FDA Adverse Event Reports on Statin-Associated Rhabdomyolysis

Omar, Mohamed A.; Wilson, James P.

doi:10.1345/aph.1a289

Cited by 330 publications

(181 citation statements)

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“…Statins, especially simvastatin and cerivastatin, are known to cause rhabdomyolysis Omar and Wilson (2002); www.fda.gov/ bbs/topics/answers/ans00876.html Sorivudine/5-fluorouracil (5-FU) interaction, leading to severe or fatal gastrointestinal and bone marrow toxicities. Soruvidine was withdrawn from the market in 1993…”

Section: Drug-drug Interaction Mechanism Of Interactions Referencesmentioning

confidence: 99%

In Vitro Evaluation of Metabolic Drug–Drug Interactions: Concepts and Practice

2007

Drug–Drug Interactions in Pharmaceutical Development

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Section: Drug-drug Interaction Mechanism Of Interactions Referencesmentioning

confidence: 99%

In Vitro Evaluation of Metabolic Drug–Drug Interactions: Concepts and Practice

2007

Drug–Drug Interactions in Pharmaceutical Development

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“…In large clinical trials statin-induced myopathy and rhabdomyolysis have been reported in 0.1-0.5 and 0.02-0.2% of patients, respectively [6][7][8][9]. The mode of action for muscle toxicity is not known, but risk factors for this adverse reaction include high statin dose/serum concentration, female sex, age and drug-drug interactions [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Simvastatin, lovastatin and atorvastatin are all metabolized by cytochrome P450 3A4 (CYP3A4), whereas pravastatin and fluvastatin mainly have other eliminating pathways [13]. Many agents are inhibitors or inducers of CYP3A4, and the general interaction potential of simvastatin, lovastatin and atorvastatin is therefore higher than for other statins [8,10]. Of the CYP3A4 statins, simvastatin and lovastatin are more sensitive than atorvastatin in terms of relative increase in serum concentration during co-administration of CYP3A4 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Co‐medication of statins and CYP3A4 inhibitors before and after introduction of new reimbursement policy

Devold

Molden

Furu

2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • HMG‐CoA reductase inhibitors (statins) are frequently used drugs in the treatment of dyslipidaemia. • Co‐medication with interacting drugs increases the risk of statin‐induced muscular side‐effects. • Simvastatin exhibits particularly high interaction potential due to substantial metabolism via cytochrome P450 3A4 (CYP3A4). WHAT THIS STUDY ADDS • In June 2005, a new reimbursement policy was introduced by the Norwegian Medicines Agency stating that simvastatin should be prescribed as first‐line lipid‐lowering therapy. • Following introduction of the new policy, the number of patients co‐medicated with simvastatin and CYP3A4 inhibitors almost doubled. • A potential consequence is increased incidence of muscular side‐effects in the statin‐treated population. AIMS To assess the prevalence of co‐medication of statins and CYP3A4 inhibitors before and after introduction of a new Norwegian reimbursement policy, which states that all patients should be prescribed simvastatin as first‐line lipid‐lowering therapy. METHODS Data from patients receiving simvastatin, lovastatin, pravastatin, fluvastatin or atorvastatin in 2004 and 2006, including co‐medication of potent CYP3A4 inhibitors, were retrieved from the Norwegian Prescription Database covering the total population of Norway. Key measurements were prevalence of continuous statin use (two or more prescriptions on one statin) and proportions of different statin types among all patients and those co‐medicated with CYP3A4 inhibitors. RESULTS In 2004, 5.9% (n= 272 342) of the Norwegian population received two or more prescriptions on one statin compared with 7.0% (n= 324 267) in 2006. The relative number of simvastatin users increased from 39.7% (n= 112 122) in 2004 to 63.1% (n= 226 672) in 2006. A parallel increase was observed within the subpopulation co‐medicated with statins and CYP3A4 inhibitors, i.e. from 42.9% (n= 7706) in 2004 to 63.6% (n= 13 367) in 2006. For all other statins the number of overall users decreased to a similar extent to those co‐medicated with CYP3A4 inhibitors. CONCLUSIONS In both 2004 and 2006, the choice of statin type did not depend on whether the patient used a CYP3A4 inhibitor or not. Considering the pronounced interaction potential of simvastatin with CYP3A4 inhibitors, a negative influence of the new policy on overall statin safety seems likely.

