What is the interaction between amlodipine and simvastatin?

From the Guidelines

Amlodipine and simvastatin should be used with caution, with a recommended maximum dose of simvastatin at 20 mg daily when coadministered with amlodipine, due to the potential for increased risk of muscle-related side effects. This recommendation is based on the study by Wiggins et al 1, which provides guidance on the management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease.

Key Considerations

• The combination of amlodipine with simvastatin may lead to increased exposure to simvastatin, as amlodipine can inhibit the CYP3A4 enzyme responsible for simvastatin metabolism 1.
• Patients on this combination therapy should be closely monitored for signs of muscle toxicity, including myopathy and rhabdomyolysis, particularly during the initial months of treatment or after dose adjustments.
• Alternative statins that are less dependent on CYP3A4 metabolism, such as pravastatin or rosuvastatin, may be considered if higher doses of statins are required while the patient is on amlodipine therapy.

Clinical Implications

• Clinicians should exercise caution when prescribing simvastatin with amlodipine, especially in patients of Asian descent, due to potential ethnic variations in drug metabolism 1.
• The dose of simvastatin should not exceed 20 mg daily when used with amlodipine, as recommended by the American Heart Association's scientific statement on managing drug-drug interactions with statins and select cardiovascular agents 1.

From the FDA Drug Label

Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12. 3)] . Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone [see Drug Interactions (7. 2)] . Simvastatin dosage modifications are recommended for patients taking ... amlodipine [see DOSAGE AND ADMINISTRATION (2. 5)].

The interaction between amlodipine and simvastatin is that co-administration increases the systemic exposure of simvastatin. To minimize the risk of myopathy and rhabdomyolysis, it is recommended to limit the dose of simvastatin to 20 mg daily when co-administered with amlodipine 2 2.

From the Research

Interaction between Amlodipine and Simvastatin

• The interaction between amlodipine and simvastatin has been studied in several clinical trials, with results indicating that simultaneous administration of the two drugs can increase simvastatin bioavailability 3, 4.
• However, it is unclear whether this increase in bioavailability is associated with a higher risk of adverse drug events, such as myopathy or rhabdomyolysis 3.
• One study found that the combination of amlodipine and simvastatin did not increase the risk of muscular discomfort compared to control groups 5.
• Another study developed a pharmacokinetic interaction model for co-administration of simvastatin and amlodipine, which yielded a 46% increase in simvastatin bioavailability and a 13% decrease in simvastatin clearance when amlodipine 10 mg was co-administered 4.
• The study also found that the optimal simvastatin dose to minimize the interaction with amlodipine 10 mg was 60% of the usual dose 4.
• A review of the literature on statin-induced myopathy found that individual demographic features, genetic factors, and co-morbidities can increase the risk of myopathy, and that pharmacokinetic interactions with concomitant medications can also play a role 6.
• A study on independent risk factors for simvastatin-related myopathy found that simvastatin dose, ethnicity, sex, age, body mass index, and concomitant use of certain medications were independent predictors of myopathy 7.

Clinical Relevance

• The clinical relevance of the interaction between amlodipine and simvastatin is still a topic of debate, with some studies suggesting that the combination is safe and effective, while others raise concerns about the potential for increased risk of adverse events 3, 5.
• The available evidence suggests that combined treatment with amlodipine and up to 40 mg simvastatin daily may be clinically justifiable, but that patients should be monitored for adverse events and that the simvastatin dose should be reduced or the patient switched to a different statin if myopathy or muscle weakness occur 3.
• Further studies are needed to fully understand the interaction between amlodipine and simvastatin and to determine the optimal management strategy for patients taking these medications together 4, 5.