Withdrawal Of Cerivastatin Research Articles

Efficacy and safety of fenofibrate as an add-on in patients with elevated triglyceride despite receiving statin treatment

BackgroundSince the withdrawal of cerivastatin, statin–fibrate combination therapy has been questioned in China due to safety concern. The objective of this study was to evaluate the efficacy and safety profile of fenofibrate as an add-on in patients with dyslipidemia despite receiving statin therapy. MethodsThis was a prospective, multi-center, single-arm, open-label study conducted in Chinese dyslipidemia patients with high CV risk. Fenofibrate (200mg daily) was added to the existing statin treatment for 8weeks. Lipid profile and safety parameters were measured and compared between baseline and after the treatment. Five hundred and six subjects were enrolled from 28 sites from 14 cities nationwide across China. ResultsAfter 8weeks of fenofibrate treatment, the mean blood triglyceride level decreased to 1.77mmol/L (38.1% reduction vs. 3.00mmol/L at the baseline; p<0.01). Mean high-density lipoprotein cholesterol (high density lipoprotein cholesterol) was increased to 1.22mmol/L (by 17.4% from 1.07mmol/L at the baseline; p<0.01). No case of severe muscle damage (defined as elevated creatine kinase over 5 times of upper limit of normal (ULN) or rhabdomyolysis was observed. ConclusionIn statin-treated patients with high CV risk who had elevated triglyceride, adding fenofibrate could improve lipid profile with acceptable safety profiles.

G.P.28: Through myotubes normalization, CYTOO 2D+ increase sensitivity of muscle damage HCS assay

Since classical ADME/Tox tests failed to detect statin drugs family as toxicant by inducing chronic muscle damages such as myositis, rhabdomyolysis, muscle pain; which leaded to a considerable economic burden for pharmaceutical industry, e.g. cerivastatin withdrawal from the market, companies need to develop more relevant in vitro models dedicated to muscle damage drug discovery. In this context, CYTOO developed a physiological muscle model improving the sensitivity of myotoxic drug detection. When cultured on 2D+ technology, primary human myoblasts faster differentiate in myotubes containing a higher level of sarcomere striation and nuclei alignment compared to standard culture condition. Moreover, 2D+ technology standardizes myotubes formation and enables accessing new parameters for myotubes characterization upon drug treatment. Thanks to the development of new image analysis algorithms and the reduced variability of myotubes morphology, we gain access to finer and more relevant readouts. To further demonstrate the benefits of our model, we tested reference drugs inducing hypertrophy or atrophy on both standard culture condition and 2D+ platforms. Our results showed that this model is robust and compatible with High Content Screening with increased Z ′ factors compared to standard assays. Altogether, the normalization of myoblast differentiation in highly mature myotubes, coupled to enhanced image analysis capacities, demonstrated a higher predictivity over standard assays and will allow the detection of myotoxic drugs during the early phases of preclinical studies for compound development.

Cerivastatin, genetic variants, and the risk of rhabdomyolysis

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.

Effects of Cerivastatin Withdrawal on Statin Persistence

Medication-taking behavior is influenced by many factors, as described by the Health Belief Model. Information on withdrawals of drugs from the market may be an example of negative external stimuli that might influence patients' decisions to persist with long-term drug therapy. To evaluate the association between the withdrawal of cerivastatin from the market and persistence in taking all other statins in patients who recently experienced acute coronary syndrome (ACS). Patients from a large ACS registry who responded to questions about medication use during a postdischarge telephone survey between November 2000 and February 2002 were categorized into 3 groups: pre- (November 1, 2000-April 30, 2001), peri- (May 1, 2001-August 31, 2001), and post- (September 1, 2001-February 28, 2002) cerivastatin withdrawal periods. Patients were considered persistent if, at the time of the survey, they continued to take study medication that had been prescribed at discharge. Persistence with angiotensin-converting enzyme inhibitors, aspirin, and beta-blockers was also assessed to determine whether changes in statin persistence were unique to the class or related to other medication issues that affected all classes. The Kruskal-Wallis test, with post hoc Mann-Whitney U test, was used to analyze the differences in persistence between the groups. All comparisons were considered statistically significant at p less than 0.05. There were no significant differences in patient characteristics between study groups. Persistence with statins decreased during the periwithdrawal period (88.4% pre vs 76.7% peri) and rebounded in the postwithdrawal period (90.8%; p = 0.007). There were no significant differences in persistence with the other drug classes. The temporary decline in statin persistence appeared to be associated with the withdrawal of cerivastatin, while persistence with the other study medications remained constant. Clinicians need to understand the potential effect of factors such as media attention surrounding a drug's withdrawal on patients' medication-taking behavior.

