cerivastatin and Rhabdomyolysis

Topics: Animals; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Pyridines; Rhabdomyolysis; Risk Factors

Rosuvastatin is the first statin approved by the regulatory authorities since the withdrawal of cerivastatin. Although highly efficacious, this new statin has generated considerable controversy regarding its safety. Rosuvastatin was approved for clinical use based on the largest pre-approval database for all statins prior to commercial use. In this database, rosuvastatin had a similar safety profile to other approved statins up to the highest approval dose of 40 mg. As with all statins, there is a marked increase in adverse effects when the dose is titrated from 40 to 80 mg, and rosuvastatin demonstrates a similar dose/toxicity relationship. In the pre-approval data trials on 80 mg, there was a 1.0% (n = 16) incidence of myopathy and 7 patients developed rhabdomyolysis. However the

Topics: Acute Kidney Injury; Adverse Drug Reaction Reporting Systems; Biomarkers; Cholesterol, LDL; Creatine Kinase; Creatine Kinase, MM Form; Drug Approval; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Incidence; Isoenzymes; Kidney Tubules; Muscular Diseases; Product Surveillance, Postmarketing; Proteinuria; Pyridines; Pyrimidines; Rhabdomyolysis; Rosuvastatin Calcium; Sulfonamides

In recent years, US patients have increasingly been the first to receive new medications, some of which are subsequently discovered to have suspected adverse drug reactions (SADRs). As a result, the challenge of early detection has largely shifted to the US postmarketing systems.. To review the association between the use of cerivastatin sodium and the risk of rhabdomyolysis in an effort to illustrate the operation and limitations of the current US postmarketing safety-surveillance system.. For the published literature, we used previous reviews and MEDLINE searches from all years through 2003. For the unpublished literature, we used internal company documents that have become part of the public record during a trial in Nueces County, Texas.. In the published literature, cerivastatin was associated with much larger risks of rhabdomyolysis than other statins. Although only a small percentage of cerivastatin users also took gemfibrozil, approximately half of the case reports of rhabdomyolysis occurred in users of this combination therapy, and a cerivastatin-gemfibrozil interaction was supported by the results of a 3-day pharmacokinetic study. In internal company documents, multiple case reports suggested a drug-drug interaction within approximately 100 days of the launch in 1998; however, the company did not add a contraindication about the concomitant use of cerivastatin and gemfibrozil to the package insert for more than 18 months. Unpublished data available in July 1999 also suggested an increased risk of rhabdomyolysis associated with high doses of cerivastatin monotherapy. In late 1999 and early 2000, company scientists conducted high-quality analyses of the US Food and Drug Administration adverse event reporting system data. These analyses suggested that compared with atorvastatin calcium, cerivastatin monotherapy substantially increased the risk of rhabdomyolysis. To our knowledge, these findings were not disseminated or published. The company continued to conduct safety studies, some of them inadequately designed to assess the risk of rhabdomyolysis, until cerivastatin was removed from the market in August 2001.. Despite limitations of the available data, the asymmetry between the information available to the company and the information available to patients and physicians seems striking. A subjective element is present in the effort to infer whether or not the occurrence of untoward outcomes in users of a particular drug was actually the consequence of the use of that drug, and, under the current system, a pharmaceutical company's appraisal of SADRs may be influenced by economic considerations. Such an appraisal would best be made by an independent group. The US Congress should mandate and provide adequate support for independent reviews and analysis of postmarketing data.

Topics: Adverse Drug Reaction Reporting Systems; Conflict of Interest; Drug Industry; Drug Interactions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Pyridines; Rhabdomyolysis; Risk; United States; United States Food and Drug Administration

The significant age-adjusted decline in cardiovascular mortality that has occurred over the past three decades is multifactorial. However, the advent of statin therapy has markedly facilitated the optimization of dyslipidemia in patients at risk for coronary events. Statin therapy has proven to be effective in reducing morbidity and mortality in large-scale primary and secondary prevention trials. As with all therapies, the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co A) reductase inhibitors is not without clinical risks. Myopathy, albeit uncommon, was one of the earliest clinical problems associated with statin therapy. Recent data from the large-scale statin mega-trials have clarified the quantitative clinical risk-benefit relationship of reductase inhibitors relative to the induction of muscle toxicity. Histopathologic studies have clarified the potential role of statins in the syndrome of myalgias and normal creatine kinase levels. However, the precise mechanism of statin-associated muscle toxicity remains unclear and is potentially related to genetically mediated muscle enzyme defects, drug interactions, intracellular depletion of metabolic intermediates, and intrinsic properties of the statins per se.

Topics: Clinical Trials as Topic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle, Skeletal; Pyridines; Rhabdomyolysis

Because of fatal cases of rhabdomyolysis the HMG-CoA-reductase inhibitor cerivastatin had to be withdrawn from the global market in 2001. The high frequency and severity of cerivastatin-associated rhabdomyolysis caused concerns about the safety of the entire class of HMG-CoA-reductase inhibitors (statins). Still, the frequency of deadly incidents of rhabdomyolysis with cerivastatin was 16 to 80 times higher than with other statins. This seems to be due to a combination of several pharmacokinetic and pharmacodynamic characteristics of cerivastatin. Cerivastatin shows the highest oral bioavailability within its class. Interactions with other drugs like gemfibrocil may cause further elevation of cerivastatin plasma levels, thereby leading to higher frequencies of side effects in peripheral organs. With approximately 1 pM cerivastatin shows the lowest IC50 for inhibition of HMG-CoA-reductase of all statins. The combination of high systemic drug levels and high intrinsic activity potentially leads to apoptosis and energy-depletion of skeletal-muscle cells. Therefore cerivastatin-associated fatal rhabdomyolysis seems to be based on specific pharmacokinetic and pharmacodynamic properties of cerivastatin, and is not a general characteristic of all members of this drug-class. The experiences with cerivastatin support the importance of clinical studies even about well established drugs, and underline the relevance of precise reporting of adverse events by each physician.

