Fluconazole with Simvastatin Interaction Details

Brand Names Associated with Fluconazole

Brand Names Associated with Simvastatin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 27, 2023

Interaction Effect

Increased simvastatin exposure and an increased risk of myopathy and rhabdomyolysis

Interaction Summary

Coadministration of simvastatin, a CYP3A4 substrate, with fluconazole, a moderate CYP3A4 inhibitor, may increase the exposure of simvastatin and increase the risk of myopathy and rhabdomyolysis. Two case reports have described rhabdomyolysis developing 1 and 3 weeks following concomitant use . If concurrent therapy is required, monitor for signs and symptoms of myopathy and rhabdomyolysis (eg, muscle pain, tenderness, or weakness). Monitor creatine kinase (CK) levels and discontinue use if CK levels increase markedly, or if myopathy or rhabdomyolysis is diagnosed or suspected. Dose reductions of simvastatin may be needed. Fluconazole enzyme inhibitory effects may persist for 4 to 5 days after discontinuation due to its long half-life .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Concomitant use of simvastatin and fluconazole may increase atorvastatin exposure and increase risk for myopathy and rhabdomyolysis. If concurrent therapy with simvastatin and fluconazole is required, monitor for signs and symptoms of myopathy and rhabdomyolysis (ie, muscle pain, tenderness, or weakness). Monitor creatine kinase (CK) levels and discontinue use if CK levels show a marked increase, or if myopathy or rhabdomyolysis is diagnosed or suspected. Dose reductions of simvastatin may be needed.

Mechanism Of Interaction

Inhibition of CYP3A4-mediated metabolism of simvastatin by fluconazole

Literature Reports

A) A case has been reported of rhabdomyolysis likely due to an interaction between simvastatin and fluconazole. A 65-year-old woman presented unable to walk, with progressive, proximal muscle tenderness and weakness. The patient’s past medical history included obesity, hypertension, coronary artery disease, ventricular tachycardia, and hypercholesterolemia. The patient had been treated for Candida albicans infection with fluconazole 800 mg daily for 3 weeks, and had been taking simvastatin 40 mg once daily for 5 years. Severe proximal weakness was noted in her legs. Laboratory values included serum creatine kinase (CK) up to 32000 units/L, a sedimentation rate of 51 mm/hr, C-reactive protein of 22 mg/L, ALT was 671 units/L, AST was 1461 units/L, lactate dehydrogenase was 3139 units/L, and myoglobinuria. MRI revealed edematous swelling of the proximal leg muscles. No signs of metabolic or hereditary myopathy were noted after a biopsy of the left vastus medialis muscle. The patient was diagnosed with statin-induced rhabdomyolysis based on the history of simvastatin and fluconazole exposure. Simvastatin was stopped and the patient was treated with methylPREDNISolone and bicarbonate infusions. After 1 week, muscle strength had increased, and pain remitted after 2 weeks. After 4 weeks, laboratory values normalized, and the patient was able to walk 500 meters without assistance after 9 weeks .

B) A case was reported of rhabdomyolysis likely due to an interaction between simvastatin and fluconazole. An 88-year-old man with acute myeloid leukemia (AML) received remission induction chemotherapy using anti-CD33 antibody conjugated with gemtuzumab ozogamicin. He had been taking simvastatin for 2 years. The patient was also taking digoxin, levothyroxine, levoFLOXacin, acyclovir, and fluconazole upon discharge. The patient presented with severe generalized muscle weakness one week after discharge. Laboratory values 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. All medications were discontinued except for levothyroxine. The serum CK continued to rise, peaked at 87,833 units/L on day 4 of hospitalization, and declined thereafter. The Naranjo score indicates that this suspected adverse reaction is probable .

Fluconazole Overview

• Fluconazole is used to treat fungal infections, including yeast infections of the vagina, mouth, throat, esophagus (tube leading from the mouth to the stomach), abdomen (area between the chest and waist), lungs, blood, and other organs. Fluconazole is also used to treat meningitis (infection of the membranes covering the brain and spine) caused by fungus. Fluconazole is also used to prevent yeast infections in patients who are likely to become infected because they are being treated with chemotherapy or radiation therapy before a bone marrow transplant (replacement of unhealthy spongy tissue inside the bones with healthy tissue). Fluconazole is in a class of antifungals called triazoles. It works by slowing the growth of fungi that cause infection.

Simvastatin Overview

• Simvastatin is used together with diet, weight-loss, and exercise to reduce the risk of heart attack and stroke and to decrease the chance that heart surgery will be needed in people who have heart disease or who are at risk of developing heart disease. Simvastatin is also used to decrease the amount of fatty substances such as low-density lipoprotein (LDL) cholesterol (''bad cholesterol'') and triglycerides in the blood and to increase the amount of high-density lipoprotein (HDL) cholesterol (''good cholesterol'') in the blood. Simvastatin may also be used to decrease the amount of cholesterol and other fatty substances in the blood in children and teenagers 10 to 17 years of age who have familial heterozygous hypercholesterolemia (an inherited condition in which cholesterol cannot be removed from the body normally). Simvastatin is in a class of medications called HMG-CoA reductase inhibitors (statins). It works by slowing the production of cholesterol in the body to decrease the amount of cholesterol that may build up on the walls of the arteries and block blood flow to the heart, brain, and other parts of the body.

• Accumulation of cholesterol and fats along the walls of your arteries (a process known as atherosclerosis) decreases blood flow and, therefore, the oxygen supply to your heart, brain, and other parts of your body. Lowering your blood level of cholesterol and fats with simvastatin has been shown to prevent heart disease, angina (chest pain), strokes, and heart attacks.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.