided with atorvastatin and simvastatin [10]. However they made no recommendation to
avoid other azole antifungals such as miconazole. In addition, administration of miconazole oral gel is
not listed as a contraindication in the SmPCs for any of the statins [6-9,11].
What data are available to support an interaction between azoles and statins?
Miconazole
There do not appear to be any reports of an interaction between miconazole and any of the statins.
However, like fluconazole, miconazole is an inhibitor of CYP3A4 and CYP2C9, and might be expected
to interact in a similar way [2,4].
Fluconazole
Rhabdomyolysis in patients taking a statin and fluconazole has been reported [4]. A patient taking
simvastatin 40mg daily developed muscle weakness and elevated serum creatinine kinase one week
after starting fluconazole 400mg daily. Two similar cases of rhabdomyolysis have been reported in
patients taking simvastatin and fluconazole. In both cases rhabdomyolysis resolved after discontinuing
fluconazole [4]. Myopathy and rhabdomyolysis resulting in multiple organ failure and death occurred in
a patient taking atorvastatin and fluconazole. The patient was previously taking pravastatin 80mg daily
and fluconazole 150mg daily. Within one week of switching to atorvastatin 40mg he developed
myopathy, rhabdomyolysis and renal failure and later died; an interaction between the two drugs was
considered the cause [4].
Administration of fluconazole (400mg on day 1 followed by 200mg for three days) to 12 healthy
subjects taking fluvastatin 40mg resulted in an 84% increase in the AUC of fluvastatin and increased
plasma levels by 44% [4]. Fluconazole administration to 14 subjects resulted in a very small rise in the
AUC and plasma concentrations of rosuvastatin. No clinically significant adverse effects were reported
[4].
Itraconazole
Studies have shown the potential for itraconazole to increase the AUC of simvastatin from 1.5 to more
than 20 fold. High interpatient variability puts certain patients at much greater risk than others [12].
Two cases of rhabdomyolysis have been reported in patients taking simvastatin. The first was a 74
year old man who was taking simvastatin 40mg daily. Within three weeks of starting itraconazole
200mg daily, his muscles became tender and serum creatinine kinase levels were elevated. A second
patient was also taking simvastatin 40mg daily and developed symptoms of rhabdomyolysis within two
weeks of starting itraconazole 100mg twice daily. Several futher cases of raised simvastatin serum
levels have been reported in patients who have started taking itraconazole [4].
Itraconazole has been shown to result in marked rises in atorvastatin plasma levels, but no change in
fluvastatin [4]. Concomitant administration of itraconazole and rosuvastatin resulted in a small but
clinically insignificant rise in rosuvastatin plasma levels [8].
Ketoconazole
As ketoconazole is also a potent inhibitor of CYP3A4, it is expected to interact in the same way as
itraconazole. Five cases of rhabdomyolysis have been reported in patients taking simvastatin, which
developed between seven days and four weeks after starting ketoconazole [4].
What are the implications of using miconazole oral gel in patients taking statins?
There are no data available that confirm that concomitant use of miconazole and any of the statins
results in a clinically significant interaction. The basis for the manufacturer’s contraindication appears
to be extrapolation from reports of interactions between other azoles and statins. Interactions are
theoretically possible with all statins except pravastatin, but are unlikely, especially with fluvastatin and
rosuvastatin for which metabolism via CYP3A4 is less important.
Available through NICE Evidence Search at www.evidence.nhs.uk
Pravastatin
Patients taking pravastatin can use miconazole oral gel as no interaction is expected [4, 9].
Fluvastatin and rosuvastatin
Fluvastatin is predominantly metabolised by CYP2C9 and less so by CYP3A4 so theoretically is less
likely to interact with miconazole [11,12]. However, miconazole is an inhibitor of CYP2C9 so a degree
of caution is warranted [4]. Rosuvastatin undergoes limited metabolism. Approximately 10% is
metabolised, principally by CYP2C9. The manufacturer of rosuvastatin states that drug interactions
resulting from CYP450-mediated metabolism are not expected [8].
Patients taking fluvastatin or rosuvastatin can use miconazole oral gel. However, they should be
advised to report any signs of myopathy and possible rhabdomyolysis (i.e. unexplained muscle pain,
tenderness or weakness or dark coloured urine). If myopathy does occur, the statin should be stopped
immediately [4].
Atorvastatin and simvastatin
Both atorvastatin and simvastatin are metabolised by CYP3A4 [13] and the SmPC for miconazole oral
gel (Daktarin) contraindicates use of the gel in patients taking these statins. Lack of reports of any
interaction with miconazole suggests that the combination would be safe to use if considered essential
and there is no other suitable alternative. However, cases of rhabdomyolysis have been reported with
fluconazole, and as miconazole has the potential to interact similarly [4], prescribers should consider
the benefits of treatment versus the risk of using the combination.
Patients taking atorvastatin or simvastatin should use miconazole oral gel with caution [12].
They should be monitored for adverse effects and advised to report any signs of myopathy and
possible rhabdomyolysis (i.e. unexplained muscle pain, tenderness or weakness or dark coloured
urine). If myopathy does occur, the statin should be stopped immediately. For those taking high doses
of atorvastatin (i.e. 80mg), consider temporarily reducing the dose or even stopping treatment during
the course of miconazole [6, 10]. If long term antifungal treatment is needed, it would seem safer to
prescribe a non-azole antifungal agent for patients taking atorvastatin or simvastatin.
