On January 8, 2008, the Medicines and Healthcare products Regulatory Agency (MHRA), the United Kingdom's equivalent to the Saudi Food and Drug Authority (SFDA), issued an advise for Statin users in the latest issue of Drug Safety Update newsletter.

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.

Simvastatin and atorvastatin: interactions

Many important interactions for simvastatin (Zocor) and atorvastatin (Lipitor) 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 gives important dose restrictions for atorvastatin and simvastatin when used in combination with other drugs. Both drugs interact with grapefruit juice.

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.

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