Atorvastatin with Itraconazole Interaction Details

Brand Names Associated with Atorvastatin

Brand Names Associated with Itraconazole

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Mar 04, 2024

Interaction Effect

Increased atorvastatin exposure and an increased risk of myopathy or rhabdomyolysis

Interaction Summary

Itraconazole is a potent CYP3A4 inhibitor, and atorvastatin is a CYP3A4 substrate; coadministration significantly increased atorvastatin exposure[1][2]. Clinically significant rhabdomyolysis has been cited in case reports of patients treated concomitantly with atorvastatin and itraconazole [3][4]. Therefore, evaluate the benefit/risk of coadministration and if used concomitantly use caution and do not exceed atorvastatin doses of 20 mg daily [5][6]. Evaluate patients to ensure that the lowest necessary dose of atorvastatin is being used. Monitor the patient for signs and symptoms of myopathy or rhabdomyolysis (muscle pain, tenderness, or weakness). If myopathy or rhabdomyolysis is diagnosed or suspected, or if creatine kinase (CK) levels show a marked increase, temporarily withhold or discontinue atorvastatin [6].

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Concomitant use of atorvastatin and itraconazole may cause elevated atorvastatin plasma concentrations and may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Evaluate the benefit/risk of coadministration and if used concomitantly do not exceed atorvastatin doses of 20 mg daily[5][6]. Evaluate patients to ensure that the lowest necessary dose of atorvastatin is being used. Monitor the patient for signs and symptoms of myopathy or rhabdomyolysis (muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during upward dosage titration of either drug. If myopathy or rhabdomyolysis is diagnosed or suspected, or if creatine kinase (CK) levels show a marked increase, temporarily withhold or discontinue atorvastatin [6].

Mechanism Of Interaction

Inhibition of CYP3A4-mediated metabolism of atorvastatin by itraconazole

Literature Reports

A) A 63-year-old female with familial hypercholesterolemia and previous myocardial infarction with bypass was treated with 80 mg of lovastatin and 3 g of niacin daily for 10 years without indications of toxicity. She was also taking timolol maleate and aspirin. Two weeks after itraconazole 100 mg twice daily was added for tinea corporis, the patient developed weakness, pain on motion, and tenderness to touch in her arms, back, and legs. This was later diagnosed as drug-induced rhabdomyolysis and hepatotoxicity. Eighteen days after termination of lovastatin, niacin, and itraconazole therapy, and initiation of ubiquinone 210 mg daily, the symptoms had disappeared [4].

B) A case was reported of rhabdomyolysis in a healthy 74-year-old male three weeks following the addition of itraconazole to a stable regimen including simvastatin 40 mg daily, lisinopril, and aspirin. The patient had abnormal serum concentrations of creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. After all three drugs were discontinued and the patient started to ingest large quantities of water, his condition began to improve [3].

C) Itraconazole is a potent inhibitor of CYP3A4 enzymes, and atorvastatin is at least partially metabolized by CYP3A4. Atorvastatin has two active metabolites, 2-hydroxyatorvastatin and 4-hydroxyatorvastatin. To determine the effect of coadministration of itraconazole and atorvastatin, 10 healthy volunteers ingested itraconazole 200 mg or matching placebo on days 1 through 4. Atorvastatin 40 mg was coadministered on the morning of day 4, and another dose of itraconazole or placebo was given on day 5. The AUC and the half-life (t1/2) of atorvastatin increased by 3.3-fold and 2.9-fold, respectively, in the presence of itraconazole. The Cmax and Tmax of atorvastatin were not significantly changed. Cmax of 2-hydroxyatorvastatin plummeted from 9.8 nanogram/mL (17.1 nanomol/L) during the placebo phase to 1.7 nanogram/mL (3.0 nanomol/L) during the itraconazole phase. While these results are not as dramatic as the inhibition of simvastatin and lovastatin metabolism that is seen with itraconazole administration, the risk of myopathy can not be ruled out when atorvastatin and itraconazole are given concomitantly [2].

D) The coadministration of atorvastatin and itraconazole resulted in a significant increase of atorvastatin AUC of 150%, Cmax of 38%, and half-life of 30%. In the randomized, three-way crossover study involving 18 healthy volunteers, the effect of itraconazole on the pharmacokinetics of single-dose atorvastatin 20 mg, cerivastatin 0.8 mg, and pravastatin 40 mg was assessed. The increase in atorvastatin AUC was significantly greater than the increase in the AUC of cerivastatin and of pravastatin [1].

E) Coadministration of itraconazole 200 mg once daily with single dose of atorvastatin 40 mg for 4 days increased the atorvastatin AUC by 3.32-fold and Cmax by 1.2 fold compared with atorvastatin alone [5].

References

1 ) Mazzu A, Lasseter K, Shamblen E, et al: Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000; 68:391-400.

2 ) Kantola T, Kivisto KT, & Neuvonen PJ: Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64:58-65.

3 ) Horn M: Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals (letter). Arch Dermatol 1996; 132:1254.

4 ) Lees RS & Lees AM: Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole (letter). N Eng J Med 1995; 333:664-665.

5 ) Product Information: ATORVALIQ(R) oral suspension, atorvastatin calcium oral suspension. CMP Pharma Inc (per FDA), Farmville, NC, 2023.

6 ) Product Information: LIPITOR(R) oral tablets, atorvastatin calcium oral tablets. Pfizer (Per FDA), New York, NY, 2012.

Atorvastatin Overview

• Atorvastatin 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. Atorvastatin 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. Atorvastatin 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). Atorvastatin 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 atorvastatin 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.

Return To Our Drug Interaction Homepage

Feedback, Question Or Comment About This Information?

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.