Influence of Regulatory Measures on the Rate of Spontaneous Adverse Drug Reaction Reporting in Italy

The reporting of adverse drug reactions (ADRs) is the mainstay of post-marketing surveillance systems. Under-reporting and selective reporting are considered the main limitations of a spontaneous reporting-based pharmacovigilance system. However, excessive reporting induced by external events may also impair signal detection by increasing the noise level. The aim of this study was to examine the influence of regulatory measures and other external factors on the rate of ADR reporting in Italy, focusing on four situations occurring in the last 10 years: ACE inhibitor-induced cough; HMG-CoA reductase inhibitors ('statins') and rhabdomyolysis; nimesulide and hepatic toxicity; and cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') and increase in cardiovascular risk. The study was based on data from spontaneous reporting in six Italian regions collected from January 1995 to December 2005. We analysed a 10-year period as a reasonable time interval around the four situations of interest, highlighting the influence of regulatory measures on the rate of ADR reporting (number of reports per million inhabitants). Chi-squared tests were used to assess the statistical significance of any changes in ADR reporting. Drug sales data were also studied to examine possible changes in drug use. Sales data were expressed as daily defined dose per 1000 inhabitants per day. ACE inhibitors: a 5-fold increase in the reporting rate of ACE inhibitor-induced cough was observed in 1998 and 1999 following a restriction on reimbursement for angiotensin receptor blockers introduced in 1998 and removed at the end of 1999. Statins: after the withdrawal of cerivastatin in 2001, the ADR reporting rate increased more than 4-fold, with musculoskeletal ADRs representing about 60% of all the ADRs reported in that year, and progressively decreased in the following years. Nimesulide: an increase in hepatic ADR reporting was observed after withdrawal of the drug from the Finnish and Spanish markets in 2002. Coxibs: no important changes in the rate of cardiovascular events reporting in the period 2000-4 were observed. In 2005, after the withdrawal of rofecoxib in September 2004, both the ADR reporting rate and sales of the drug decreased drastically. Our data suggest that spontaneous ADR reporting can be influenced in different ways by external events. Our data emphasize the need for educational initiatives aimed at increasing the doctor's and patient's awareness of the usefulness and the limitations of spontaneous reporting in the pharmacovigilance system. Such initiatives should use appropriate risk communication strategies in order to avoid unnecessary alarm, which could cause unjustified interruption of therapies or misplaced confidence in new drugs.

CYP2D6*4 polymorphism is associated with statin-induced muscle effects

Statin use is associated with a variety of overtly related muscle symptoms including muscle pain, myalgia, creatine kinase elevations without pain with myolysis and myositis (rhabdomyolysis), a potentially fatal side effect that led to the withdrawal of cerivastatin in 2001. Unintended drug response phenotypes have an impact on patient compliance and sometimes patient health and the assessment of risk on an individual basis could enhance therapeutic benefit. We therefore investigated whether common single nucleotide polymorphisms were associated with the expression of broadly grouped atorvastatin-induced muscle events in a case-control study (n=263 samples, n=388 SNPs). Of a number of associations identified in a discovery sample (51 atorvastatin-induced muscle and 55 normal) only those corresponding to the CYP2D6*4 allele were significantly associated in the sample (24 atorvastatin-induced muscle and 133 normal) (Discovery P=0.004, odds ratio=3.6; Validation P=0.036, odds ratio=2.7; total P=0.001, odds ratio=2.5). The frequency of the CYP2D6*4 allele was about 50% in atorvastatin-induced muscle patients but only 28% in controls, similar to that of other patient types (28.5%). The association was independent of various demographic variables and not explained by gross demographic, clinical or population-structure differences among cases and controls. Surprisingly, the CYP2D6*4 allele appeared similarly distributed among controls and patients expressing simvastatin-induced muscle events (n=169, frequency in case participants=49.2%, P=0.067, odds ratio=1.7). Our results suggest that the CYP2D6*4 allele is associated with broadly related muscle events caused by at least two structurally dissimilar HMG-CoA reductase inhibitors, and as such, may have implications for a better understanding of this statin-wide phenomena.