Topics: Animals; Anticholesteremic Agents; Biological Availability; Cause of Death; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis; Risk Factors; Survival Analysis

The noted myotoxicity and subsequent withdrawal of cerivastatin from the worldwide market in August 2001 has demonstrated that the safety of statins is not a class effect. The total rhabdomyolysis rate for cerivastatin was 16 - 80 times more frequent than with other statins without providing additional efficacy. Cerivastatin has a pharmacokinetic profile (high potency, bioavailability, lipophilicity and renal excretion) that is different from other statins, which may explain the high myotoxicity rate. The cerivastatin experience has also provided insights into high-risk populations (i.e., the elderly, women, those with renal impairment, co-administration of interacting drugs) that are more prone to statin-induced myopathy. Ultimately, the lessons learned from this experience may significantly improve the safety of statin use in the future.

Topics: Aged; Area Under Curve; Biological Availability; Drug Interactions; Female; Half-Life; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metabolic Clearance Rate; Pyridines; Rhabdomyolysis; Safety

Topics: Aged; Aged, 80 and over; Drug Therapy, Combination; Female; Gemfibrozil; Humans; Male; Middle Aged; Pyridines; Rhabdomyolysis

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are a frequently prescribed class of drugs that are generally well tolerated by most patients. A rare, yet serious side effect associated with these drugs is rhabdomyolysis. Although all HMG-CoA reductase inhibitors can cause this adverse effect, prevalence may differ among specific agents. Over a 16-month period, in three hospitals, 11 patients experienced cerivastatin-induced rhabdomyolysis, but no cases of rhabdomyolysis associated with any other HMG-CoA reductase inhibitors were reported.

Topics: Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle, Skeletal; Pyridines; Rhabdomyolysis

Cerivastatin is the new 3rd-generation of the synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, the 1st drugs of choice for treating hypercholesterolemia. A potent inhibitor of HMG-CoA reductase, it possesses a high affinity for liver tissue and decreases plasma low-density lipoprotein cholesterol at microgram doses. Cerivastatin produces reductions in low-density lipoprotein cholesterol of 31.3% and 36.1% at doses of 0.3 and 0.4 mg/day, respectively It is an uncomplicated agent with regard to its pharmacokinetic profile, low potential for interaction with other drugs, and suitability for use in those with impaired renal function. Most other statins have been implicated in causing rhabdomyolysis, either as monotherapy or in combination with other agents. We report what to our knowledge is the most profound case yet in the literature of rhabdomyolysis in association with cerivastatin-gemfibrozil combination therapy, in regard both to the extreme elevation in serum creatinine kinase and to the patient's near-paralytic weakness.

Topics: Aged; Drug Therapy, Combination; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Pyridines; Rhabdomyolysis; Severity of Illness Index

Topics: Female; Gemfibrozil; Humans; Hypolipidemic Agents; Middle Aged; Pyridines; Rhabdomyolysis

Rhabdomyolysis is a rare but potentially fatal complication associated with the use of cholesterol synthesis inhibitors (statins). The complication can develop in susceptible patients and with the concomitant use of medications that impede the biodegradation of statins, for example, biotransformation via the cytochrome P450 system. This may result in the plasma and tissue concentrations of statins, and their active metabolites, increasing to levels that are toxic for striated muscle. Myopathy is present when plasma activity levels of creatinine kinase are raised to in excess of 10 times the upper limit of the normal value. Muscular complaints which may be indicative of myotoxicity and subsequent myopathy are present in 1-7% of statin users. Albeit to varying degrees, all statins can induce myotoxicity especially at high dosages. Rhabdomyolysis was clearly more prevalent under cerivastatin users than the users of other statins and was therefore recently withdrawn from the market. Statins should be withdrawn immediately if myopathy is suspected. Prompt withdrawal may prevent rhabdomyolysis.

Topics: Creatine Kinase; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug and Narcotic Control; Drug Interactions; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Mixed Function Oxygenases; Muscular Diseases; Netherlands; Pyridines; Rhabdomyolysis

Concomitant use of gemfibrozil with statins, particularly with cerivastatin, increases the risk of rhabdomyolysis, but the mechanism of this potentially fatal drug interaction remains unclear. Our aim was to study the effect of gemfibrozil on cerivastatin pharmacokinetics.. In a randomized, double-blind crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 3 days. On day 3, each subject ingested a single 0.3-mg dose of cerivastatin. Plasma concentrations of cerivastatin, its metabolites, and gemfibrozil were measured up to 24 hours.. During gemfibrozil treatment, the area under the plasma concentration-time curve [AUC(0-infinity)] of parent cerivastatin was on average 559% (range, 138% to 995%; P =.0002) and the peak concentration in plasma was 307% (138% to 809%; P =.0019) of the corresponding values in the placebo phase. Gemfibrozil increased the AUC(0-infinity) of cerivastatin lactone, on average, to 440% (94% to 594%; P =.0024) and that of metabolite M-1 to 435% (216% to 802%; P =.0002) of the control (placebo) values, whereas the AUC(0-24) of metabolite M-23 was decreased to 22% (11% to 74%; P =.0017).. Gemfibrozil greatly increases plasma concentrations of cerivastatin, cerivastatin lactone, and metabolite M-1, whereas the level of metabolite M-23 is markedly reduced by gemfibrozil. Gemfibrozil therefore inhibits the formation of M-23, which is thought to be dependent on CYP2C8. The increased exposure to cerivastatin in the presence of gemfibrozil may explain the high incidence of myopathy observed with this combination, although the role of pharmacodynamic interactions between these 2 agents cannot be excluded.

