Simvastatin and Ketoconazole Topical: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Ketoconazole Topical
Simvastatin
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased simvastatin exposure and an increased risk of myopathy or rhabdomyolysis
Interaction Deep Dive
The concurrent use of ketoconazole and simvastatin is contraindicated2 as it may increase simvastatin exposure and may also increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Under no circumstances simvastatin be coadministered with ketoconazole, and up to one week after discontinuation of treatment with ketoconazole 1. Myopathy and rhabdomyolysis have been observed in patients treated with simvastatin or another HMG-CoA reductase inhibitor following the initiation of therapy with ketoconazole 43.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated metabolism of simvastatin
Literature reports
3 reports — tap to read
a) A 73-year-old man was admitted to the hospital with rapid progressive muscle weakness. He had been taking simvastatin 20 mg daily for the previous 7 months for hypercholesterolemia. Three weeks prior to admission, treatment with ketoconazole 200 mg daily was initiated for a generalized pruritic rash which was fungal in origin. Examination showed weakness and tenderness of the lower limbs, upper limbs, and trunk, and the patient was unable to sit or walk alone. The serum creatine phosphokinase (CK) concentration was 43,900 international units/L (normal: 50 to 200 international units/L), and serum aldolase, aspartate aminotransferase, alanine aminotransferase, and lactase dehydrogenase levels were also elevated. His urine was positive for myoglobin, and a diagnosis of rhabdomyolysis and hepatotoxicity was made. Simvastatin and ketoconazole were both discontinued, and the CK returned to normal in 2 months. The patient showed marked improvement and neither the simvastatin nor ketoconazole were reinstituted 3.
b) Simvastatin and ketoconazole coadministration were thought to precipitate rhabdomyolysis in a 54-year-old woman. She had been receiving therapy with simvastatin 20 mg daily for one year when ketoconazole 400 mg daily was initiated for candida paronychia. Within a few days of cotherapy, she experienced flu-like symptoms and had difficulty climbing stairs and running, although her liver function and blood panel were normal. Four weeks later, she was admitted to the hospital with generalized weakness and muscle pain. Rhabdomyolysis was diagnosed based on a serum creatine phosphokinase level of 31,200 international units/L, serum aldolase level of 121 international units/L, and myoglobin in the urine. Ketoconazole and simvastatin were both discontinued, and over the next week the patient's muscle strength returned to normal and serum levels decreased. A month after hospital discharge, simvastatin was reinstated without a similar adverse effect 3.
c) Prostate cancer managed by a statin was associated with development of rhabdomyolysis when high-dose ketoconazole was added to the treatment regimen. A 73-year-old man with metastatic prostate cancer was treated with simvastatin for hypercholesterolemia for 8 years. Progressive prostatic cancer developed while the patient was receiving leuprolide and bicalutamide, and treatment was subsequently switched to leuprolide plus ketoconazole and hydrocortisone. The patient began to experience progressive proximal muscle weakness in the arms and legs. Plasma creatine kinase and aspartate aminotransferase were greatly increased, and electromyography demonstrated acute diffuse noninflammatory myopathy. The patient improved after the medications were discontinued 4.
Common questions
Can I take Simvastatin and Ketoconazole Topical together?
Increased simvastatin exposure and an increased risk of myopathy or rhabdomyolysis Always confirm with your pharmacist or prescriber before making any change.
How serious is the Simvastatin and Ketoconazole Topical interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Simvastatin or Ketoconazole Topical need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (4)
- Product Information: Ketoconazole oral tablet, ketoconazole oral tablet. Taro Pharmaceuticals U.S.A. Inc. (per DailyMed), Hawthorne, NY, 2024. DailyMed
- Product Information: ZOCOR(R) oral tablets, simvastatin oral tablets. Organon LLC (per FDA), Jersey City, NJ, 2023. DailyMed
- Gilad R & Lampl Y: Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol 1999; 22:295-297.
- Itakura H, Vaughn D, Haller DG, et al: Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and simvastatin in prostate cancer. J Urol 2003; 169(2):613. DOI
Keep reading about Ketoconazole Topical
Keep reading about Simvastatin
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