Advice on drug interactions with simvastatin and atorvastatin

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

The MHRA issued updated advice in 2012 relating to drug interactions with simvastatin associated with an increased risk of myopathy/rhabdomyolysis. This was based on analysis of clinical trial data, spontaneously reported cases and drug-drug interaction studies. The changes include contraindications to concomitant use or dose adjustments with certain medicines and maximum dose recommendations.

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.

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.

Drug interactions associated with increased risk of myopathy/rhabdomyolysis

Interacting Drug Simvastatin prescribing advice Atorvastatin prescribing advice Ciclosporin* Avoid if possible: consider Danazol temporary suspension of atorvastatin if interacting drug is Gemfibrozil Contraindicated with simvastatin taken for short period Itraconazole

Ketoconazole – suspend simvastatin treatment Itraconazole: do not exceed 40 mg Posaconazole if interacting drug is taken for atorvastatin daily Erythromycin short period or consider changing Erythromycin: a lower dose of Clarithromycin to atorvastatin if the interacting atorvastatin should be considered. Telitromycin drug is required long term and HIV protease can be taken with a reduced dose Clarithromycin: do not exceed 20 mg of atorvastatin – see atorvastatin atorvastatin daily inhibitors (e.g. nelfinavir) prescribing advice Ciclosporin: Do not exceed 10mg Atorvastatin daily Nefazodone Gemfibrozil: Avoid concurrent use. Other fibrates† Do not exceed 10mg simvastatin If used concurrently with daily (except with fenofibrate fenofibrate where fenofibrate where fenofibrate dose should not dose should not exceed 200mg exceed 200mg daily) daily Amiodarone Do not exceed 20mg simvastatin Predicted to increase the risk of Amlodipine daily rhabdomyolysis Verapamil Diltiazem

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Fusidic acid Avoid concomitant use - temporarily discontinued throughout the duration of fusidic acid treatment to ensure clearance of systemic fusidic acid, statin therapy may be reintroduced 7 days after the last dose of systemic fusidic acid Grapefruit juice Avoid grapefruit juice when taking Limit intake of grapefruit juice to simvastatin very small quantities (or avoid altogether) Warfarin / Monitor INR before starting treatment and regularly during treatment, courmarins† especially with dose changes. Statins may affect coumarin anticoagulation and increase the risk of haemorrhagic events. Ezetimibe† The BNF states that ezetimibe potentially increases the risk of rhabdomyolysis when given with statins Severe Anecdotal †Warfarin/courmarins, fibrates, and ezetimibe are important potential interactions to consider for all statins *Ciclosporin interacts with all statins and is contraindicated with rosuvastatin

Advice: Practices may want to run searches to identify patients on:

1. Simvastatin/Atorvastatin (any dose) and contra-indicated drugs. Any patients on simvastatin and any of these drugs should be reviewed for alternative lipid lowering treatment, taking into consideration any dose recommendations of alternative drugs. 2. Simvastatin at doses greater than 20mg and amlodipine, verapamil, amiodarone or diltiazem. a. Simvastatin used for primary prevention (no diabetes mellitus): Consider changing to first line choice of Atorvastatin 20mg or reducing simvastatin dose to 20mg b. Simvastatin used for secondary prevention or diabetes: i. Patient stable – advise patient of interaction and if they are happy to continue, make no change but advise them to report any symptoms such as muscle pains immediately. ii. Patient cholesterol well controlled consider reducing simvastatin dose to 20mg and recheck cholesterol levels after a month iii. Patient cholesterol less well controlled consider switching to atorvastatin 10mg daily and recheck cholesterol after a month, increase atorvastatin dose as required.

It is up to the practice to decide how best to proceed with contacting and reviewing any patients identified. If you would like further advice, please contact a member of the Prescribing and Medicines Management Team.

Information taken from: Drug safety Update Aug 2012 vol 6, issue 1: S1 BNF online. Accessed 28/3/18 Is there an interaction between erythromycin and statins? Medicines Q&A 68.6, April 2016

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