Topics: Administration, Oral; Adult; Area Under Curve; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Pyridines; Reference Values; Rhabdomyolysis

Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin.. This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1.. The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin.. Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.

Topics: Cells, Cultured; Drug Interactions; Female; Genetic Variation; Haplotypes; HEK293 Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Male; Organic Anion Transporters; Polymorphism, Single Nucleotide; Pyridines; Rhabdomyolysis

Active medical-product-safety surveillance systems are being developed to monitor many products and outcomes simultaneously in routinely collected longitudinal electronic healthcare data. These systems will rely on algorithms to generate alerts about potential safety concerns.. We compared the performance of 5 classes of algorithms in simulated data using a sequential matched-cohort framework, and applied the results to 2 electronic healthcare databases to replicate monitoring of cerivastatin-induced rhabdomyolysis. We generated 600,000 simulated scenarios with varying expected event frequency in the unexposed, alerting threshold, and outcome risk in the exposed, and compared the alerting algorithms in each scenario type using an event-based performance metric.. We observed substantial variation in algorithm performance across the groups of scenarios. Relative performance varied by the event frequency and by user-defined preferences for sensitivity versus specificity. Type I error-based statistical testing procedures achieved higher event-based performance than other approaches in scenarios with few events, whereas statistical process control and disproportionality measures performed relatively better with frequent events. In the empirical data, we observed 6 cases of rhabdomyolysis among 4294 person-years of follow-up, with all events occurring among cerivastatin-treated patients. All selected algorithms generated alerts before the drug was withdrawn from the market.. For active medical-product-safety monitoring in a sequential matched cohort framework, no single algorithm performed best in all scenarios. Alerting algorithm selection should be tailored to particular features of a product-outcome pair, including the expected event frequencies and trade-offs between false-positive and false-negative alerting.

Topics: Adverse Drug Reaction Reporting Systems; Algorithms; Anticholesteremic Agents; Electronic Health Records; Humans; Product Surveillance, Postmarketing; Pyridines; Rhabdomyolysis; Sensitivity and Specificity

An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Aryl Hydrocarbon Hydroxylases; Case-Control Studies; Clopidogrel; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Platelet Aggregation Inhibitors; Pyridines; Rhabdomyolysis; Ticlopidine

The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.. This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.. Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63).. We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.

Topics: Adult; Aged; Aged, 80 and over; Aryl Hydrocarbon Hydroxylases; Case-Control Studies; Cytochrome P-450 CYP2C8; Female; Genetic Variation; Genome-Wide Association Study; Glucuronosyltransferase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Organic Anion Transporters; Polymorphism, Single Nucleotide; Pyridines; Rhabdomyolysis; Risk; Ryanodine Receptor Calcium Release Channel

Cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor withdrawn from the market because of serious adverse effects, is metabolized primarily by CYP2C8. The occurrence of associated myotoxicity and rhabdomyolysis were attributed to altered cerivastatin pharmacokinetics on account of gemfibrozil-inhibition or genetic variations in CYP2C8 and drug transporters involved in cerivastatin clearance. However, the effect of CYP2C8 genetic variation on cerivastatin metabolism has not been fully elucidated.. In this study, patients (n=126) with confirmed cases of rhabdomyolysis after cerivastatin administration had their CYP2C8 gene resequenced and the metabolism of cerivastatin by the discovered CYP2C8 variants was assessed in proteins expressed in Escherichia coli.. In this unique patient population, 12 novel single nucleotide polymorphisms were discovered of which six were exclusively found in patients not using gemfibrozil. Three rare exonic variants resulted in amino acid substitutions and a frame shift deletion (V472fsL494 generating a defective mostly heme-free CYP2C8 protein). A particular promoter located deletion (-635_-634delTA) was tightly linked to CYP2C8*3. Heterologously expressed CYP2C8.3 and CYP2C8.4 displayed an increase in cerivastatin metabolic clearance of up to six-fold compared with the wild-type enzyme. Similarly, an independent sample of microsomes from human livers carrying the CYP2C8*3 and CYP2C8*4 alleles exhibited a 2-fold to 14-fold increase in normalized cerivastatin intrinsic clearance, compared with microsomes from livers carrying only the wild type allele.. Gain or loss of catalytic function found in the CYP2C8 gene could certainly alter cerivastatin pharmacokinetics and may influence, at least in part, susceptibility to the development of myotoxicity.

Topics: Alleles; Animals; Aryl Hydrocarbon Hydroxylases; Biocatalysis; Crystallography, X-Ray; Cytochrome P-450 CYP2C8; Haplotypes; Humans; Kinetics; Liver; Microsomes, Liver; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Pyridines; Rats; Recombinant Proteins; Rhabdomyolysis; Sequence Analysis, DNA

The occurrence of rhabdomyolysis during statin treatment for dyslipidemia is a well-known side effect. However, the differential diagnosis of rhabdomyolysis is large. We report on a patient treated with statin who presented a rhabdomyolysis. The persistence of laboratory abnormalities allowed to discover a metabolic rhabdomyolysis, namely a carnitine palmitoyltransférase II deficiency. The diagnosis of the genetic abnormality allows to modify the therapeutic care.

