WHO Drug Information Vol. 16, No. 2, 2002
(2002; 91 pages) View the PDF document
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Open this folder and view contentsHerbal Medicines
Open this folder and view contentsCurrent Topics
Open this folder and view contentsGood Clinical Practices
Close this folderSafety Information
View the documentStatins: rhabdomyolysis and myopathy
View the documentTamoxifen and risks of thromboembolic events
View the documentOral contraceptives and risk of cervical cancer
View the documentHIV-associated lipodystrophy syndrome overview
Open this folder and view contentsRegulatory Action
Open this folder and view contentsEssential Medicines
Open this folder and view contentsRecent Publications and Sources of Information
View the documentProposed International Nonproprietary Names: List 87
 

Statins: rhabdomyolysis and myopathy

Statins belong to a class of cholesterol-lowering agents that inhibit the liver enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rhab-domyolysis (1-6).

The statins approved for sale in Canada include atorvastatin (Lipitor®), cerivastatin (Baycol®), fluvastatin (Lescol®), lovastatin (Mevacor®, Apo-Lovastatin®, Gen-Lovastatin®), pravastatin (Pravachol®, Apo-Pravastatin®, Bio Pravastatin®, Lin-Pravastatin®) and simvastatin (Zocor®). In August 2001, Bayer voluntarily suspended the marketing and distribution of Baycol® in Canada (7, 8). The continued scrutiny of postmarketing reports of rhabdomyolysis, including related deaths, has revealed an increased reporting rate of rhabdomy-olysis with Baycol compared to other statins, especially when gemfibrozil is prescribed concurrently (7).

The Canadian Adverse Drug Reaction Monitoring Program (CADRMP) has received reports of rhab-domyolysis or myopathy with all statins approved for sale in Canada (Table 1). In severe cases, rhabdomyolysis can result in kidney failure (8). The statin cases of rhabdomyolysis outlined in Table 1 with which acute renal failure was also reported were: atorvastatin (2 cases), cerivastatin (15), lovastatin (5), pravastatin (1) and simvastatin (2). The reports of rhabdomyolysis with a fatal outcome were: atorvastatin (1), cerivastatin (2) and lovastatin (1).

Table 1. Rhabdomyolysis, myopathy and increased CPK reactions associated with statins as reported to the CADRMP from date marketed in Canada to 24 August 2001*

 

Drug and year marketed in Canada: no. of reports

Reaction

Atorvastatin
1997

Cerivastatin
1998

Fluvastatin
1994

Lovastatin
1988

Pravastatin
1990

Simvastatin
1990

Rhabdomyolysis

10

54

-

12

3

7

Myopathy

32

8

5

24

17

34

CPK increased with myopathy

16

11

1

6

4

6

CPK increased without myopathy

5

6

-

4

6

5

Total no. of reports received

231

121

43

182

123

170

 

CPK = creatine phosphokinase, CADRMP = Canadian Adverse Drug Reaction Monitoring Program.

* These data cannot be used to determine the incidence of adverse drug reactions because neither patient exposure nor the amount of time the drug was on the market has been taken into consideration.

†Each report may contain more than one of these reactions; however, reports were only included in the most significant category.

‡ Myopathy may include muscle symptoms such as myositis, myalgia, muscle ache, muscle weakness, muscle cramp, muscle discomfort.


Various factors may increase the risk of myopathy and rhabdomyolysis with statins. Rhabdomyolysis can occur with all statins when used alone and particularly when combined with other drugs or chemicals that are themselves myotoxic or that elevate the concentrations of the statin to the toxic range (9). Evidence suggests that myopathy is dose-dependent, (9) and it is usually recommended that statin therapy be initiated at lower therapeutic doses (1-6). Combined use with niacin in lipid-lowering doses, with fibric acid derivatives such as bezafibrate, fenofibrate and gemfibrozil, (1-6) or with drugs or foods that inhibit the cytochrome P450 (CYP450) system, particularly CYP3A4, (including but not limited to cyclosporins, macrolide antibiotics, antidepressants such as nefazodone, azole antifungals and grapefruit juice) can potentially increase the toxicity of statins (1,3,5,6,9)

Atorvastatin, cerivastatin, lovastatin and simvastatin are metabolized mainly by CYP3A4 (10). Lovastatin and simvastatin may particularly be affected by the inhibition of first-pass metabolism, which could result in 10- to 20-fold elevations (oral availability increasing from 5% to 100%) in steady-state concentrations with a marked potential for drug toxicity (9). Pravastatin is not metabolized by CYP3A4 to a clinically significant extent (2). Fluvastatin is metabolized mainly by CYP2C9 (4, 10) and would have a different spectrum of interactions than would statins metabolized by CYP3A4 (9). Further information concerning drug interactions may be obtained from the product monograph of each statin (1-6). In addition, caution should be exercised when using statins in patients with impaired renal function (1-6).

The product monograph of each statin has no clear recommendation for biochemical monitoring of muscle effect (creatine phosphokinase [CPK] measurement). In the absence of symptoms, there is no evidence to suggest that routine monitoring of plasma CPK activity is of benefit (10). However, further investigation is required to provide more definitive monitoring guidelines. It was suggested in a recent review article (10) that it is important to measure the baseline CPK level at least once before starting statin therapy.

Patients taking a statin or a fibrate should be made aware of rhabdomyolysis as a potential side effect. They should be advised to report promptly any signs of muscle problems (i.e., unexplained muscle weakness, tenderness or pain, either occurring at rest or exacerbated by exercise) and dark urine, particularly if these symptoms are accompanied by malaise or fever.

Duc Vu, Mano Murty, and Marielle McMorran, Bureau of Licensed Product Assessment, Canada

References

1. Mevacor, lovastatin tablets [product monograph]. Kirkland (QC): Merck Sharp & Dohme Canada. 10 September (1998).

2. Pravachol, pravastatin sodium tablets [product monograph]. Montréal (QC): Bristol-Myers Squibb Canada. 22 February (2000).

3. Zocor, simvastatin tablets [product monograph]. Kirkland (QC): Merck Frosst Canada. 23 August 1999).

4. Lescol, fluvastatin sodium capsules [product monograph]. Dorval (QC): Novartis Pharmaceuticals Canada. 14 February (2001).

5. Lipitor, atorvastatin calcium tablets [product monograph]. Kirkland (QC): Pfizer Canada. 31 May (2001).

6. Baycol, cerivastatin sodium tablets [product monograph]. Etobicoke (ON): Bayer. 27 December (2000).

7. Market withdrawal of Baycol (cerivastatin) [Dear Healthcare Professional letter]. Toronto (ON): Bayer; August 8 2001. http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/advisory/industry/baycol_cerivastatin_e.html.

8. Voluntary withdrawal of Baycol [public advisory]. Ottawa (ON): Health Canada; August 10 2001. http://www.hc-sc.gc.ca/english/protection/warnings/2001/2001_89e.htm.

9. Herman RJ. Drug interactions and the statins. Canadian Medical Association Journal, 161(10):1281-1286 (1999).

10. Baker, S.K., Tarnopolsky, M.A. Statin myopathies: pathophysiologic and clinical perspectives [review]. Clinical Investigastive Medicine, 24(5):258-271 (2001).

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