Statins Macrolides

ATORVASTATIN, SIMVASTATIN MACROLIDES Macrolides may t levels of atorvastatin and simvastatin the risk of myopathy t over 10-fold when eiythromycin is co-administered with a statin Macrolides inhibit CYP3A4-mediated metabolism of atorvastatin and simvastatin. Also, erythromycin and clarithromycin inhibit intestinal P-gp, which may t the bioavailability of statins Avoid co-administration of macrolides with atorvastatin or simvastatin (temporarily stop the statin if the patient needs macrolide therapy). Manufacturers also recommend that patients be warned to look for the early signs of rhabdomyolysis when other statins are co-ingested with macrolides... 

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

Oral colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea) in 50% to 80% of patients before relief of the attack. Non-GI adverse effects include neutropenia and axonal neuromyopathy, which may be worsened in patients taking other myopathic drugs (e.g., statins) or in those with renal insufficiency. Colchicine should not be used concurrently with macrolide antibiotics (especially clarithromycin) because reduced biliary excretion may lead to increased plasma colchicine levels and agranulocytosis. 

Simvastastin is a statin and there is an increased risk of myopathy when simvastatin is given with clarithromycin (macrolide). 

The macrolide antibiotic erythromycin together with statins enhances the risk of rhabdomyolysis (SED-13, 1328) (112), as do clarithromycin and azithromycin (113). 

Erythromycin may cause increases in the semm levels of simvastatin. The CSM has advised that this should not be co-prescribed with simvastatin. In the first instance the pharmacist should check local policies for management of hospital acquired chest infections/pneumonia to ascertain first and second line choices. If erythromycin or any macrolide cannot be avoided then a practical way forward may be to avoid taking any dose of simvastatin for the duration of the course of macrolide. In addition a recent Dmg Safety Update from the Medicines and Healthcare Products Regulatory Agency (MHRA, 2008) on statins has highlighted statin dmg interactions and the appropriate actions to take. 

Macrolides can cause drug interactions, through inactivation of liver enzymes, with antiarrhythmic dmgs, anticoagulants, antipsychotic drugs, anxiolytics and antiepileptic drugs. Erythromycin in particular can increase the risk of myopathy if taken in combination with lipid-lowering statins. Such combinations should be avoided. 

In order to reduce the risk of myopathy the CSM in the UK have advised that statins should be used with care in patients who are at increased risk of this adverse effect. Among other risk factors, they mention concomitant use with fibrates, such as gemfibrozil , (p.llOO), and with inhibitors of CYP3A4 such as ciclosporin , (p.l097), macrolides ,(p.ll04), azoles , (p.l093), and protease inhibitors , (p.1108). They also recommend that patients should be made aware of the risks of myopathy and rhabdomyolysis, and asked to promptly report muscle pain, tenderness, or weakness, especially if accompanied by malaise, fever, or dark urine. A 2002 advisory on the use of statins gives some important safety recommendations, which are useful in the context of interactions ... 

Cases of acnte rhabdomyolysis have been reported between lovas-tatin and azithromycin, clarithromycin, or erythromycin and between simvastatin and clarithromycin or roxithromycin. Macrolide antibacterials have also been potentially implicated in cases of rhabdomyolysis with atorvastatin and pravastatin. Pharmacokinetic stndies sn est that the macrolides increase the levels of the statins metabolised by CYP3A4 (namely atorvastatin, Iovastatin and simvastatin). 

To be on the safe side, any patient taking any statin who is given a macrolide (except probably azithromycin) should be warned to be alert for any signs of myopathy (i.e. otherwise unexplained muscle pain, tenderness or weakness or dark coloured urine). If myopathy does occur, the statin should be stopped immediately. See also muscle toxicity , (p.l086), for further guidance on monitoring, and risk factors for muscle toxicity. 

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