Simvastatin with Itraconazole Interaction Details

Brand Names Associated with Simvastatin

Brand Names Associated with Itraconazole

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 10, 2023

Interaction Effect

Increased simvastatin exposure and an increased risk of myopathy and rhabdomyolysis

Interaction Summary

Coadministration of itraconazole and simvastatin, as well as use up to 2 week of itraconazole discontinuation, is contraindicated as this may increase simvastatin exposure and the risk of serious adverse events, including rhabdomyolysis. If coadministration is required, temporarily suspend simvastatin during the duration of itraconazole treatment. Simvastatin is a CYP3A4 substrate and itraconazole is a potent inhibitor of CYP3A4. The Cmax of simvastatin and simvastatin acid (active metabolite) were both increased 13.1-fold when itraconazole was coadministered . In a case report, when itraconazole was added to a stable regimen including simvastatin, the patient developed rhabdomyolysis within 3 weeks .

Severity

Contraindicated

Onset

Unspecified

Evidence

Established

How To Manage Interaction

Coadministration of itraconazole and simvastatin, as well as use up to 2 week of itraconazole discontinuation, is contraindicated as this may increase simvastatin exposure and the risk of serious adverse events, including rhabdomyolysis. If coadministration is required, temporarily suspend simvastatin during the duration of itraconazole treatment .

Mechanism Of Interaction

Inhibition of CYP3A4-mediated simvastatin metabolism by itraconazole

Literature Reports

A) The simvastatin and simvastatin acid (active metabolite) Cmax were both increased 13.1-fold when itraconazole 200 mg once daily for 4 days was coadministered with a single 80-mg dose of simvastatin .

B) In one case report, a 74-year-old man was given itraconazole 200 mg for toenail fungus. He had been taking simvastatin 40 mg daily, lisinopril, and aspirin for hypertension and type IIa hyperlipidemia. After 3 weeks of therapy, he experienced pain in the lower and upper extremities and neck, muscle tenderness, and brown urine. Abnormal lab values on examination included creatine kinase (22.8 million units/L), aldolase (423,600 units/L), lactate dehydrogenase (927,000 units/L), aspartate aminotransferase (990,000 units/L), and alanine aminotransferase (446,000 units/L). The patient was diagnosed with rhabdomyolysis .

C) In a double-blind, randomized, crossover study, 12 healthy volunteers were given either 200 mg itraconazole or placebo orally once daily for 4 days. On day 4, each subject received a single 40-mg dose of lovastatin. For up to 24 hours, plasma concentrations of lovastatin, lovastatin acid, itraconazole, hydroxyitraconazole, and creatine kinase were determined. Itraconazole increased the Cmax and the AUC of lovastatin more than 20-fold. In addition, itraconazole increased the mean Cmax and the AUC of the active metabolite, lovastatin acid, by 13-fold (0 to 24) and 20-fold, respectively. During the itraconazole phase and within 24 hours of lovastatin administration, the plasma creatine kinase was increased 10-fold in one subject .

D) A randomized, double-blind, crossover study design in 2 phases was utilized to determine the effects of itraconazole administration on the pharmacokinetics of simvastatin and pravastatin. Ten healthy volunteers received itraconazole 200 mg daily or placebo for 4 days, and also ingested simvastatin 40 mg or pravastatin as a single dose on the morning of the fourth day. Itraconazole increased the Cmax and the AUC values of unchanged simvastatin by at least 10-fold. Itraconazole also increased the Cmax of simvastatin acid from 13 nanograms (ng)/mL to 217 ng/mL and the AUC of simvastatin acid from 52.5 ng/mL to 977 ng/mL. Pravastatin pharmacokinetics were not significantly altered by the presence of itraconazole, suggesting the CYP3A4 enzymes play a large role in the metabolism of simvastatin but not pravastatin .

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.

Itraconazole Overview

• Itraconazole capsules (Sporanox, Tolsura) are used to treat fungal infections in the lungs that can spread throughout the body. Itraconazole capsules (Sporanox) are also used to treat fungal infections of the fingernails and toenails. Itraconazole oral solution (liquid) is used to treat yeast infections of the mouth and throat or of the esophagus (tube that connects the throat to the stomach). Itraconazole is in a class of antifungals called triazoles. It works by slowing the growth of fungi that cause infection.

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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.