Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, a key enzyme in the synthesis of cholesterol. These agents have revolutionized the treatment of hypercholesterolemia and atherosclerosis, with over 100 million prescriptions written annually, and nearly $20 billion in annual sales.1,2 Statins have consistently demonstrated at least 30% reductions in cardiovascular clinical endpoints with limited drug-related adverse effects.1
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Some investigators estimate that about 50% of patients who might benefit from statins are not taking them due to fear of rare but serious myopathy associated with their use.1,3,4 Statin-induced myopathy and rhabdomyolysis received significant attention in the press in 2001 when Bayer Pharmaceuticals removed cerivastatin from the market. Rhabdomyolysis and myopathy occurred more often in patients receiving a cerivastatin-fibrate combination and at higher statin doses. At the time of the cerivastatin withdrawal, the FDA had received reports of 31 rhabdomyolysis-related deaths. Overall, more than 100 deaths had been linked to cerivastatin-induced rhabdomyolysis, representing a rate of 16 to 80 times more frequent than other statins.3
The rate of myalgia associated with statins is estimated to be 10–15%, whereas the incidence of rhabdomyolysis is much lower.1 In 2006, Law and Rudnicka systematically evaluated the rates of myopathy and rhabdomyolysis in 20 clinical trials.5 They identified a rhabdomyolysis rate of 3.4 per 100,000 person-years (for all statins except cerivastatin), with a range of 1.6–6.5 per 100,000 person-years. Additionally, the incidence of statin-induced rhabdomyolysis was higher with lovastatin, simvastatin, or atorvastatin (4.2 per 100,000 person-years), with a 10% case fatality rate. Law and Rudnicka also reported an incidence of myopathy of 11 per 100,000 person-years. Epidemiological studies have shown that rhabdomyolysis is about 12 times more common when statins are combined with fibrates.4 Fibrate monotherapy can also cause these reactions.4 A few cases of ezetimibe-related myopathy have also been reported.6
Warnings and Label Changes
In September, a Dear Healthcare Professional letter was issued by Biogen IDEC/Genentech regarding revisions to the prescribing information for rituximab (Rituxan) regarding a case of progressive multifocal leukoencephalopathy (PML).19 The patient received rituximab in a long-term safety study and developed JC virus infection with resultant PML. The patient died 18 months after receiving the last rituximab dose. Healthcare professionals treating patients with rituximab should consider PML in any patient presenting with new onset neurologic symptoms. In these cases, consultation with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated. The warnings and precautions sections of the prescribing information as well as the boxed warning for rituximab have been updated.20
On September 4, the FDA announced that the manufacturers of all TNF-α blockers must strengthen existing warnings in the product labeling regarding development of invasive fungal and other opportunistic infections.21 At least 12 patients who developed invasive fungal infections while receiving anti-TNF agents have died. Medication Guides are now also required upon medication dispensing.22 It has come to the attention of the FDA that healthcare professionals are not reliably identifying cases of histoplasmosis and other invasive fungal infections, leading to treatment delays and deaths. The FDA has reviewed over 240 reports of histoplasmosis, of coccidioidomycosis and blastomycosis in patients on TNF blockers. For patients at risk of histoplasmosis and other invasive fungal infections, clinicians should consider empiric antifungal treatment until the pathogen(s) are identified. When possible, an infectious disease consult should be obtained. As with any serious infection, consider stopping the TNF blocker until the infection has been diagnosed and adequately treated. The Boxed Warning and the Warnings and Precaution of the drug labels were updated and the drug manufacturers were also required to educate prescribers about these risks.
On October 16, the FDA announced a new “boxed warning” regarding life-threatening infections and PML associated with efalizumab (Raptiva, Genentech) treatment.23,24 This decision was based on the FDA’s postmarket surveillance, which identified a case of PML in a 70-year-old who received efalizumab for over four years.25 This patient was not receiving any other immunosuppressants and did not appear immune compromised. Physicians and other healthcare professionals treating patients with efalizumab need to be alert to new onset neurologic symptoms and provide consultation with a neurologist, brain MRI, and lumbar puncture, as clinically indicated.
