Rhabdomyolysis with statins

One of the ways blood statin levels can become elevated is if the interacting drug inhibits the metabolism of the statin, with the result that it is cleared from the body more slowly and it begins to accumulate (see pharmacokinetics below). The overall risk of myopathy with the statins is quite low and commonly quoted as 0.5%, although one report puts the incidence of mild myopathies with a statin alone as up to 7%. The incidence seems to rise markedly if other drugs are being taken concurrently. Thus a literature review of published reports for the period 1985 to 2000 found 15 cases of rhabdomyolysis with statins alone, but 54 cases when combined with other drugs. Other patient-related risk factors for myopathy in-clude ... 

Rhabdomyolysis is disintegration and death of muscle cells (myocytes). It is an important but rare side effect of treatment with statins. 

Statins Yes Reduces LDL Ila Ik with niacin Myositis, liver dysfunction, rhabdomyolysis with cerivastatin... 

Avoid use with statins, since the combination may increases risk of myositis and rhabdomyolysis. 

Post-2000 Renal rhabdomyolysis with the statin, cerivastin cardio-toxicity with the COX-2 inhibitor, rofecoxib and liver damage with the selective serotonin and norepinephrine reuptake inhibitor, atomoxetine. 

While rhabdomyolysis from statins is rare, the risk is increased when they are used in combination with agents that share similar metabolic pathways. Atorvastatin is metabolized by CYP3A4, which is inhibited by diltiazem. 

Rhabdomyolysis is a problem with several lipid-lowering drugs (SEDA-13, 1325 SEDA-13, 1328 SEDA-13, 1330 SEDA-19, 409), especially when they are used in combination (37). In individuals with pre-existing renal insufficiency this can lead to an earlier need for chronic dialysis (38). All statins can cause myopathy and rhabdomyolysis, but not all statins are alike. For example, the evidence to date, based on almost 2 decades of experience, points to an extremely low risk of myopathy and rhabdomyolysis with lovastatin, and lovastatin 20 mg tablets are being considered for non-prescription availability in several countries (39). Furthermore, muscle adverse effects do not necessarily occur after a change from one statin to another (40). Interactions between various hypolipidemic drugs and other drugs also sometimes cause rhabdomyolysis (SEDA-18, 426). For instance, itraconazole markedly increases plasma concentrations of lovastatin, and in one subject plasma creatine kinase was increased 10-fold within 24 hours of administration of this combination (41). 

Rhabdomyolysis has been attributed to the combination of fusidic acid with statins. 

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

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]. 

HMG-CoA reductase inhibitors (statins) are the most common therapeutic medication used in patients with elevated low-density lipoprotein cholesterol. Significant side effects associated with statins are infrequent. Myalgia and arthralgia are common (1-7%) but frank rhabdomyolysis is... 

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]. 

Among the adverse effects of statins, rhabdomyolysis is considered to be a rare but significant one [30]. Global gene expression analysis of two skeletal muscle cell lines (differentiated rat L6 myo-tubes and a human skeletal muscle cell line) treated with statins... 

Coenzyme Q deficiency is implicated at least in part in the development of many of the side effects of statins, such as myopathies and rhabdomyolysis with renal failure, increased incidence of neoplasia, cataracts, peripheral neuropathies, and also some psychiatric disturbances. Despite this long list, the medical literature describes statins as well tolerated dmgs, and their use in some cases is indiscriminate. Health News (September 2001), a publication of the Massachusetts Medical Society, recently... 

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. ... 

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). 

The risk of rhabdomyolysis when statins are co-administered with another CYP3A4 inhibitor has been reported in a retrospective analysis [23 ]. Pravastatin was not associated with an increased risk whereas simvastatin was. The EIDOS and DoTS descriptions of muscle damage due to statins are shown in Figure 1. 

Drug-drug interactious Statins In a systematic screening of the World Health Organization s adverse drug reactions database, 53 cases of rhabdomyolysis with azithromycin and statins were investigated retrospectively [118 ]. Rhabdomyolysis occurred shortly after initial treatment with azithromycin in 23% of cases. In 11 patients an interaction was suggested. With the exception of one patient, the statins were prescribed at the recommended daily doses. 

A randomised, open-label, controlled trial of daptomycin to treat osteomyelitis associated with prosthetic devices revealed increases in CPK levels in 16% of those treated with 6mg/kg, and 21.7% of those treated with 8mg/kg. Daptomycin was given for between 6 and 8 weeks [148 ]. Similarly, a retrospective analysis of the use of daptomycin (4-6mg/kg) for complicated skin and soft-tissue infections with or without associated bacteraemia revealed a favourable safety profile. The most common adverse event reported was elevation of blood CPK [149 ]. A similar retrospective analysis investigating the safety of prolonged (>14days) daptomycin in 2263 patients reported increased blood CPK, nausea, diarrhoea, vomiting, thrombocytopenia, rash, pyrexia and increased blood creatinine at a rate of between 0.1% and 2.2% [150 ]. In contrast to this, a retrospective study assessed the safety of co-administration of daptomycin with statins. There was no significant increase in rhabdomyolysis with the combination [ISl ]. 

Gemfibrozil 600 mg tablets 1200 mg/day in two doses, 30 minutes before meals abdominal pain, and rash. Increased risk of rhabdomyolysis when given with a statin. Fibric acids are associated with gallstones, myositis, and hepatitis. 

Fibrates are the most effective triglyceride-lowering agents and also raise HDL cholesterol levels. Combination therapy with a fibrate, particularly gemfibrozil, and a statin has been found to increase the risk for myopathy. Of the 31 rhabdomyolysis deaths reported with cerivastatin use, 12 involved concomitant gemfibrozil.25 Therefore, more frequent monitoring, thorough patient education, and consideration of factors that increase the risk as reviewed previously should be considered. 

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