Diltiazem with Simvastatin Interaction Details

Brand Names Associated with Diltiazem

Brand Names Associated with Simvastatin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 13, 2023

Interaction Effect

Increased simvastatin exposure and an increased risk of myopathy and rhabdomyolysis

Interaction Summary

Concomitant use of diltiazem with simvastatin increases simvastatin exposure and may increase the risk of myopathy or rhabdomyolysis. If coadministration is necessary, do not exceed simvastatin 10 mg daily and diltiazem 240 mg daily. Discontinue use if myopathy is diagnosed or suspected .

Severity

Major

Onset

Rapid

Evidence

Established

How To Manage Interaction

Concomitant use of diltiazem with simvastatin increases simvastatin exposure and may increase the risk of myopathy or rhabdomyolysis. If coadministration is necessary, do not exceed simvastatin 10 mg daily and diltiazem 240 mg daily. Discontinue use if myopathy is diagnosed or suspected .

Mechanism Of Interaction

Inhibition of CYP3A4-mediated simvastatin metabolism

Literature Reports

A) In a crossover study of 10 healthy volunteers, coadministration of sustained-release (SR) diltiazem 120 mg twice daily for 14 days with a single dose of simvastatin 20 mg resulted in a 5-fold increase in mean simvastatin AUC compared with simvastatin alone. In addition, subjects who had an increased average steady-state exposure of diltiazem had a greater increase in simvastatin exposure. Simulations by computer with diltiazem SR 480 mg daily revealed an 8- to 9-fold mean increase in simvastatin AUC. Conversely, in a randomized, 4-way, crossover study (n=10) concomitant administration of diltiazem SR 120 mg daily for 2 weeks with pravastatin 20 mg resulted in no significant change in pravastatin AUC or Cmax. Diltiazem plasma concentrations were not significantly changed when coadministered with pravastatin .

B) Simvastatin AUC increased up to 5-fold with coadministration of simvastatin and diltiazem in a pharmacokinetic study. Subjects received diltiazem 120 mg twice daily for 10 days and on day 10 a single, 80-mg dose of simvastatin was administered. The mean ratio (with diltiazem/without diltiazem) of simvastatin was 3.1 for AUC and 2.88 for Cmax. The corresponding ratios for simvastatin acid (beta-hydroxyacid of simvastatin) were 2.69 for AUC and 2.69 for Cmax. In a similar study (except the duration of diltiazem was 14 days and the dose of simvastatin was 20 mg), ratios were 4.6 for AUC and 3.6 for Cmax .

C) In a fixed-order, 2-arm study, diltiazem significantly increased the serum concentration of simvastatin when administered concomitantly to 10 healthy adults (5 males and 5 females; mean age of 27 years). In the first arm, participants were administered a single oral dose of simvastatin 20 mg followed by a 2-week washout period between arms 1 and 2. In the second arm, patients were administered a single oral dose of simvastatin after 2 weeks of diltiazem 120 mg twice daily. Following an overnight fast, simvastatin was administered at 8 am and a standard lunch was provided the day of the study. Blood samples were drawn at 0, 1/4, 1/2, 3/4, 1, 11/2, 2, 21/2, 3, 4, 6, 8, 12, and 24 hours after dosing to determine simvastatin serum concentrations. Serum concentrations of diltiazem were determined using blood samples obtained at 0, 1, 4, 8, 12, and 24 hours. Coadministration of diltiazem with simvastatin resulted in a significant increase in the AUC and Cmax by 4.8-fold and 3.6-fold, respectively. Concomitant use of diltiazem and simvastatin significantly increased the simvastatin half-life by 2.3-fold. There was no change in the time to reach Cmax .

D) The combination of simvastatin and diltiazem may result in severe myositis and rhabdomyolysis. One case report described a 75-year-old male who complained of extreme weakness and diffuse muscle pain and who had a history of stable angina pectoris, myocardial infarction, hyperlipidemia, and impaired renal function. The patient was receiving simvastatin 80 mg/day and diltiazem 240 mg daily. Upon admission, his serum creatinine was 8.5 mg/dL (750 mcmol/L) and myoglobin was positive in serum and urine. Simvastatin-induced rhabdomyolysis was diagnosed, and all medications were discontinued. The patient's muscle pain disappeared and concentrations of CPK and transaminases returned to normal after hemodialysis and intensive physiotherapy. The patient, however, remained hemodialysis-dependent. The authors conclude that diltiazem increases the serum concentration of simvastatin resulting in rhabdomyolysis. Close clinical monitoring of patients receiving combination therapy with diltiazem and simvastatin is warranted .

E) Nineteen patients receiving simvastatin and diltiazem experienced a 33.3% decrease in cholesterol levels, compared with 116 patients not receiving diltiazem who had a 24.75% reduction in cholesterol with simvastatin. These results suggest that patients receiving diltiazem may need a lower starting dose of simvastatin, since the synergistic effect on cholesterol reduction may also increase the risk of myopathy . However, only one patient enrolled in the Scandinavian Simvastatin Survival Study experienced myopathy, and she was also receiving diltiazem .

Diltiazem Overview

• Diltiazem is used to treat high blood pressure and to control angina (chest pain). Diltiazem is in a class of medications called calcium-channel blockers. It works by relaxing the blood vessels so the heart does not have to pump as hard. It also increases the supply of blood and oxygen to the heart.

• High blood pressure is a common condition, and when not treated it can cause damage to the brain, heart, blood vessels, kidneys, and other parts of the body. Damage to these organs may cause heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other problems. In addition to taking medication, making lifestyle changes will also help to control your blood pressure. These changes include eating a diet that is low in fat and salt, maintaining a healthy weight, exercising at least 30 minutes most days, not smoking, and using alcohol in moderation.

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.