Topics: Atorvastatin; Carnitine O-Palmitoyltransferase; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyridines; Pyrroles; Rhabdomyolysis

In a systematic screening of the World Health Organization Adverse Drug Reaction database, VigiBase, in July 2008, a measure of association used to detect interactions (Omega) highlighted azithromycin with the individual statins atorvastatin, lovastatin and simvastatin and rhabdomyolysis. The aim was to examine all reports including rhabdomyolysis-azithromycin and statins in VigiBase to assess if the data were suggestive of an interaction.. The individual case reports in VigiBase and the original files were reviewed. In order to investigate the reporting over time for rhabdomyolysis with azithromycin and statins to VigiBase, Omega values were generated retrospectively.. The reporting over time showed that rhabdomyolysis under concomitant use of azithromycin and statins was reported more often than expected from 2000 and onwards in Vigibase. After exclusion of possible duplicates and follow-up reports, 53 cases from five countries remained. Rhabdomyolysis occurred shortly after initiation of azithromycin in 23% of cases. In 11 patients an interaction had been suggested by the reporter. With the exception of one patient, the statin doses reported were within the recommended daily doses.. Case reports in VigiBase are suggestive that interactions between azithromycin and statins resulting in rhabdomyolysis may occur. This analysis showed the potential of the newly developed disproportionality measure, Omega, which can help to identify drug interactions in VigiBase in the future. The results also showed that reviewing spontaneous reports can add information to drug interactions not established previously.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Atorvastatin; Azithromycin; Databases, Factual; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Male; Middle Aged; Pravastatin; Pyridines; Pyrroles; Rhabdomyolysis; Simvastatin

To estimate the extent of reporting to FDA through statin-associated rhabdomyolysis data.. Data included incidence rates (IRs) of hospitalized rhabdomyolysis among statin users from a population-based study, and comparable reported AERS cases and national estimates of statin use from an AERS analysis. Using IRs, national estimates of statin use and average days supply per prescription, we estimated the number of US statin-associated cases of hospitalized rhabdomyolysis. We compared this estimate to the observed number of cases reported to FDA to evaluate the extent of reporting. We repeated this method for atorvastatin, cerivastatin, pravastatin, and simvastatin and statin combinations. We performed sensitivity analyses to check for biases such as misclassification of statin use and cohort selection bias. We evaluated potential time-dependent cerivastatin reporting by a "Dear Health Care Provider (DHCP)" letter.. The estimated extent of reporting to FDA varied by statin (atorvastatin, 5.0%; cerivastatin, 31.2%; simvastatin, 14.2%; all four combined, 17.7%; and non-cerivastatin statins combined, 9.9%). No pravastatin-associated cohort cases occurred. Across a reasonable value range, sensitivity analyses did not significantly alter the results; overall the cohort was similar to national statin-users. There was a large increase in AERS reports after the cerivastatin DHCP letter and the estimated extent of reporting increased from 14.8 to 35.0%.. The extent of reporting of adverse events to FDA varied by statin and may be influenced by publicity. For statins-associated rhabdomyolysis, the estimated extent of reporting appears to range from 5 to 30% but in the absence of stimulated reporting appears to be 5-15%.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Atorvastatin; Child; Child, Preschool; Female; Heptanoic Acids; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Infant; Male; Middle Aged; Pravastatin; Pyridines; Pyrroles; Retrospective Studies; Rhabdomyolysis; Simvastatin; United States; United States Food and Drug Administration

Although HMG-CoA reductase inhibitors such as statins are the most widely used cholesterol-lowering agents, there is a risk of myopathy or rhabdmyolysis occurring in patients taking these drugs. It has been reported that a number of lipophilic statins cause apoptosis in various cells, but it is still not clear whether intracellular acidification is involved in statin-induced apoptosis. There have been few studies aimed at identifying compounds that suppress statin-induced myotoxicity. In the present study, we examined the relationship between cerivastatin-induced apoptosis and intracellular acidification and the effect of bicarbonate on cerivastatin-induced apoptosis using an RD cell line as a model of in vitro skeletal muscle. Cerivastatin reduced the number of viable cells and caused dramatic morphological changes and DNA fragmentation in a concentration-dependent manner. Moreover, cerivastatin-induced apoptosis was associated with intracellular acidification and caspase-9 and -3/7 activation. On the other hand, bicarbonate suppressed cerivastatin-induced pH alteration, caspase activation, morphological change and reduction of cell viability. Accordingly, bicarbonate suppressed statin-induced apoptosis. The strategy to combine statins with bicarbonate can lead to reduction in the chance of the severe adverse events including myopathy or rhabdmyolysis.

Topics: Apoptosis; Biological Transport; Caspase 3; Caspase 7; Caspase 9; Cell Line, Tumor; Cell Shape; Cell Survival; DNA Fragmentation; Dose-Response Relationship, Drug; Enzyme Activation; Fluorobenzenes; Humans; Hydrogen-Ion Concentration; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle, Skeletal; Protective Agents; Pyridines; Pyrimidines; Rhabdomyolysis; Rhabdomyosarcoma, Embryonal; Rosuvastatin Calcium; Sodium Bicarbonate; Sulfonamides

Active surveillance of population-based health networks may improve the timeliness of detection of adverse drug events (ADEs). Active monitoring requires sequential analysis methods. Our objectives were to (1) evaluate the utility of automated healthcare claims data for near real-time drug adverse event surveillance and (2) identify key methodological issues related to the use of healthcare claims data for real-time drug safety surveillance.. We assessed the ability to detect ADEs using historical data from nine health plans involved in the HMO Research Network's Center for Education and Research on Therapeutics (CERT). Analyses were performed using a maximized sequential probability ratio test (maxSPRT). Five drug-event pairs representing known associations with an ADE and two pairs representing 'negative controls' were analyzed.. Statistically significant (p < 0.05) signals of excess risk were found in four of the five drug-event pairs representing known associations; no signals were found for the negative controls. Signals were detected between 13 and 39 months after the start of surveillance. There was substantial variation in the number of exposed and expected events at signal detection.. Prospective, periodic evaluation of routinely collected data can provide population-based estimates of medication-related adverse event rates to support routine, timely post-marketing surveillance for selected ADEs.