A clinical advisory on the use and safety of statins standardized the terminology for statin-induced muscle-related symptoms.3 The following definitions were identified:
- Myalgia: muscle ache/weakness without creatine kinase (CK) elevation
- Myopathy: broad term for any muscle symptom or pathology
- Myositis: muscular symptoms with a CK elevation and rhabdomyolysis
- Rhabdomyolysis: muscle symptoms with marked CK elevation > 10 times the upper limit of normal (ULN) with a creatinine elevation and occasional presence of brown urine with urinary myoglobin
The mechanism of statin-induced myopathy has not been determined but is believed to be a class effect.1,7 There are a number of proposed mechanisms mostly involving a deficiency of one of the main synthetic products of the HMG-CoA reductase pathway. These mechanisms include impaired cholesterol synthesis with secondary abnormal myocyte membrane behavior; impaired synthesis of the compounds in the cholesterol synthesis pathway, including mevalonate and ubiquinone (coenzyme Q10 or CoQ10); or abnormalities in prenylated protein causing altered intracellular messaging.7 Although statin-induced myopathy is usually considered a noninflammatory or toxic myopathy, experimental evidence also suggests the contribution of an autoimmune reaction.7
Clinical Presentation and Drug Characteristics
Patients may present with mild fatigue to fulminant rhabdomyolysis requiring hospitalization. The most common symptoms are myalgia, weakness, low back and proximal muscle pain or generalized body aches, and/or dyspnea.4 Fatigue and muscle pain are often the most common chief complaint for statin-induced rhabdomyolysis, as are a subacute progression of low back pain and proximal muscle pain over the ensuing weeks.1,4 A high index of suspicion is necessary for any patient presenting with an elevated CK. The time of statin use before the development of rhabdomyolysis can range from one week to four years, the average being about six months to one year.1,4 This timeframe is shortened when a statin is combined with a fibrate, with an average onset of 32 days.4
Statin pharmacodynamics and pharmacokinetics may play a role in the incidence of myopathy.1,7,8 Lovastatin, simvastatin, and atorvastatin are predominantly metabolized by the hepatic microsomal cytochrome (CYP) 450 3A4 system (simvastatin also has some CYP 3A5 metabolism). Both rosuvastatin and fluvastatin are also metabolized via the CYP450 2C9 system, with fluvastatin having some involvement of CYP 3A4 activity. Pravastatin undergoes sulfation and is hydrophilic lending to a lower risk of myopathy.1,7,8 Concurrent administration of a statin with other drugs metabolized by the same CYP450 isozyme leads to higher statin levels and a greater risk of myopathy.1,9 Many drugs which are substrates for the CYP3A4 isozyme and therefore many potential interactions can occur. Drugs with interactions include the following: fibrates (gemfibrozil > fenofibrate), nicotinic acid, cyclosporine, tacrolimus, azoles, macrolides (erythromycin, clarithromycin), protease inhibitors, verapamil, amiodarone, warfarin, fluoxetine, and diazepam.1,7,9 These agents should be used cautiously along with statins.
Because pravastatin and rosuvastatin are more hydrophilic than other statins, they are thought to have lower myopathy risks, but still cause myopathy.1,4,7,10 Since rosuvastatin is a relatively new agent, there are limited data on it.7 The choice of a statin may be more important in patients with moderate to severe renal dysfunction, since this is also a risk factor for myopathy. Both atorvastatin and fluvastatin have minimal renal excretion.1 Other risk factors for statin myopathy include excessive alcohol consumption, cocaine use, strenuous exercise, grapefruit juice ingestion (>1 quart/day), age over 80 years, hypertension, diabeties, a low body mass index, hypothyroidism, hypertriglyceridemia, hepatic disease, genetic polymorphisms of CYP450 isozymes, multisystem disease, among others.1,4,9 Certain genetic determinants may be associated with statin-associated myopathy risk.9,11
In February 2008, a Biological Product License Application (BLA) was submitted to the U.S. Food and Drug Administration (FDA) for the pegylated anti–tumor necrosis factor (TNF)-α monoclonal antibody (MAb), certolizumab pegol (Cimzia), for treating rheumatoid arthritis (RA).12 In April 2008, the agent received FDA approval for treating adults with moderate to severe Crohn’s disease.13 UCB has commenced efforts to develop additional rheumatology indications for certolizumab pegol.14 A pooled safety analysis from the certolizumab studies noted a low incidence of injection site pain and therapy discontinuations due to adverse drug reactions. Common side effects were headache, nasopharyngitis, and upper respiratory infections. A drug application for RA was accepted for review in both Canada and Europe in early 2008.15
On June 27, Centocor submitted a BLA for golimumab to treat adults with active RA, psoriatic arthritis, and ankylosing spondylitis. Golimumab is administered as a monthly SC injection. An IV infusion therapy is also being investigated. Additionally, an application was submitted in Europe for the same indications.16
The FDA has sent a complete response letter to Roche regarding their BLA application for IV tocilizumab (Actemra), submitted to treat adult patients with moderate to severely active RA.17 Five trials involving more than 4,000 patients have been conducted, with one still ongoing. In the completed Phase 3 trials, primary endpoints have been met.18