Prescribing issues
As the SmPC for miconazole oral gel (Daktarin) contraindicates the coadministration of drugs
metabolised by CYP3A4, this would exclude patients taking atorvastatin, simvastatin, fluvastatin and
rosuvastatin from using the gel. However, if no suitable alternative exists it may be necessary to
prescribe miconazole in combination with a statin. Prescribers should be aware that by doing this they
will be prescribing Daktarin outside of the product licence and will take responsibility for their decision
to do this should any adverse effects occur. If adverse effects do occur, these should be reported to
the MHRA via the Yellow Card Scheme.
Limitations
Data for drug interations with miconazole are limited. Most data available are for azoles other than
miconazole.
References
1. Summary of Product Characteristics – Daktarin oral gel. Janssen-Cilag Ltd. Date of last
revision of text 5/12/13. Accessed via www.medicines.org.uk on 01/04/14.
2. Sweetman, S (Ed), Martindale: The Complete Drug Reference. London. Pharmaceutical
Press. Accessed via www.medicinescomplete.com on 01/04/14.
3. Khanderia S, editor. Joint Formulary Committee. British National Formulary. 67th ed. London:
British Medical Association and Royal Pharmaceutical Society of Great Britain. March 2014.
4. Baxter K, editor. Stockley’s Drug Interactions. London: Pharmaceutical Press. Accessed via
www.medicinescomplete.com on 01/04/14.
5. Australian Adverse Drug Reactions Bulletin. Miconazole oral gel elevates INR; December
2002, Volume 21, number 4.
6. Summary of Product Characteristics – Lipitor. Pfizer Ltd. Date of last revision of text 08/13.
Accessed via www.medicines.org.uk on 01/04/14.
Available through NICE Evidence Search at www.evidence.nhs.uk
7. Summary of Product Characteristics – Zocor. Merck Sharp & Dohme Ltd. Date of last revision
of text 11/13. Accessed via www.medicines.org.uk on 01/04/14.
8. Summary of Product Characteristics – Crestor. Astra Zeneca UK Ltd. Date of last revision of
text 23/12/13. Accessed via www.medicines.org.uk on 01/04/14.
9. Summary of Product Characteristics – Lipostat. Bristol-Myers Squibb Pharmaceuticals Ltd.
Date of last revision of text 24/04/13. Accessed via www.medicines.org.uk on 01/04/14.
10. Medicines and Healthcare products Regulatory Agency – Drug Safety Update; January 2008,
Volume 1, issue 6.
11. Summary of Product Characteristics – Lescol. Novartis Pharmaceutical UK Limited. Date of
last revision of text 01/11/13. Accessed via www.medicines.org.uk on 01/04/14.
12. White CM. An evaluation of CYP3A4 drug interactions with HMG-CoA reductase inhibitors.
Formulary 2000; 35: 343-52.
13. Gubbins PO. Triazole antifungal agents drug-drug interactions involving hepatic cytochrome
P450. Expert Opin Drug Metab Toxicol 2011; 7: 1411-29.
Bibliography
The following resources were used for background reading:
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Cytochrome P450 Drug Interaction Tables. Indiana University: School of Medicine, Division of
Pharmacology. Accessed via http://www.medicine.iupui.edu/clinpharm on 01/04/14.
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Martin J, Fay M. Cytochrome P450 drug interactions: are they clinically relevant? Aust Prescr
2001; 24: 10-2.
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Zhang W, Ramamoorthy Y, Kilicarslan T et al. Inhibition of cytochromes P450 by antifungal
imidazole derivatives. Drug Metab Dispos 2002: 30; 314-18.
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Sweetman S (Ed) Martindale: The Complete Drug Reference, London: Pharmaceutical Press.
Itraconazole, ketoconazole, miconazole, fluconazole monographs. Accessed via
www.medicinescomplete.com on 01/04/14.
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Scheen AJ. Cytochrome P450-mediated cardiovascular drug interactions. Expert Opin Drug
Metab Toxicol 2011; 7: 1065-82.
Quality Assurance
Prepared by
Simone Henderson. North West Medicines Information Centre, Liverpool.
Date Prepared
March 2010
This version prepared April 2014
Checked by
Joanne McEntee. North West Medicines Information Centre, Liverpool.
Christine Proudlove. North West Medicines Information Centre, Liverpool.
Date of check
March 2010
This version checked April 2014
Search strategy
 Embase: Miconazole + [HMG-COA reductase inhibitors or atorvastatin or fluvastatin or
pravastatin or rosuvastatin or simvastatin].
 Embase: CYTOCHROME P450 + [FLUCONAZOLE OR ITRACONAZOLE OR PYRROLE
DERIVATIVE OR KETOCONAZOLE OR CLOTRIMAZOLE OR MICONAZOLE OR
VORICONAZOLE]. Searched limited to Review and English language.
 Medline: Miconazole + [HMG-COA reductase inhibitors or atorvastatin or fluvastatin or
pravastatin or rosuvastatin or simvastatin].
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medline: AZOLES + CYTOCHROME P-450 ENZYME SYSTEM. Review and English
language
Electronic Medicines Compendium – Summary of Product Characteristics for Daktarin oral
gel, simvastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin.
Reactions Weekly www.adisonline.com searched: Miconazole + [atorvastatin or fluvastatin or
pravastatin or rosuvastatin or simvastatin].
In-house database/ resources
Available through NICE Evidence Search at www.evidence.nhs.uk