Myopathy, with statins

Ballantyne CM, Corsini A, Davidson MH, et al. Risk of myopathy with statin therapy in high-risk patients. Arch. Intern. Med., 2003, 163, 553-564. 

All drugs in this group inhibit liver enzymes and cause interactions with many other drugs. In particular, they increase the risk of myopathy with statins (Chapter 4). 

A case report describes a 48-year-old man taking ezetimibe 10 mg daily, and rosuvastatin 5 mg on alternate days, who developed rhabdomyolysis within 3 weeks of starting to drink 200 mL of pomegranate juice twice weekly. Although the patient had been stable taking ezetimibe with rosuvastatin for 15 months he had a history of myopathy with statins and had an elevated creatine kinase before statin treatment had started. ... 

Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JDScripps Mercy Clinical Research Center. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002 137(7) 581-5. 

The rate of myopathy with a statin alone in the general population is 0.1-0.5% and 0.2-2.5% with combination therapy. Rhabdomyolysis is very rare at 0.02-0.04%. However, the latter carries a significant morbidity and mortality. In a review of Food and Drug Administration (FDA) reports published in 2002, there were 38 deaths in 631 patients (6.3%) [31]. Pravastatin and fluvastatin have been less frequently implicated in fatal cases of rhabdomyolysis [31]. It is postulated that the more hepatoselective hydrophilic statins, such as pravastatin, are less likely to penetrate muscle cells than are lipophilic statins, and therefore represent a lower risk for myopathy, particularly in the event of an interacting drug increasing their blood levels to within the toxic range [26, 32]. 

Niacin Use with statins Increased risk myopathy, myositis ... 

The British National Formulary (BNF) recommends that fibrates or nicotinic acid should not be combined with statins because of the potential for myopathy and rhabdomyolysis with this combination [54]. This is widely discussed in the medical literature. Numerous deaths have been reported and the high mortality associated with concurrent use of cerivastatin and gemfibrozil was partly instrumental in the decision to withdraw cerivastatin from the market in 2001 [34]. It appears that the high mortality in patients using concurrent gemfibrozil and cerivastatin was due to interactions at the level of glucuronidation, CYP2C8 inhibition and OATP inhibition [17, 55]. 

AMIODARONE SIMVASTATIN t risk of myopathy with high doses (>40 mg daily) of simvastatin Uncertain amiodarone inhibits intestinal P-gp, which may t the bioavailability of statins Avoid >20 mg daily doses of simvastatin in patients taking amiodarone if higher doses are required, switch to an alternative statin... 

FIBRATES STATINS Gemfibrozil may t atorvastatin, rosuvastatin and simvastatin levels (risk of myopathy with simvastatin) Uncertain Avoid co-administration of simvastatin and gemfibrozil. When using other statins, warn patients to watch for the features of myopathy... 

The increased risk of myopathy observed during concomitant treatment with statins and fibrates may be partly pharmacokinetic in origin. In interactions between fibrates and statins there may be differences between... 

Isackson PJ, Ochs-Balcom HM, Ma C, Harley JB, Peltier W, Tamopolsky M, Sripathi N, Wortmann RL, Simmons Z, Wilson JD, Smith SA, Barboi A, Fine E, Baer A, Baker S, Kaufman K, Cobb B, Kilpatrick JR, Vladutiu GD (2011) Association of common variants in the human eyes shut ortholog (EYS) with statin-induced myopathy evidence for additional functions of EYS. Muscle Nerve 44(4) 531-538... 

Ezetimibe is used for secondary prevention against established atherosclerotic CVD to achieve an optimal atherogenic cholesterol level in patients with intolerance to high-doses of statins. It can further be used in combination with statins to achieve lower LDL-C levels in very-high-risk patients [59]. Ezetimibe inhibits the Niemann-Pick Cl-Like 1 (NPClLl)-dependent intestinal cholesterol absorption in the apical brush border membrane of jejuna enterocytes [14], and thus it only moderately lowers LDL-C (12-25 %) [60]. Meanwhile, common adverse effects associated with ezetimibe therapy include gastrointestinal disturbances, while infrequent adverse effects such as rash, angioedema, anaphylaxis, hepatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis may occur [46]. 

Adverse effects are bradycardia, headache, flushing, palpitations and ankle oedema. There is an increased risk of myopathy if diltiazem is used together with statins (see page 77). 

Because concurrent use of niacin and a statin can cause myopathy, the statin should be administered at no more than 25% of its maximal dose. Patients also should be instructed to discontinue therapy if flu-like muscle aches occur. Routine measurement of creatine kinase (CK) in patients taking niacin and statins does not assnre that severe myopathy will be detected before onset of symptoms, as patients have developed myopathy after several years of concomitant use of niacin with a statin. 

---