Monitoring and Management
Other than avoiding use of a statin, there are no known therapies to prevent statin-induced myopathy.1,3 CoQ10 supplementation lacks strong scientific support for improving statin-induced myopathy and therefore is not widely recommended.1,2
Routine CK monitoring is not recommended, but baseline CK level may be obtained prior to commencing statin therapy in high-risk patients, or those already on agents known to cause myopathy.1,7 Symptoms of myalgia should be monitored during statin therapy with an attempt to use the lowest dose.1 Consider obtaining a CK level in patients with muscle-related symptoms. Discontinue the statin if a patient has a CK level > 10 X ULN with muscle soreness, tenderness, or pain. Evaluate muscle symptoms six to 12 weeks after starting therapy and at each follow-up appointment.3
The role of other causes of myopathy (e.g., hypothyroidism, trauma, seizures, infection, drug abuse, dermatomyositis, strenuous activity) should be ruled out. A thyroid-stimulating hormone level and a careful neurologic examination should be obtained, as well as a lipid panel.1,4,11 The use of other medications and herbal therapies should also be ascertained. If specific rheumatologic disorders are suspected, more specific tests should be ordered (e.g., ESR, ANA, CRP, anti-Jo antibody).4 Both myalgia and arthralgia are reversible upon drug discontinuation, usually within two to three weeks.8 Remember to also follow liver enzymes in these patients, obtaining them initially and then approximately every 12 weeks thereafter, then annually or more frequently if needed.3
In patients who report intolerable myalgia regardless of CK levels, discontinue the statin. A rechallenge with that or another statin may be attempted. In patients with moderate to severe CK elevations or rhabdomyolysis, the statin should be discontinued. Use of a lower-dose hydrophilic statin is still considered risky.4 Patients with clinically significant rhabdomyolysis need to be hospitalized for intravenous (IV) hydration and urine alkalinization.1 Many patients intolerant of statins will be intolerant of ezetimibe.1,4 Bile acid sequestrants and resins may be the safest choice for these to lower cholesterol.1,4
Michele Kaufman is a freelance medical writer based in New York City.
- Harper CR, Jacobson TA. The broad spectrum of statin myopathy: From myalgia to rhabdomyolysis. Curr Opin Lipidol. 2007; 18:401-408.
- Koumis T, Nathan JP, Rosenberg JM, Cicero LA. Strategies for the prevention and treatment of statin-induced myopathy: Is there a role for ubiquinone supplementation. Am J Health-Syst Pharm. 2004; 61:515-519.
- Pasternak RC, Smith C Jr, Bairney-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Stroke. 2002;33:2337-2341.
- Antons KA, Williams CD, Baker SK, Phillips PS. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med. 2006;119:400-409.
- Law M, Rudnicka AR. Statin Safety: A systematic review. Am J Cardiol. 2006;97(Suppl):52C-60C.
- Slim H, Thompson PD. Ezetimibe-related myopathy: A Systematic review. J Clin Lipidol. 2008;2:328-334.
- Christopher-Stine L. Stain myopathy: An update. Curr Opin Rhematol. 2006;16:647-653.
- Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle – Are all statins the same? Drug Safety. 2002;25:649-663.
- Klopstock T. Drug-induced myopathies. Curr Opin Neurol. 2008;21:590-595.
- McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97(suppl):89C-94C.
- Link E for the SEARCH Collaborative Group. SCLO1B1 variants and statin-induced myopathy – A genomewide study. N Engl J Med. 2008;359:789-799.
- UCB files for R.: www.ucb-group.com/news/3019.asp. Last accessed October 20, 2008.
- FDA approves Cimzia to treat Crohn’s disease. www.fda.gov/bbs/topics/NEWS/2008/NEW01821.html. Last accessed October 20, 2008.
- EULAR RAPID results: www.medicalnewstoday.com/articles/111632.php Last accessed October 20, 2008.
- Additional RA indications/RA in Europe: http://hugin.info/133973/R/1239755/265632.pdf Last accessed October 20, 2008.
- BLA submitted for Golimumab. www.drugs.com/nda/golimumab_080627.html. Last accessed October 20, 2008.
- Drug Watch. Adult and juvenile rheumatoid arthritis drugs in development. Formulary. 2008;43:260.
- FDA issues complete response letter to Roche for ACTEMRA (tocilizumab) biologics license application. www.rocheusa.com/newsroom/current/2008/pr2008091801.html. Last accessed November 4, 2008.
- Important drug warning new safety information. www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf. Last accessed October 20, 2008.
- Prescribing information. www.fda.gov/medwatch/safety/2008/Rituxan_PI.pdf. Last accessed October 20, 2008.
- FDA: manufacturers of TNF-blocker drugs must highlight risk of fungal infections. www.fda.gov/bbs/topics/NEWS/2008/NEW01879.html. Last accessed October 20, 2008.
- Information for healthcare professionals Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab) www.fda.gov/cder/drug/InfoSheets/HCP/TNF_blockersHCP.htm. Last accessed October 20, 2008.
- FDA approves updated labeling for psoriasis drug Raptiva. www.fda.gov/bbs/topics/NEWS/2008/NEW01905.html. Last accessed October 21, 2008.
- Prescribing information. www.gene.com/gene/products/information/pdf/raptiva-prescribing.pdf. Last accessed October 21, 2008.
- Important safety information. www.gene.com/gene/products/information/pdf/raptiva_dhcp.pdf. Last Accessed accessed October 21, 2008.