Fluconazole and Simvastatin: 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
Fluconazole
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.
Fluconazole (Diflucan) can slow down how your body breaks down simvastatin (Zocor). When that happens, more simvastatin builds up in your blood than usual. Simvastatin is a cholesterol medicine, and too much of it raises the chance of muscle problems, including a rare but serious condition called rhabdomyolysis, where muscle tissue breaks down.
Watch for muscle pain, tenderness, or weakness, especially if it comes on for no clear reason. Dark or cola-colored urine is another warning sign. The good news is your care team knows how to handle this. They may adjust your simvastatin dose or keep a closer eye on you while you take both. Please don't stop either medicine on your own, just call your pharmacist or doctor.
Effect: Fluconazole (moderate CYP3A4 inhibitor) inhibits CYP3A4-mediated metabolism of simvastatin (CYP3A4 substrate), increasing simvastatin exposure (AUC/Cmax) and the risk of myopathy and rhabdomyolysis.
Direction: Increased simvastatin effect and toxicity. Neither drug requires bioactivation, so this is a straightforward inhibitory accumulation.
- Onset: Delayed (case reports at 1 and 3 weeks).
- Evidence: Probable; severity major.
- Management: Monitor for muscle pain, tenderness, weakness; check CK. Discontinue if CK rises markedly or myopathy/rhabdomyolysis is suspected. Simvastatin dose reduction may be needed. Note fluconazole's inhibitory effect can persist 4 to 5 days after stopping due to its long half-life.
What happens
Increased simvastatin exposure and an increased risk of myopathy and rhabdomyolysis
Interaction Deep Dive
When simvastatin, which is metabolized by CYP3A4, is given together with fluconazole, a moderate inhibitor of CYP3A4, simvastatin exposure may rise, raising the likelihood of myopathy and rhabdomyolysis1. Rhabdomyolysis emerging at 1 and 3 weeks after the drugs were used together has been reported in two cases 23. Should combined treatment be necessary, watch for indications of myopathy and rhabdomyolysis (for example, muscle pain, tenderness, or weakness). Track creatine kinase (CK) levels and stop treatment if CK rises substantially, or if myopathy or rhabdomyolysis is diagnosed or suspected. It may be necessary to lower the simvastatin dose. Because fluconazole has a long half-life, its enzyme inhibiting effects can continue for 4 to 5 days after it is stopped 1.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated metabolism of simvastatin by fluconazole
How to manage this interaction
This combination is used cautiously, and your care team has clear ways to manage it.
- Keep taking both as prescribed unless your doctor or pharmacist tells you otherwise.
- Your simvastatin dose may need to be adjusted and individualized by your care team.
- Your team may monitor you more closely, including checking a blood test called creatine kinase (CK).
- Report any muscle pain, tenderness, or weakness, or dark urine, right away.
Remember that fluconazole can keep affecting simvastatin for about 4 to 5 days after your last fluconazole dose, so keep watching for symptoms during that time and mention this interaction to your pharmacist.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
a) An instance of rhabdomyolysis probably resulting from an interaction between simvastatin and fluconazole has been described. A 65-year-old woman came in unable to walk, with worsening, proximal muscle tenderness and weakness. Her prior medical background included obesity, hypertension, coronary artery disease, ventricular tachycardia, and hypercholesterolemia. She had received treatment for Candida albicans infection with fluconazole 800 mg daily over 3 weeks, and had taken simvastatin 40 mg once daily for 5 years. Marked proximal weakness was observed in her legs. Her laboratory findings included serum creatine kinase (CK) as high as 32000 units/L, a sedimentation rate of 51 mm/hr, C-reactive protein of 22 mg/L, ALT of 671 units/L, AST of 1461 units/L, lactate dehydrogenase of 3139 units/L, and myoglobinuria. MRI showed edematous swelling of the proximal leg muscles. No indications of metabolic or hereditary myopathy were found following a biopsy of the left vastus medialis muscle. She was diagnosed with statin-induced rhabdomyolysis on the basis of her exposure to simvastatin and fluconazole. Simvastatin was discontinued and she was managed with methylPREDNISolone and bicarbonate infusions. Following 1 week, muscle strength had improved, and pain resolved after 2 weeks. After 4 weeks, laboratory values returned to normal, and she was able to walk 500 meters unaided after 9 weeks 2.
b) An instance of rhabdomyolysis likely resulting from an interaction between simvastatin and fluconazole was described. An 88-year-old man with acute myeloid leukemia (AML) was given remission induction chemotherapy with anti-CD33 antibody conjugated with gemtuzumab ozogamicin. He had been on simvastatin for 2 years. At discharge, the patient was also taking digoxin, levothyroxine, levoFLOXacin, acyclovir, and fluconazole. He presented with severe generalized muscle weakness one week following discharge. His laboratory findings included serum creatine kinase (CK) 52716 units/L, CK-MB fraction 81.5 nanogram/mL, serum creatinine 1.2 mg/dL (110 mcmol/L), BUN 30 mg/dL (11 mmol/L), troponin I less than 0.4 mcg/L, calcium 8.3 mg/dL (2.07 mmol/L), potassium 5.1 mEq/L (5.1 mmol/L), ALT 724 units/L, AST 2367 units/L, alkaline phosphatase 187 units/L. Every medication was stopped apart from levothyroxine. The serum CK kept increasing, reaching a peak of 87,833 units/L on day 4 of hospitalization, and then decreased. The Naranjo score suggests that this suspected adverse reaction is probable 3.
Common questions
Can I take Fluconazole and Simvastatin together?
Fluconazole can raise simvastatin levels and increase the risk of serious muscle problems, so watch for muscle pain or weakness and let your care team adjust the dose or monitor you. Do not stop either medicine on your own. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Fluconazole and Simvastatin interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Fluconazole and Simvastatin interaction managed?
This combination is used cautiously, and your care team has clear ways to manage it. Keep taking both as prescribed unless your doctor or pharmacist tells you otherwise. Your simvastatin dose may need to be adjusted and individualized by your care team. Your team may monitor you more closely, including checking a blood test called creatine kinase (CK). Report any muscle pain, tenderness, or weakne… 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 Fluconazole or Simvastatin 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 (3)
- Product Information: DIFLUCAN(R) oral tablets, suspension, fluconazole oral tablets, suspension. Roerig (per FDA), New York, NY, 2023. DailyMed
- Findling O, Meier N, Sellner J, et al: Clinical reasoning: rhabdomyolysis after combined treatment with simvastatin and fluconazole. Neurology 2008; 71(15):e34-e37. PubMed
- Shaukat A, Benekli M, Vladutiu G, et al: Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother 2003; 37:1032-1035. PubMed
Keep reading about Fluconazole
Keep reading about Simvastatin
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