Topics: Adverse Drug Reaction Reporting Systems; Algorithms; Celecoxib; Competitive Medical Plans; Health Maintenance Organizations; Humans; Insurance Claim Review; Lactones; Medical Records Systems, Computerized; Myocardial Infarction; Naproxen; Population Surveillance; Product Surveillance, Postmarketing; Pyrazoles; Pyridines; Retrospective Studies; Rhabdomyolysis; Sulfonamides; Sulfones; Time Factors; Treatment Outcome; United States

Topics: Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Cyclooxygenase 2 Inhibitors; Drug and Narcotic Control; Drug Approval; Health Policy; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactones; Myocardial Infarction; Probability; Product Surveillance, Postmarketing; Pyridines; Research Design; Rhabdomyolysis; Risk Assessment; Stroke; Sulfones; Treatment Outcome; United States; United States Food and Drug Administration

We report on a patient who developed acute rhabdomyolysis after taking cerivastatin. A 74-year-old hypercholestrerolaemic woman taking cerivastatin (0.15 mg/day) for 22 days complained of general muscle weakness and muscle pain. Her serum creatinine phosphokinase level was 19,190 IU/L. Serum myoglobin was over 3000 ng/mL. Serum concentration of cerivastatin at 6 h after taking the last dose (0.15 mg) was 8062.5 ng/L, which was almost 5.7 times higher than that of normal persons. The serum concentration of cerivastatin showed that the half-life of cerivastatin in this patient was 22.4 h, compared with 2.4 h for normal controls. Cerivastatin is catabolized by cytochrome P450, 3A4 and 2C8 to M-1, and by 2C8 to M-23. The ratio of M-23 to M-1 in her serum was much lower than that of control persons (0.64 vs. 2.08). She had previously taken simvastatin which is metabolized by CYP3A4, without any sign and symptoms of rhabdomyolysis. These results suggest that the slowed clearance of cerivastatin in this patient might have been compounded by cytochrome P450, 2C8 dysfunction.

Topics: Acute Disease; Aged; Aryl Hydrocarbon Hydroxylases; Creatinine; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Female; Half-Life; Humans; Hypercholesterolemia; Metabolic Clearance Rate; Myoglobin; Myoglobinuria; Pyridines; Rhabdomyolysis; Simvastatin; Time Factors

Statins are currently the mainstay of dyslipidemia management for the primary and secondary prevention of cardiovascular disease. Controversial concerns about the safety of the newly marketed statin rosuvastatin have been raised on the basis of premarketing studies and a few postmarketing reports.. We reviewed rosuvastatin-associated adverse events reported to the US Food and Drug Administration over its first year of marketing. On the basis of prescription data obtained from IMS Health, rates of adverse event reports (AERs) per million prescriptions were calculated. Rates of rosuvastatin-associated AERs over its first year of marketing were compared with those seen with atorvastatin, simvastatin, and pravastatin over the concurrent timeframe and during their respective first years of marketing. Comparison was also made to the first year of marketing of cerivastatin. The primary analysis examined the composite end point of AERs of rhabdomyolysis, proteinuria, nephropathy, or renal failure. With either timeframe comparison, rosuvastatin was significantly more likely to be associated with the composite end point of rhabdomyolysis, proteinuria, nephropathy, or renal failure AERs. Reported cases of rhabdomyolysis, proteinuria, or renal failure tended to occur early after the initiation of therapy and at relatively modest doses of rosuvastatin. The increased rate of rosuvastatin-associated AERs relative to other widely used statins was also observed in secondary analyses when other categories of AERs were examined, including adverse events with serious outcomes, liver toxicity, and muscle toxicity without rhabdomyolysis.. The present analysis supports concerns about the relative safety of rosuvastatin at the range of doses used in common clinical practice in the general population.

Topics: Consumer Product Safety; Drug Evaluation; Drug Prescriptions; Fluorobenzenes; Humans; Kidney Diseases; Morbidity; Product Surveillance, Postmarketing; Proteinuria; Pyridines; Pyrimidines; Renal Insufficiency; Retrospective Studies; Rhabdomyolysis; Rosuvastatin Calcium; Sulfonamides

Cerivastatin, a lipid-lowering agent, was voluntarily withdrawn from the market because of high risk of rhabdomyolysis when used as monotherapy and as comedication with fibrates, especially gemfibrozil. Thereafter, investigators found a five-fold increase in the area under the curve (AUC) when cerivastatin was used as comedication with gemfibrozil and theorized that the increase was associated with inhibition of the hepatic uptake and metabolism. By contrast, a number of pharmacoepidemiological investigations--one of which involved evaluation of the Food and Drug Administration (FDA) database for suspected adverse drug reactions and 11 cohort studies of statin and fibrate users in United States showed the risk of rhabdomyolysis to be greater in cerivastatin than in other statins used in either monotherapy or in comedication with fibrates, especially gemfibrozil. This incident regarding risk of rhabdomyolysis in cerivastatin monotherapy was taken to court in the United States and unpublished company (manufacturer of cerivastatin) documents were opened. The incident was then analyzed and discussed in the Journal of American Medical Association (JAMA) as a concern of the current US post-marketing surveillance system. The company's action and timing were judged and found to be inappropriate (although companies of this sort generally have insurmountable conflicts of interest), and the work of the US regulatory system and funding for post-marketing safety management were found to be insufficient. On the basis of the current situation, the authors and editors recommend further improvement of post-marketing regulations including the establishment of an independent drug safety board to oversee post-marketing surveillance. Among the opened, unpublished data, was the finding that cerivastatin obviously induced myopathy in a dose-dependent manner when administrated as monotherapy. As for other statins, only limited data was available for the relationship between the dosage and the rate of myopathy. For the safety use of statins, this should be clarified by proper surveillance system.

