Simvastatin and Nefazodone: 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
Nefazodone
No brand names on recordSimvastatin
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.
Let me explain this one, because it's an important pairing. Simvastatin (Zocor) is a cholesterol medicine, and nefazodone is an antidepressant. Your body clears simvastatin using a liver enzyme called CYP3A4. Nefazodone strongly blocks that enzyme, so simvastatin can build up to much higher levels in your blood, about 20 times higher in one study.
When simvastatin levels climb too high, the biggest concern is muscle damage, including a serious form called rhabdomyolysis. That's why these two are not meant to be taken together. The good news is your care team has safe ways to handle this, so please talk with your doctor or pharmacist before changing anything.
Contraindicated combination. Nefazodone is a strong CYP3A4 inhibitor; simvastatin is a CYP3A4 substrate (its active acid metabolite is formed and cleared via this pathway). Inhibition markedly reduces simvastatin clearance.
- Direction: increased simvastatin/simvastatin acid exposure (~20-fold AUC/Cmax increase reported).
- Consequence: dose-dependent risk of myopathy and rhabdomyolysis.
- Onset: delayed; evidence: established.
- Management: avoid coadministration. If nefazodone is required, temporarily suspend simvastatin for the duration of nefazodone therapy. Monitor for myalgia, weakness, and dark urine; check CK if symptomatic.
What happens
An increased risk of myopathy or rhabdomyolysis
Interaction Deep Dive
Taking nefazodone together with simvastatin is contraindicated because it may raise the likelihood of myopathy and rhabdomyolysis. Because CYP3A4 is responsible for metabolizing simvastatin, and nefazodone acts as a potent inhibitor of CYP3A4, giving the two together can elevate simvastatin plasma levels. Should the combination be necessary, simvastatin should be temporarily withheld for as long as nefazodone therapy continues1. In healthy adult volunteers who had taken nefazodone 200 mg twice daily over 6 days, administering a single 40-mg dose of simvastatin produced roughly 20-fold rises in the plasma concentrations of both simvastatin and simvastatin acid2. Both myopathy and rhabdomyolysis have been documented in patients (whether or not renal impairment was present) receiving other HMG-CoA reductase inhibitors either on their own or in combination with nefazodone. An analogous interaction involving simvastatin and nefazodone has likewise been described453.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated simvastatin metabolism by nefazodone
How to manage this interaction
This combination is contraindicated, so your care team will usually avoid using them at the same time.
- Do not start, stop, or change either medicine on your own. Keep taking what you were prescribed until you speak with your prescriber or pharmacist.
- Your team may temporarily pause simvastatin while you are treated with nefazodone, or choose a different option for one of the two.
- Report any unexplained muscle pain, tenderness, weakness, or dark or cola-colored urine right away.
Ask your pharmacist or doctor to review this pairing so they can tailor a safe plan for you.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
5 reports — tap to read
a) A pharmacokinetic study reported roughly 20-fold rises in the plasma levels of simvastatin and simvastatin acid when a single 40-mg dose of simvastatin was given to healthy adult volunteers who had taken nefazodone 200 mg twice daily for 6 days. 2.
b) Postmarketing reports have described rhabdomyolysis in patients taking nefazodone and simvastatin together 2.
c) Myositis and rhabdomyolysis occurred in a 44-year-old man when nefazodone was taken alongside simvastatin. He had been on simvastatin for 19 weeks without any symptoms. About one month after nefazodone was begun, he reported dark urine and myalgias in his thighs and calves. Once nefazodone and simvastatin were stopped, all symptoms and laboratory abnormalities cleared within three weeks 3.