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“…Our review focused on chronic-use medications known to increase risk for HMG-CoA inhibitor (statin) myopathy. 8,[11][12][13][14][15][16] Patients prescribed short-term, potent CYP3A4 inhibitors were excluded from our review. Patients who receive short-term therapy with potent CYP3A4 inhibitors (e.g., clarithromycin, erythromycin, itraconazole, and ketoconazole) should be counseled to temporarily withhold their statin therapy.…”

Section: Frequency Of Simvastatin Prescriptions With Potentially Intementioning

confidence: 99%

“…8,12,13 Several medications have been identified that increase the risk of myopathy when administered concurrently with statins, primarily by decreasing the metabolism of the statin (Figure 2). 8,[14][15][16][17][18] Although these drug-drug interactions are well documented as increasing risk for myopathy, published studies documenting the frequency of prescribing interacting drugs are lacking. Einarson and colleagues 19 studied the extent of drug interactions and health care utilization in patients receiving statins.…”

mentioning

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Frequency of Simvastatin Prescriptions With Potentially Interacting Medications in a Veterans Affairs Health Care System

Petropoulos¹,

Bello-Quintero²

2004

JMCP

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levated low-density lipoprotein (LDL) cholesterol has been identified as a primary risk-reduction target in patients at risk for coronary heart disease (CHD). Numerous epidemiological studies have demonstrated a relationship between elevated LDL and the incidence of CHD. Use of LDL-lowering therapy, including hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), has been shown to significantly reduce risk for major coronary events and coronary deaths. Statins are recommended as standard treatment for elevated LDL and are widely used in clinical practice. 1 Results from clinical trials with statins show a decrease in CHD and total mortality, revascularization procedures, and stroke. 2-6 A meta-analysis demonstrates a decrease of 31% in major coronary events and 21% in total mortality with use of statins compared with placebo. 7 Statins are generally well tolerated, with elevated liver enzymes and myopathy reported as the most common adverse effects. 8,9 Myopathy is a general term for muscle disease and includes myalgia, myositis, and rhabdomyolysis ( Figure 1). The prevalence of statin rhabdomyolysis is rare. A review of adverse drug events reported to the U.S. Food and Drug Administration (FDA) showed an overall reporting rate of 0.15 cases of fatal rhabdomyolysis per 1 million statin prescriptions. 10 However, the true incidence of statin rhabdomyolysis is unknown because of the underreporting of adverse drug reactions during the postmarketing period of medications. All statins seem to have a potential for causing rhabdomyolysis. The risk of myopathy is dose related and increases with statin serum concentration. 9,11 Most myopathy associated with statins occurs in patients of older age, small body frame, multisystem disease (including chronic renal insufficiency), multiple medications, perioperative periods, or specific drug-drug interactions. 8,12,13 Several medications have been identified that increase the risk of myopathy when administered concurrently with statins, primarily by decreasing the metabolism of the statin (Figure 2). 8,[14][15][16][17][18] Although these drug-drug interactions are well documented as increasing risk for myopathy, published studies documenting the frequency of prescribing interacting drugs are lacking. Einarson and colleagues 19 studied the extent of drug interactions and health care utilization in patients receiving statins. However, Einarson focused on concomitant drugs whose levels increased from the statin therapy and short-term concomitant therapy, which could increase statin serum concentrations.The primary objective of this review is to quantify the proportion of patients in a primary care setting on simvastatin, the ABSTRACT OBJECTIVE: The primary objective of this review is to quantify the proportion of patients on simvastatin, an HMG-CoA reductase inhibitor (commonly known as statin), who received concurrent prescriptions for potentially interacting c...

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FDA Adverse Event Reports on Statin-Associated Rhabdomyolysis

Abstract: Compared with the other statins, simvastatin and cerivastatin were implicated in a relatively higher number of reports. Because of the various limitations of a spontaneous reporting-system database, caution is urged when interpreting the relative number of cases reported.

Cited by 330 publications

References 21 publications

In Vitro Evaluation of Metabolic Drug–Drug Interactions: Concepts and Practice

In Vitro Evaluation of Metabolic Drug–Drug Interactions: Concepts and Practice

Co‐medication of statins and CYP3A4 inhibitors before and after introduction of new reimbursement policy

Frequency of Simvastatin Prescriptions With Potentially Interacting Medications in a Veterans Affairs Health Care System

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