The Use of Statins in Postoperative Adhesion Prevention

The Use of Statins in Postoperative Adhesion Prevention

Clinical efficacy and cost–effectiveness of rosuvastatin

Rosuvastatin, which was approved by the FDA in 2003 and has been available in Europe since 2002, is the newest and most efficacious of the currently available 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). More than 8 million patients have now been treated with rosuvastatin for up to 3 years, and initial concerns about the tolerability of this agent, prompted by the withdrawal of cerivastatin, have been answered. In fact, the lack of interactions of rosuvastatin with drugs metabolized by cytochrome P450 3A4 may provide a safety advantage not shared by other potent statins. Finally, rosuvastatin enables the majority of patients to achieve their cholesterol goals at initial doses, without the need for further dose titration and associated costs, and studies in both the USA and the UK have established its cost–effectiveness.

Liver toxicity of rosuvastatin therapy

We report here a case of clinically significant liver toxicity after a brief course of rosuvastatin, which is the first statin approved by the regulatory authorities since the withdrawal of cerivastatin. Whether rosuvastatin has a greater potential compared with other statins to damage the liver is unclear and the involved mechanisms are also unknown. However, rosuvastatin is taken up by hepatocytes more selectively and more efficiently than other statins, and this may reasonably represent an important variable to explain the hepatotoxic potential of rosuvastatin. Our report supports the view that a clinically significant risk of liver toxicity should be considered even when rosuvastatin is given at the range of doses used in common clinical practice.

Impact of Safety Alerts on Measures of Disproportionality in Spontaneous Reporting Databases

Disproportionality analysis of spontaneous reporting is increasingly used, but it may be influenced in unknown ways by safety alerts (notoriety bias). To explore the consequences of safety alerts on reporting disproportionality. Within the French national pharmacovigilance database, disproportionality of reporting was tested, using the reporting odds ratio (ROR) and its 95% confidence interval, before and after four safety alerts: valvulopathies with pergolide; tuberculosis with infliximab; strokes with atypical antipsychotics; and rhabdomyolysis with HMG-CoA reductase inhibitors (statins) [after cerivastatin withdrawal]. No cases of valvulopathy were reported in association with pergolide before the safety alert and 63 cases were reported after the alert, (ROR 9400; 95% CI 4300, 20 000), of which five had occurred before the alert. Twenty-five reports mentioned rhabdomyolysis associated with statins (not including cerivastatin) before the safety alert (ROR 5.8; 95% CI 3.8, 9.0), and 63 did so after the alert (ROR 9.4; 95% CI 7.0, 13.0). Approximately 280 cases involving cerivastatin were reported after its withdrawal. There were two reports of tuberculosis associated with infliximab before the alert (ROR 1500; 95% CI 130, 18 000) and seven after the alert (ROR 430; 95% CI 110, 1700). There was one report of a stroke in association with atypical antipsychotic treatment before the safety alert (ROR 0.10; 95% CI 0.01, 0.63) and 16 after the alert (ROR 1.10; 95% CI 0.70, 1.90). After excluding events involving treatment with anticoagulant agents, the RORs for stroke in association with atypical antipsychotic treatment were 0.14 (95% CI 0.02, 1.00) before the alert and 2.0 (95% CI 1.2, 3.4) after the alert. Disproportionality in spontaneous reporting databases increases after a safety alert because of increased reporting of the event of interest, including reports of such events that occurred before the alert. This may overflow to increased reporting of the event in association with other drugs.