Topics: Adverse Drug Reaction Reporting Systems; Consumer Product Safety; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Approval; Drug Interactions; Drug Therapy, Combination; Gemfibrozil; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Product Surveillance, Postmarketing; Pyridines; Rhabdomyolysis; Risk; United States; United States Food and Drug Administration

Based on the recent cerivastatin experience, we retrospectively evaluated the effect of notifying a drug alert utilizing a computerized drug-handling system.. The evaluation was carried out during three periods: period I corresponded to all prescriptions issued during April, 2001 ("baseline period"), before the Spanish Drug Agency issued alerts on the concomitant therapy with cerivastatin and gemfibrozil; period II (June) corresponded to a time in which a first informative note had been released; and period III (July) after the second warning alert was issued.. Data collected included the reading of 2,693,656 drug prescriptions, 1,937,083 (71.9%) of which contained patient information. Forty-four patients received combined therapy with cerivastatin and gemfibrozil over the three periods, yielding 55 exposures: 27 during the baseline period, and 28 between periods II and III, when the alert bulletins had already been released. Moreover, 41.6% of doctors included in the follow-up repeated the hazardous prescription during those two periods.. The effect of the informative notes about the risk of prescribing cerivastatin and gemfibrozil concomitantly on doctors' prescribing habits was limited. The system for screening information from drug prescriptions presented herein allows the early detection of drug interactions by identifying the doctors who issue hazardous prescriptions as well as patients at the highest risk of adverse drug reactions, thus allowing a personal feedback with both of them.

Topics: Drug Interactions; Drug Prescriptions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Medical Records Systems, Computerized; Practice Patterns, Physicians'; Pyridines; Retrospective Studies; Rhabdomyolysis; Spain

In August 2001, cerivastatin was removed from European and USA markets because of a higher risk of rhabdomyolysis associated with its use in comparison with other statins. The objective of this study was to compare cholesterol-lowering drug use in Italy before and after the withdrawal of cerivastatin from the market, and to evaluate if the withdrawal influenced patients compliance and physicians prescribing habits. After August 2001, 48% of cerivastatin users discontinued any statin treatment. The major risk factor for discontinuation was a concomitant use of fibrate during the first 7 months of 2001 (OR = 2.3; 95% CI = -2.9). Comparing the discontinuation of statin therapy between 2001 and 2000 we can estimate that there was a 5% increase, corresponding to about 200,000 patients, who discontinued statin therapy during autumn 2001 because of cerivastatin emergency.

Topics: Aged; Drug Utilization; Female; Health Services Research; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Italy; Male; Middle Aged; Patient Compliance; Pyridines; Rhabdomyolysis; Risk Assessment

A hypercholesterolemic patient medicated with cerivastatin for 22 days resulted in acute rhabdomyolysis. CYP2C8 and CYP3A4 are the major enzymes responsible for the metabolism of cerivastatin, and a transporter, OATP2, contributes to uptake of cerivastatin to the liver. In this study, the patient's DNA was sequenced in order to identify a variant that would lead to the adverse effect of cerivastatin. Three nucleotide variants, 475delA, G874C, and T1551C, were found in the exons of CYP2C8. The patient was homozygous for 475delA variant that leads to frameshift and premature termination. Accordingly, the patient is most likely lacking the enzyme activity. The patient's children were both heterozygous for the mutation. The patient had three nucleotide variants in exon 4 (A388G) and exon 5 (C571T and C597T) of OATP2 that were all heterozygous. No nucleotide variation in the exons of CYP3A4 was identified. To our knowledge, this is the first report showing that the adverse effect of cerivastatin might be caused by the genetic variant of CYP2C8.

Topics: Aged; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C8; Exons; Female; Frameshift Mutation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis

Skeletal muscle degeneration is a side effect of cholesterol-lowering hydroxymethylglutaryl coenzyme A reductase inhibitors. The expression of the cell-cell adhesion proteins, neural cell adhesion molecule and neural-cadherin was studied in a case of rhabdomyolysis induced by the hydroxymethylglutaryl coenzyme A reductase inhibitor cerivastatin. Neural cell adhesion molecule and N-cadherin participate in the interactions of muscle cells during skeletal myogenesis. In the adult muscle, neural cell adhesion molecule is restricted to neuromuscular sites but is re-expressed in denervated muscle and in rhabdomyolysis. Our results show expression of neural cell adhesion molecule in regenerative skeletal muscle fibers but not in degenerated or unaffected fibers in cerivastatin-induced rhabdomyolysis. In contrast, N-cadherin was not expressed. The presence of apoptotic cells was studied by a fluorescence-based Tdt-mediated dUTP nick-end labeling in the same sections. Apoptosis was detected in degenerative fibers and inflammatory cells but not in regenerative fibers. We hypothesize that the expression of neural cell adhesion molecule in regenerative fibers may have a protective role against apoptosis during rhabdomyolysis. Cerivastatin-induced rhabdomyolysis appears to have common features with rhabdomyolysis of other causes. The immunohistochemical study of neural cell adhesion molecule can serve as an additional tool in the evaluation of muscle regeneration in rhabdomyolysis.

Topics: Aged; Aged, 80 and over; Antigens, CD; Cadherins; Cell Adhesion Molecules; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Muscle Fibers, Skeletal; Neural Cell Adhesion Molecules; Pyridines; Regeneration; Rhabdomyolysis

Topics: Adverse Drug Reaction Reporting Systems; Conflict of Interest; Drug Approval; Drug Industry; Drug Interactions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Pyridines; Rhabdomyolysis; Risk; United States; United States Food and Drug Administration

Topics: Adverse Drug Reaction Reporting Systems; Conflict of Interest; Drug Approval; Drug Industry; Drug Interactions; Drug Labeling; Expert Testimony; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Liability, Legal; Pyridines; Rhabdomyolysis; Risk; United States; United States Food and Drug Administration

Cerivastatine was administered as a reversible HMG-CoA reductase inhibitor (statine) to treat hypercholesterolemia until its withdrawal from the market following 52 reports of death due to drug-related rhabdomyolysis and acute renal failure. In most cases, cerivastatine was applied in combination with drugs which influenced the liver metabolism of cerivastatine via cytochromeoxidase P 450 isoenzymes. We report a well-documented case of acute rhabdomyolysis following cerivastatine monotherapy. The diagnosis was confirmed additionally by muscle biopsy.Finally,we give an overview of the current knowledge concerning therapy with HMG-CoA reductase inhibitors,1 year after the withdrawal of cerivastatine from the market.

