Drug Safety Update

Statins: interactions, and updated advice for atorvastatin

Detailed recommendations for dose restrictions when used with some other drugs as interactions may increase the risk of adverse effects, or reduce the effectiveness of statin treatment.

Article date: January 2008

Statins are effective and widely used treatments for the prevention of cardiovascular events. Consideration of possible drug interactions is important because comorbidity is common in statin users. Interactions may increase the risk of serious adverse reactions (such as myopathy or rhabdomyolysis) or, in some cases, reduce the effectiveness of treatment.

This article summarises the most important and common interactions with statins. It includes updated advice for atorvastatin (Lipitor), particularly potential interactions with clarithromycin, itraconazole, and ciclosporin. Healthcare professionals should refer to Summaries of Product Characteristics for full details of interactions.

Simvastatin and atorvastatin: interactions

Many important interactions for simvastatin (Zocor) and atorvastatin relate to drugs that inhibit or induce metabolism via the cytochrome P450 (CYP3A4) enzyme, or that affect transport proteins.

Starting dose

If co-prescription with a drug that increases systemic exposure to statins is unavoidable, it is particularly important to start on the lowest statin dose. For atorvastatin and simvastatin the starting dose is 10 mg daily.

Maintenance doses

The table below gives important dose restrictions for atorvastatin and simvastatin when used in combination with other drugs. Both drugs interact with grapefruit juice.

Interacting drug or food   Simvastatin prescribing advice   Atorvastatin prescribing advice
Potent CYP3A4 inhibitors, including itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, and HIV protease inhibitors   All are contraindicated with simvastatin   Avoid if possible: consider temporary suspension of atorvastatin if interacting drug is taken for short period; Itraconazole: do not exceed 40 mg atorvastatin daily; Clarithromycin: do not exceed 20 mg atorvastatin daily; HIV protease inhibitors: monitor lipid levels to ensure lowest necessary dose of atorvastatin is used
Ciclosporin*   Do not exceed 10 mg simvastatin daily   Do not exceed 10 mg atorvastatin daily
Danazol   Do not exceed 10 mg simvastatin daily   No restriction in Summary of Product Characteristics
Verapamil, amiodarone   Do not exceed 20 mg simvastatin daily   Monitor lipid levels to ensure lowest necessary dose of atorvastatin is used
Diltiazem   Do not exceed 40 mg simvastatin daily   Monitor lipid levels to ensure lowest necessary dose of atorvastatin is used
Grapefruit juice   Avoid grapefruit juice   Limit intake of grapefruit juice to very small quantities (or avoid altogether)
Warfarin/courmarins†   Monitor INR before starting treatment and regularly during treatment, especially with dose changes   Monitor INR before starting treatment and regularly during treatment, especially with dose changes
Fibrates†   Increased risk of myopathy when used with fibrates; do not exceed 10 mg simvastatin daily (except with fenofibrate); gemfibrozil increases systemic exposure to simvastatin   Increased risk of myopathy when used with fibrates; gemfibrozil increases systemic exposure to atorvastatin
Ezetimibe†   Additive risk of myopathy cannot be ruled out   Additive risk of myopathy cannot be ruled out

*Ciclosporin interacts with all statins and is contraindicated with rosuvastatin—see below.

† Warfarin/courmarins, fibrates, and ezetimibe are important potential interactions to consider for all statins—see below.

Medicines that reduce plasma concentrations of simvastatin and atorvastatin

Inducers of CYP3A4 (eg, efavirenz, rifampicin, St John’s wort) may reduce plasma concentrations of simvastatin and atorvastatin. Colestipol reduces plasma levels of atorvastatin, but lipid-lowering effects may be greater than when either drug is given alone.

Important interactions to consider with all statins

Warfarin/courmarins

Statins may affect coumarin anticoagulation and increase the risk of haemorrhagic events. Patients who are receiving warfarin should have INR monitoring before starting statins and regularly throughout treatment, especially with statin dose changes. Caution is particularly necessary with fluvastatin (Lescol), which is metabolised by CYP2C9. However, for pravastatin (Lipostat), which is not metabolised by cytochrome P450, warfarin interaction is less of a concern.

Fibrates

The use of fibrates alone is occasionally associated with myopathy; use with statins may increase this risk. Furthermore, gemfibrozil increases systemic exposure to simvastatin, atorvastatin, and rosuvastatin (Crestor). Careful monitoring is therefore needed, and maximum daily dose of simvastatin is 10 mg daily when used with fibrates (except fenofibrate). For rosuvastatin, start with 5 mg and do not exceed 20 mg during use with fibrates.

Ezetimibe

Ezetimibe has no pharmacokinetic interaction with statins. However, ezetimibe alone is associated with a risk of myopathy and an additive risk with statins cannot be ruled out.

Other important interactions with fluvastatin, pravastatin, and rosuvastatin

Fluvastatin

Caution is needed with ciclosporin, fluconazole, phenytoin, and glibenclamide—see product information for details.

Rosuvastatin

Rosuvastatin is not associated with cytochrome P450 interactions. Ciclosporin is contraindicated with rosuvastatin (Crestor). HIV protease inhibitors strongly increase exposure to rosuvastatin (through an unknown mechanism) and are not recommended for combination use. Antacids reduce rosuvastatin plasma levels.

Pravastatin

Pravastatin is not associated with cytochrome P450 interactions. Caution is needed with ciclosporin, erythromycin, and clarithromycin. Cholestyramine and colestipol decrease plasma levels of pravastatin.

Further information

Letter sent to healthcare professionals for atorvastatin in December 2007Letter sent to healthcare professionals for atorvastatin in December 2007

Prescribing advice for fibrates: Drug Safety Update November 2007; Vol 1, Issue 4: 2

 

Article citation: Drug Safety Update January 2008; Vol 1, Issue 6: 2

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