Rhabdomyolysis, statin-associated

Omar MA, Wilson JP (2002) FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother 36 288-295. 

Baycol (cerivastatin) was developed by Bayer A.G. and approved by the FDA for use in the United States in 1997. It is a member of a class of cholesterol-lowering drugs that are commonly referred to as statins . Statins such as Baycol lower cholesterol levels by blocking a specific enzyme in the body that is involved in the synthesis of cholesterol. Although all statins have been associated with very rare reports of rhabdomyolysis, a muscle disorder, cases of fatal rhabdomyolysis in association with the use of Baycol have been reported significantly more frequently than for other approved statins. On 8 August 2001, Bayer announced that it was voluntarily withdrawing Baycol from the US market because of reports of sometimes fatal rhabdomyolysis. 

In a review of the FDA spontaneous reports of statin-associated rhabdomyolysis covering the period November 1997 to March 2000, an azole antifungal was potentially implicated in 2 cases of rhabdomyolysis involving atorvastatin. ... 

Pravastatin. The clinical relevance of the modest changes in pravastatin levels with different azole antifungals seems likely to be small, and a clinically significant interaction would not be expected. Note that in a review of the FDA spontaneous reports of statin-associated rhabdomyolysis for the period November 1997 to March 2000, azole antifungals were not identified as a potentially interacting drug in any of the reports for pravastatin. ... 

There are at least 5 documented cases of rhabdomyolysis, one of which was fatal, " in patients given eielosporin and simvastatin. Another report describes a case of rhabdomyolysis when clopidogrel was added to treatment with eielosporin and simvastatin. In a review of the FDA spontaneous reports of statin-associated rhabdomyolysis covering the period November 1997 to March 2000, eielosporin was potentially implicated in 31 cases of rhabdomyolysis involving simvastatin. ... 

Dreier JP, Endres M Statin-associated rhabdomyolysis tri ered by grapefruit caisumption. 

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. 

Crestor Astra-Zeneca) and lovastatin + niacin (Advicor Kos Pharmaceutical) — that can also cause rhabdomyolysis remain on the market. Although scientists agree that the other statins "seem to have essentially identical safety profiles and benefif-risk rafios," FDA said the ADRs associated with Baycol "have been reported significantly more frequently than for other approved statins." ... 

Rhabdomyolysis is the destruction of skeletal muscle tissues and may be associated with lipid-regulating drugs such as the fibrates and the statins. The risk of this side-effect is increased in patients with renal impairment and with hypothyroidism. Rhabdomyolysis may also occur with nicotinic acid, the antipsychotic aripiprazole, and the anaesthetic propofol. 

Skeletal muscle effects All statins have been associated with myalgia, myopathy (ie, muscle pain, tenderness, or weakness with creatine phosphokinase [CPK] values above 10 times the ULN), and rhabdomyolysis. Factors that may predispose patients... 

Most drug interactions associated with rhabdomyolysis occur when ciclosporin is combined with simvastatin or lovastatin. It has been suggested that if a statin is to be combined with ciclosporin, pravastatin or fluvastatin should be chosen instead (80). 

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... 

CoA) reductase] are prescribed chronically to the elderly (162). The initial success of statins was impressive and the FDA approved six of them (22-27,Fig. 13.7) (163).Although all approved statins have been associated with a very low incidence of rhabdomyolysis, only one, cerivastatin (27), was withdrawn from the U.S. market because of it (164,165). The ability of statins to reduce the levels of A/3s in vitro and in vivo was reported (85, 86, 166, 167) but at doses exceeding the approved human dosage. A cyclohexylalanine-based statin... 

In this case example, the FDA s SRS + AERS database, through the end of the second quarter of 2005, was data mined to determine the lower 95% confidence interval limit of the EBGM scores (denoted as EB05), a measure of disproportional-ity, for rhabdomyolysis associated with the use of statins. The drugs of interest were atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin. The event of interest was rhabdomyolysis. 

Figures 40.2-40.5 show the frequency and EB05 scores, both total and cumulative by year, of rhabdomyolysis associated with the use of the statins. AEs in the FDA database are codified using the MedDRA dictionary. It is important to note that a single case report may contain more than one preferred term.

Figure 40.2 The number of cases of rhabdomyolysis in the AERS database associated with the statins...

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