Topics: Acute Disease; Anticholesteremic Agents; Aryl Hydrocarbon Hydroxylases; Biopsy; Coenzymes; Comorbidity; Creatine Kinase; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diagnosis, Differential; Drug Interactions; Electromyography; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver Cirrhosis, Alcoholic; Liver Function Tests; Middle Aged; Muscle, Skeletal; Neurologic Examination; Pancreatic Diseases; Pyridines; Rhabdomyolysis; Stomach Neoplasms; Ubiquinone

Topics: Disclosure; Drug and Narcotic Control; Drug Industry; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis; United States

Topics: Area Under Curve; Biological Availability; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis

Topics: Anticholesteremic Agents; Creatine Kinase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Lovastatin; Meta-Analysis as Topic; Muscular Diseases; Pravastatin; Pyridines; Randomized Controlled Trials as Topic; Retrospective Studies; Rhabdomyolysis; Transaminases; Treatment Outcome

Topics: Drug Industry; Germany; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis

A worldwide frequently applied HMG-CoA-reductase-inhibitor ("statin") recently has been withdrawn from the market. This obviously has been caused by serious adverse events. The question is whether the package inserts sufficiently inform about the risks. But, although they list up numerous side effects, they lack informations concerning the frequency of them, so the patients when reading the package inserts become confused. Thus they have to rely on their doctors choice regarding the danger outlined in the inserts. In that respect packing inserts could be improved.

Topics: Adverse Drug Reaction Reporting Systems; Anticholesteremic Agents; Austria; Dose-Response Relationship, Drug; Drug Information Services; Drug Labeling; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Patient Education as Topic; Pyridines; Renal Insufficiency; Rhabdomyolysis

Statins are now widely prescribed and without doubt save many lives. However there are rare potentially serious side-effects, including acute renal failure. Patient education and physician vigilence are vital.

Topics: Acute Disease; Aged; Humans; Male; Muscle Weakness; Pyridines; Renal Insufficiency; Rhabdomyolysis

Topics: Acute Kidney Injury; Aged; Drug Therapy, Combination; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Pyridines; Rhabdomyolysis

Topics: Drug and Narcotic Control; Hospital Information Systems; Hospitals, University; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Medical Records Systems, Computerized; Pakistan; Patients; Pharmacy Service, Hospital; Pyridines; Rhabdomyolysis

Topics: Cardiomyopathies; Drug Therapy, Combination; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Acute Kidney Injury; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Pyridines; Rhabdomyolysis

Topics: Dose-Response Relationship, Drug; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis

We report a patient with renal insufficiency who developed rhabdomyolysis 1 month after initiating cerivastatin and gemfibrozil for hyperlipidemia. Myopathy caused by HMG-CoA reductase inhibitors (statins) alone is rare, but occurs more frequently when a statin is used with gemfibrozil, a medication that likely has a direct toxic effect on muscles. Predisposing factors to the development of myopathy from the combination include use of medications affecting statin metabolism, higher doses of statins, renal insufficiency, diuretics, and hypothyroidism. It has been proposed that alternate-day therapy with a statin and fibrate, spacing of doses in a single day, or use of lower doses of statins may prevent the development of myopathy. Currently, no predictable method to determine who is at risk for myopathy exists, nor is there a reliable screening test. Therefore, patients should be advised to watch for generalized muscle pain or weakness, and if it occurs, stop medications and report symptoms immediately.

Topics: Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Drug Approval; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis; United States; United States Food and Drug Administration

Topics: Hepatocytes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscles; Pravastatin; Pyridines; Rhabdomyolysis

Topics: Cardiovascular Diseases; Cholesterol; Coenzymes; Drug Synergism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis; Ubiquinone; United States; United States Food and Drug Administration

Topics: Aged; Antipsychotic Agents; Drug Interactions; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis; Risk Factors; Risperidone

Topics: Drug Interactions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis

Topics: Drug Therapy, Combination; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Cyclosporins; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyridines; Rhabdomyolysis; Time Factors

Topics: Age Factors; Humans; Male; Middle Aged; Pyridines; Rhabdomyolysis

Rhabdomyolysis is an uncommon complication associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. We observed six cases of cerivastatin-associated rhabdomyolysis: two patients developed acute renal failure requiring hemodialysis, and one patient died. Four of the patients had impaired renal function, and five were prescribed drugs with the potential to interact with cerivastatin. Also, five of the six patients presented with symptoms of rhabdomyolysis 3-4 weeks after starting cerivastatin therapy.

