Simvastatin with Cyclosporine Interaction Details

Brand Names Associated with Simvastatin

Brand Names Associated with Cyclosporine

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

Interaction Effect

An increased risk of myopathy or rhabdomyolysis

Interaction Summary

The concomitant use of cycloSPORINE (an inhibitor of CYP3A4 and OATP1B1) and simvastatin (a substrate of CYP3A4 and OATP1B1) may increase plasma concentrations of simvastatin and increase the risk of myopathy or rhabdomyolysis. Coadministration of cycloSPORINE and simvastatin is contraindicated.

Severity

Contraindicated

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of cycloSPORINE and simvastatin is contraindicated due to increased risk of myopathy and rhabdomyolysis.

Mechanism Of Interaction

Inhibition of CYP3A4-mediated metabolism of simvastatin by cyclosporine; inhibition of OATP1B1-mediated simvastatin transport by cyclosporine

Literature Reports

A) The effect of concurrent administration of a single dose of simvastatin 20 mg with cycloSPORINE in 10 renal transplant patients was investigated. Five patients were treated with cycloSPORINE, azathioprine, and prednisolone and five were treated with azathioprine and prednisolone. The simvastatin mean area under the concentration-time curve (AUC) was significantly higher and the mean Cmax was higher in the cycloSPORINE-treated group. Time to Cmax was the same in both groups .

B) A long-term study followed 26 heart transplant patients taking an average daily dose of simvastatin 10 mg daily and triple immunosuppressive therapy including cycloSPORINE, azathioprine, and corticosteroids. The control group consisted of 26 heart transplant patients also on triple immunosuppressive therapy, but not on simvastatin therapy. After one year, data were available for 21 simvastatin patients and 21 controls. Results indicated that simvastatin 10 mg daily had lowered serum levels of total cholesterol, LDL cholesterol, and triglycerides. These reductions are similar to what can be achieved in the general population using simvastatin at doses of 20 mg to 40 mg daily. Two patients in the simvastatin group developed mild myopathies with creatine phosphokinase (CK) levels at 5 and 44 times the upper normal limit. These increases in CK were seen following dose increases of simvastatin from 5 mg daily to 10 mg daily, and from 10 mg daily to 15 mg daily, respectively. Both patients recovered completely when simvastatin was reduced to its original dose .

C) Rhabdomyolysis was reported in 2 cycloSPORINE-treated heart transplant patients receiving simvastatin 20 mg and 40 mg daily, respectively. Discontinuation of simvastatin, a dose reduction of cycloSPORINE, and intense hydration led to normalization of lab values within 1 week .

D) A 55-year-old woman developed fatal rhabdomyolysis after receiving concomitant therapy with simvastatin and cycloSPORINE. The woman had several comorbid diseases including hyperlipidemia, type 2 diabetes mellitus, morbid obesity, chronic renal failure and hypertension. She had taken simvastatin 10 mg/day for an unknown period of time prior to receiving a renal transplant. Simvastatin was discontinued and then reinitiated 4 months after the renal transplant. The dosage of simvastatin was increased 3 months later to 20 mg/day. Three months later the patient presented to the hospital with profound weakness and fatigue. Concomitant use of prednisone, azathioprine, famotidine, insulin and metoprolol was also noted. Laboratory results were remarkable and demonstrated a greatly increased creatine kinase level, marked hyperkalemia, hypocalcemia, and hyperphosphatemia. A cycloSPORINE level was within the therapeutic range. The patient's muscle weakness continued and despite correction of metabolic imbalances the patient expired 10 days into her hospital course .

E) A post-transplant patient on numerous medications including simvastatin and cycloSPORINE experienced generalized weakness and severe muscle pain in his limbs. This was accompanied by elevated CPK (3878 U/L), LDH (585 U/L), and GOT (133U/L), and myoglobin in the urine. Electromyography revealed myopathic changes in the deltoid and vastus lateralis muscles. Tacrolimus replaced the cycloSPORINE and after 8 days of hospitalization the patient's muscle strength returned and muscle enzyme levels were within normal limits .

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.

Cyclosporine Overview

• Cyclosporine and cyclosporine (modified) are used with other medications to prevent transplant rejection (attack of the transplanted organ by the immune system of the person who received the organ) in people who have received kidney, liver, and heart transplants. Cyclosporine (modified) is also used alone or with methotrexate (Rheumatrex) to treat the symptoms of rheumatoid arthritis (arthritis caused by swelling of the lining of the joints) in patients whose symptoms were not relieved by methotrexate alone. Cyclosporine (modified) is also used to treat psoriasis (a skin disease in which red, scaly patches form on some areas of the body) in certain patients who have not been helped by other treatments. Cyclosporine and cyclosporine (modified) are in a class of medications called immunosuppressants. They work by decreasing the activity of the immune system.

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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.