Simvastatin and Ketoconazole: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 4, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Ketoconazole
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.
These two medicines should not be taken together. Ketoconazole blocks a liver enzyme (called CYP3A4) that normally breaks down simvastatin. When that enzyme is slowed, simvastatin builds up in your body to much higher levels than intended.
Too much simvastatin can hurt your muscles. This can range from muscle aches and weakness to a serious condition called rhabdomyolysis, where muscle breaks down and can damage your kidneys. Because this combination is considered off-limits, please don't stop or change anything on your own. Talk with your pharmacist or doctor, who can safely pick a different option for you.
Contraindicated combination. Ketoconazole is a potent CYP3A4 inhibitor; simvastatin is a CYP3A4 substrate (an active drug, not a prodrug), so inhibition markedly increases simvastatin systemic exposure (AUC/Cmax).
- Direction: increased simvastatin exposure, raising risk of myopathy and rhabdomyolysis.
- Evidence: probable; documented myopathy/rhabdomyolysis with statin plus ketoconazole.
- Onset: unspecified; risk present from initiation.
- Management: do not coadminister, and avoid simvastatin until up to one week after ketoconazole discontinuation. Prescriber should select an alternative lipid agent or non-interacting antifungal, and counsel on muscle pain, weakness, and dark urine.
What happens
Increased simvastatin exposure and an increased risk of myopathy or rhabdomyolysis
Interaction Deep Dive
Taking ketoconazole together with simvastatin is contraindicated1, because this combination can raise simvastatin exposure and may heighten the likelihood of skeletal muscle toxicity, such as rhabdomyolysis. Simvastatin should never be given alongside ketoconazole, and this prohibition extends to as long as one week following the end of ketoconazole treatment 2. Cases of myopathy and rhabdomyolysis have been reported in individuals receiving simvastatin or a different HMG-CoA reductase inhibitor after ketoconazole therapy was started 43.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated metabolism of simvastatin
How to manage this interaction
This pair is not meant to be used together. The good news is your care team has clear ways to handle it.
- Keep taking your prescribed medicines exactly as directed, and don't stop either one on your own.
- Tell your pharmacist or doctor that you are prescribed both so they can choose a safe alternative (for example, a different statin or a different antifungal).
- Because the effect can last, simvastatin should stay on hold until up to one week after ketoconazole is finished.
- Report any muscle pain, tenderness, weakness, or dark-colored urine right away.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
3 reports — tap to read
a) A 73-year-old man was hospitalized for rapidly progressing muscle weakness. For the preceding 7 months he had taken simvastatin 20 mg daily to treat hypercholesterolemia. Three weeks before he was admitted, he started ketoconazole 200 mg daily for a widespread itchy rash of fungal origin. On examination there was weakness and tenderness affecting the lower limbs, upper limbs, and trunk, and he could not sit or walk without assistance. His serum creatine phosphokinase (CK) measured 43,900 international units/L (normal: 50 to 200 international units/L), and serum aldolase, aspartate aminotransferase, alanine aminotransferase, and lactase dehydrogenase were likewise raised. Myoglobin was detected in his urine, and he was diagnosed with rhabdomyolysis and hepatotoxicity. Both simvastatin and ketoconazole were stopped, and the CK normalized within 2 months. The patient improved considerably, and neither simvastatin nor ketoconazole was restarted 3.
b) The combined use of simvastatin and ketoconazole was believed to have triggered rhabdomyolysis in a 54-year-old woman. She had been on simvastatin 20 mg daily for one year when ketoconazole 400 mg daily was started to treat candida paronychia. Within a few days of the combined therapy she developed flu-like symptoms and had trouble climbing stairs and running, though her liver function and blood panel were normal. Four weeks afterward she was admitted to the hospital with widespread weakness and muscle pain. Rhabdomyolysis was diagnosed on the basis of a serum creatine phosphokinase level of 31,200 international units/L, a serum aldolase level of 121 international units/L, and myoglobin in the urine. Both ketoconazole and simvastatin were discontinued, and over the following week her muscle strength normalized and her serum levels fell. One month after leaving the hospital, simvastatin was restarted without a comparable adverse reaction 3.
c) Prostate cancer being treated with a statin was linked to the onset of rhabdomyolysis after high-dose ketoconazole was added to the regimen. A 73-year-old man with metastatic prostate cancer had received simvastatin for hypercholesterolemia for 8 years. His prostate cancer progressed while he was on leuprolide and bicalutamide, and his treatment was then changed to leuprolide plus ketoconazole and hydrocortisone. The patient started to develop progressive proximal muscle weakness in the arms and legs. Plasma creatine kinase and aspartate aminotransferase rose markedly, and electromyography showed acute diffuse noninflammatory myopathy. The patient improved after the medications were stopped 4.
Common questions
Can I take Simvastatin and Ketoconazole together?
Ketoconazole and simvastatin should not be taken together because ketoconazole makes simvastatin build up and raises the risk of serious muscle damage; contact your pharmacist or doctor to switch to a safer option and keep simvastatin on hold until about a week after ketoconazole ends. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Simvastatin and Ketoconazole 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 is the Simvastatin and Ketoconazole interaction managed?
This pair is not meant to be used together. The good news is your care team has clear ways to handle it. Keep taking your prescribed medicines exactly as directed, and don't stop either one on your own. Tell your pharmacist or doctor that you are prescribed both so they can choose a safe alternative (for example, a different statin or a different antifungal). Because the effect can last, simvastat… Management is individual — always follow your own care team's guidance.
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 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: ZOCOR(R) oral tablets, simvastatin oral tablets. Organon LLC (per FDA), Jersey City, NJ, 2023. DailyMed
- Product Information: Ketoconazole oral tablet, ketoconazole oral tablet. Taro Pharmaceuticals U.S.A. Inc. (per DailyMed), Hawthorne, NY, 2024. 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
Keep reading about Simvastatin
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