Topics: Acute Kidney Injury; Aged; Creatine Kinase; Drug Interactions; Fatal Outcome; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyridines; Renal Dialysis; Renal Insufficiency; Rhabdomyolysis

Topics: beta 2-Microglobulin; Biomarkers; Drug Therapy, Combination; Gemfibrozil; Humans; Hyperlipidemias; Kidney Diseases; Kidney Tubules; Magnetic Resonance Spectroscopy; Male; Membrane Glycoproteins; Pyridines; Rhabdomyolysis; Trypsin Inhibitor, Kunitz Soybean

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis

Topics: Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis

Topics: Acute Kidney Injury; Drug Therapy, Combination; Gemfibrozil; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Drug Therapy, Combination; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Pyridines; Rhabdomyolysis

Topics: Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypothyroidism; Pyridines; Rhabdomyolysis

Topics: Acute Kidney Injury; Aged; Drug Interactions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Pyridines; Rhabdomyolysis

Topics: Cyclosporine; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Transplantation; Pyridines; Rhabdomyolysis

Topics: Aged; Anticholesteremic Agents; Drug and Narcotic Control; Drug Therapy, Combination; Gemfibrozil; Humans; Product Surveillance, Postmarketing; Pyridines; Rhabdomyolysis

Topics: Anticholesteremic Agents; Dose-Response Relationship, Drug; Drug and Narcotic Control; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Product Surveillance, Postmarketing; Pyridines; Rhabdomyolysis; United States; United States Food and Drug Administration

Topics: Anticholesteremic Agents; Drug Interactions; Drug Labeling; Humans; Product Surveillance, Postmarketing; Pyridines; Rhabdomyolysis; United States; United States Food and Drug Administration

Topics: Canada; Drug Industry; Drug Interactions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Pyridines; Rhabdomyolysis; United States; United States Food and Drug Administration

Topics: Drug Industry; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis; United States

To report a case of rhabdomyolysis resulting from concurrent use of cerivastatin and gemfibrozil. CASE SUMMARY An 82-year-old white man presented to the emergency department with severe muscle weakness and inability to walk approximately one month after starting cerivastatin. He had been taking gemfibrozil for several years without any known adverse effects. Both medications were discontinued and the patient recovered. He was discharged with a diagnosis of rhabdomyolysis secondary to his medications.. Four previous reports describing rhabdomyolysis in patients on concomitant cerivastatin and gemfibrozil have been cited. Although monotherapy with cerivastatin is well tolerated and has a low frequency of adverse events, the combination with nicotinic acid (i.e., niacin) or a fibric-acid derivative (i.e., gemfibrozil, fenofibrate) may result in severe skeletal muscle toxicity and rhabdomyolysis.. According to the Naranjo scale, a probable relationship exists between the concomitant use of gemfibrozil and cerivastatin with the resulting development of rhabdomyolysis. Concurrent use of gemfibrozil and cerivastatin is therefore contraindicated.

Topics: Aged; Aged, 80 and over; Creatine Kinase; Drug Interactions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Cholesterol, LDL; Drug and Narcotic Control; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Muscle Weakness; Product Surveillance, Postmarketing; Pyridines; Rhabdomyolysis; Risk Factors

Cerivastatin was recently withdrawn from the market after the report of more than 30 deaths in the United-States among patients receiving a combination of cerivastatin and gemfibrozil, a fibrate which is not anymore on the Belgian market. The cause of death was attributed to severe rhabdomyolysis. Cases were also reported among patients treated by cerivastatin only. Recommendations for better use of lipid-lowering drugs are given in order to optimize the benefit/risk ratio of such treatment.

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis

Topics: Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Drug and Narcotic Control; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis

Topics: Animals; Clinical Trials as Topic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Myositis; Pyridines; Rhabdomyolysis

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis

Topics: Acute Disease; Aged; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Pyridines; Rhabdomyolysis

Topics: Aged; Chest Pain; Drug Combinations; Electrocardiography; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperkalemia; Hypolipidemic Agents; Muscle, Skeletal; Pain; Pyridines; Renal Dialysis; Rhabdomyolysis

Topics: Adverse Drug Reaction Reporting Systems; Drug and Narcotic Control; Drug Industry; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Pyridines; Rhabdomyolysis

Topics: Drug Interactions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Anticholesteremic Agents; Anuria; Clopidogrel; Coronary Artery Bypass; Humans; Hypercholesterolemia; Intracranial Thrombosis; Male; Middle Aged; Muscle Weakness; Myocardial Infarction; Platelet Aggregation Inhibitors; Postoperative Complications; Pyridines; Rhabdomyolysis; Ticlopidine

Straightforward reports of unusual drug experiences are included in this section. While selected references may be cited, the purpose of a Drug Experience report is not to present an extensive review of the literature. A related section, Grand Rounds, includes papers that are well-documented patient case reports with a thorough review of the important literature to help put the case in perspective. Authors should report serious adverse drug reactions to the FDA medical products reporting program (MedWatch). Such reporting will not jeopardize the chances that AJHP will publish manuscripts on the same drug reactions.

Topics: Certification; Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Middle Aged; Pharmacists; Pyridines; Rhabdomyolysis

Topics: Cyclosporine; Drug Interactions; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pyridines; Rhabdomyolysis; Stereoisomerism

Topics: Acute Kidney Injury; Aged; Bezafibrate; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Influenza Vaccines; Male; Pyridines; Rhabdomyolysis

Gemfibrozil-statin combination therapy is a well-known risk factor for myopathy and rhabdomyolysis. Cerivastatin is a currently available statin with dual elimination; it is therefore expected to cause less drug-drug interaction. This case is the second reported case with severe rhabdomyolysis caused by cerivastatin-gemfibrozil combination. Moreover, in this case, the rhabdomyolysis was more severe and caused severe renal failure and death. The authors discuss how these drugs cause rhabdomyolysis and how rhabdomyolysis can cause renal failure.

Topics: Diabetes Mellitus; Drug Interactions; Drug Therapy, Combination; Electrocardiography; Fatal Outcome; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Myocardial Ischemia; Pyridines; Renal Dialysis; Renal Insufficiency; Rhabdomyolysis

Topics: Aged; Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Pyridines; Rhabdomyolysis

Topics: Aged; Drug Interactions; Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Pyridines; Renal Insufficiency; Rhabdomyolysis

Topics: Aged; Drug Synergism; Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Liver; Pyridines; Rhabdomyolysis; Stereoisomerism