d) Rhabdomyolysis was described in a 56-year-old patient when nefazodone was combined with simvastatin. His medication list included simvastatin, atenolol, terazosin, and fluoxetine. Because of problems with impotence and depression, his provider stopped atenolol, terazosin, and fluoxetine and started buspirone, nefazodone, lisinopril, and aspirin. His simvastatin was titrated from 40 to 80 mg/d 4 days later at a routine follow-up visit. The dose was raised because of an LDL cholesterol of 188 mg/dL. Three weeks afterward he saw his primary care physician and was given fexofenadine and azithromycin for a suspected sinus infection. His LDL was 112 mg/dL. His liver function tests (LFTs) were abnormal: aspartate aminotransferase (AST) 171 international units/L (1-45 international units/L), and alanine aminotransferase (ALT) 99 international units/L (1-55 international units/L). Five days later the patient reported leg and back aches and pains that had been present over the previous 2-3 days. His urine was "cola" colored. He was admitted to the hospital and simvastatin, fexofenadine, temazepam, and nefazodone were stopped. His creatine phosphokinase (CPK) level was elevated at 10,738 units/L (1-250 units/L) and rose after admission to 79,868 units/L before falling to normal levels 2 weeks later. His AST and ALT levels were also raised at admission (2324 and 700 international units/L) and peaked at 2665 and 1139 international units/L, respectively, before returning to normal. He was diagnosed with rhabdomyolysis and received intravenous hydration, bicarbonate, mannitol and albumin. At discharge, the patient needed physical therapy to overcome extensive muscle weakness over the following few weeks 4.
e) A case has been described of a patient who developed rhabdomyolysis after receiving simvastatin together with nefazodone. A 72-year-old man with recurrent depression, anxiety, insulin-dependent diabetes mellitus, hypertension, and hyperlipidemia was referred for severe depression and anxiety. His existing medications included paroxetine, lorazepam, mirtazapine, risperidone, zolpidem, insulin, metformin, and simvastatin. The psychiatrist stopped paroxetine, mirtazapine, lorazepam, and risperidone and started nefazodone, 100 mg twice daily, clonazepam, and trazodone. The nefazodone dose was raised to 300 mg at bedtime four weeks later. Two weeks after that, the patient was admitted to the hospital with a 3-day history of generalized weakness, a cough, a fever, and a provisional diagnosis of viral syndrome. His laboratory findings included a creatinine kinase level of 10,555 units/liter, an aspartate aminotransferase level of 72 units/liter, a lactose dehydrogenase level of 350 units/liter, and urine containing moderate blood. His blood urea nitrogen, creatinine, and alanine aminotransferase levels stayed within normal limits. Nefazodone was stopped and the patient was given intravenous hydration. Two days later he was discharged with a creatinine kinase level of 3869 units/liter. One week afterward, his weakness had nearly resolved (creatinine kinase level was 261 units/liter). He continues to take simvastatin and venlafaxine without complications. The author believes the patient's rhabdomyolysis resulted from the interaction between nefazodone and simvastatin 5.
Common questions
Can I take Simvastatin and Nefazodone together?
Nefazodone can raise simvastatin levels dramatically and increase the risk of serious muscle damage, so this combination is contraindicated. Don't change anything yourself, but contact your doctor or pharmacist to arrange a safer plan. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Simvastatin and Nefazodone interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Simvastatin and Nefazodone interaction managed?
This combination is contraindicated, so your care team will usually avoid using them at the same time. Do not start, stop, or change either medicine on your own. Keep taking what you were prescribed until you speak with your prescriber or pharmacist. Your team may temporarily pause simvastatin while you are treated with nefazodone, or choose a different option for one of the two. Report any unexpl… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
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 Nefazodone 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 (5)
- Product Information: ZOCOR(R) oral tablets, simvastatin oral tablets. Organon & Co (per FDA), Jersey City, NJ, 2022. DailyMed
- Product Information: SERZONE(R) oral tablets, nefazodone hcl oral tablets. Bristol-Myers Squibb Company, Princeton, NJ, 2005.
- Jacobson RH, Wang P, & Glueck CJ: Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. JAMA 1997; 277:296. DOI
- Skrabal M, Stading J, & Monoghan M: Rhabdomyolysis associated with simvastatin-nefazodone therapy. South Med J 2003; 96(10):1034-1035. PubMed
- Thompson M & Samuels S: Rhabdomyolysis with simvastatin and nefazodone. Am J Psychiatry 2002; 159(9):1607. PubMed
Keep reading about Nefazodone
Keep reading about Simvastatin
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