New MHRA recommendations on simvastatin …

1 ABHB Medicine Management team contact details at September 2012 Page 1 of 2 new mhra recommendations on simvastatin interactions implications for patients taking AMLODIPINE & simvastatin 40mg/day The August 2012 edition of the MHRA s Drug Safety Update (vol 6, issue 1)1 highlights updated contraindications and dose recommendations for simvastatin when used with a number of other medicines. These changes have been driven by concerns over the risks of myopathy and/or rhabdomyolysis at higher plasma concentrations of simvastatin . A full updated listing of all the interactions is provided in table 1 overleaf. Key points to note are that: simvastatin is now contraindicated with ciclosporin, danazol and gemfibrozil The maximum recommended dose for simvastatin in conjunction with amlodipine or diltiazem is now 20 mg/day 2 As amlodipine and simvastatin 40mg/day are widely co prescribed in Gwent the following advice has been issued by ABHB Medicines Management for patients on this combination: 1.

2 Patients should be reviewed opportunistically at their next scheduled appointment. 2. Consider each patient individually taking into account: multiple drug therapy and the possibility of drug interactions, co morbidities, and other patient factors The risk of myopathy is greater in: elderly patients (>65 years); women; patients with renal impairment or hypothyroidism; patients who consume large quantities of alcohol; those with a history of previous muscle problems during treatment with statins or other lipid lowering drugs; or those with family history of muscle disorders. the need to monitor patients for efficacy/adverse effects following a change in therapy. 3. OPTIONS in order of preference: a) Change to an alternative Formulary statin for cost implications see table 2 atorvastatin* 10mg/day (for dose effects on LDL C see table 3) Note The SmPC details an 18% increase in the area under the curve for atorvatstatin (80mg) with amlodipine (10mg); no specific recommendation is made on the pravastatin* does not interact with b) Reduce simvastatin to 20mg/day The interaction with amlodipine will lead to an increase in simvastatin exposure and a likely lipid lowering effect above what would be expected for 20mg/day.

3 OTHER OPTIONS: c) Maintain simvastatin at off label dose of 40mg/day discuss the risks and benefits of this off label option with the Note due to the interaction with amlodipine, exposure to adverse effects is similar to that associated with simvastatin 80mg when given alone. There is some evidence that separating the amlodipine/ simvastatin dosing interval by 4 hours can reduce the maximum plasma concentration of d) Change to an alternative Formulary calcium channel blocker for cost implications see table altering the calcium channel blocker is clinically less desirable particularly where patients are well controlled on amlodipine diltiazem or verapamil are NOT options as the maximum dose of simvastatin is also 20mg/day *Although NICE CG67 (2008) states that for both the primary and secondary prevention of CVD where there are potential drug interactions a lower dose than simvastatin 40mg/day or alternative preparation such as pravastatin may be chosen, CG67 also recommends that therapy should be initiated with a drug with a low acquisition cost (publication of CG67 pre dated the availability of low cost generic atorvastatin).

4 ABHB Medicine Management team contact details at September 2012 Page 2 of 2 Table 1 Drug interactions associated with increased risk of myopathy/rhabdomyolysis: Interacting agents Prescribing recommendations Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors (eg, nelfinavir) Nefazodone Ciclosporin Danazol Gemfibrozil Contraindicated with simvastatin Other fibrates (except fenofibrate) Do not exceed 10 mg simvastatin daily Amiodarone Amlodipine Verapamil Diltiazem Do not exceed 20 mg simvastatin daily Fusidic acid Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered. Grapefruit juice Avoid grapefruit juice when taking simvastatin Table 2 Cost implications: Calcium channel blocker Statin Comparative costs for 28 days treatment (Drug Tariff Sept 2012) Amlodipine 5mg/10mg simvastatin 40mg + simvastatin 20mg + Pravastatin 20mg + Pravastatin 40mg + Atorvastatin 10mg + Atorvastatin 20mg + Amlodipine 5mg/10mg Atorvastatin 40mg + Nifedipine 30mg + Table 3 Absolute reductions (mmol/l) inc.

5 95% CIs and percentage reduction in serum LDL C according to statin and daily dose:7 Statin 10mg/day 20mg/day 40mg/day 80mg/day Atorvastatin ( to ), 37% ( to ), 43% ( to ), 49% ( to ), 55% Pravastatin ( to ), 20% ( to ), 24% ( to ), 29% ( to ), 33% simvastatin ( to ), 27% ( to ), 32% ( to ), 37% ( to ), 42% Note for secondary prevention of CVD NICE advice8 is to consider increasing statin dose if a total cholesterol of < 4 mmol/litre or an LDL cholesterol of < 2 mmol/litre is not attained the use of 4 and 2 is intended to guide treatment rather than be a figure patients are expected to achieve. Related ABHB Guidance: The Use of High Intensity Statins for Acute Coronary Syndrome (ACS) of February 2012 at: ABHB protocol%5 BFeb12% 1 2 simvastatin SmPC 3 ATORVASTATIN SmPC 4 PRAVASTATIN SmPC 5 GMC guidance on off label prescribing #10 6 Park CG, Lee H, Choi JW et al.

6 Int J Clin Pharmacol Ther. 2010 Aug;48(8):497 503. 7 Law MR, Wald NJ, Rudnicka AR. BMJ 2003;326:1427 31. 8