Combined hormone replacement therapy improves lipids but may increase leucocytes

Dear Sir, Recent clinical trial data have cast doubt on the efficacy of oral hormone replacement therapy (HRT) for decreasing cardiovascular events. One of the postulated mechanisms is the upregulation of inflammation leading to accelerated atherosclerosis, plaque instability or thrombosis. Thus, plasma C-reactive protein levels increase during HRT, an effect that is attenuated with statin therapy [1]. On the other hand, some markers of inflammation may be reduced with HRT therapy, including levels of cell adhesion molecules [2], whilst other markers seem not to be influenced by HRT [3]. In a randomized, double-blind, controlled study, we evaluated the efficacy of continuous combined HRT with 1 mg oestradiol and 0.5 mg norethisterone acetate (Activelle®, Novo Nordisk A/S, Bagsvaerd, Denmark) compared with placebo in lowering total and LDL cholesterol levels in women at high risk for cardiovascular disease (CVD). The subjects were postmenopausal women aged 40–75 years (mean 64 years) with LDL cholesterol levels ≥4.1 mmol L−1. All had at least one other CVD risk factor. Major exclusions were the standard ones for the use of HRT. All provided written informed consent and the study was approved by the regional ethics committee. Subjects (n = 113) were treated with a cholesterol-lowering diet for 14 weeks and continued the diet throughout. If LDL cholesterol levels remained ≥4.1 mmol L−1 at week 5, they started therapy with cerivastatin 300 μg at week 6. At week 14, subjects were randomized to HRT or matching placebo. Combined oestrogen and progestin was provided in one daily tablet containing oestradiol 1 mg and norethisterone acetate 0.5 mg. HRT or placebo was planned to continue for 36 weeks. However, due to withdrawal of cerivastatin in August 2000, the study was stopped prematurely. At that time 23 subjects had received HRT or placebo for 12 weeks or more. Laboratory samples were obtained after an overnight fast. Total cholesterol and triglyceride concentrations were measured using automated analyser equipments (Hitachi 911; Hitachi Limited, Tokyo, Japan) and reagents from Boehringer Mannheim (Mannheim, Germany). HDL cholesterol concentrations were measured on a Hitachi 911 analyzer using the direct, enzymatic inhibition assay of Boehringer Mannheim. LDL cholesterol was calculated using the Friedewald formula. Standard methods were used to determine liver transaminase, creatinine, erythrocyte, platelet and leucocyte counts. Analyses were performed at the Department of Clinical Chemistry, Ullevål University Hospital, Oslo, Norway. For statistical analyses, an analysis of covariance model was used with the change from randomization to week 12 as response, group as fixed factor and the values at randomization as covariate. The mean difference between groups over the randomized period, P-values for the between-group comparison and 95% confidence intervals were calculated using the Statistical Analysis System version 6.12 (SASTM; SAS, Cary, NC, USA). Continuous combined HRT reduced total cholesterol by 0.7 mmol L−1 (95% CI, −1.1, −0.3) or 14% and LDL cholesterol levels by 0.6 mmol L−1 (95% CI, −1.0, −0.1) or 20% (Table 1). Levels of HDL cholesterol were also reduced by 0.3 mmol L−1 (95% CI, −0.4, −0.1) or 14%. Levels of glucose, liver transaminases, creatinine, erythrocytes and platelets did not differ between the groups (data not shown). However, levels of leucocytes increased in the HRT group compared with placebo after adjustment for baseline levels (mean difference 0.7 × 109 L−1, 95% CI, 0.3–1.2). In this study HRT resulted in a further reduction in total and LDL cholesterol levels, in addition to the reduction due to the combination of diet and cerivastatin. However, HDL cholesterol levels were reduced and the leucocyte count increased. The effects of HRT on lipid levels are in accordance with earlier data. Whilst therapy with oestrogen alone reduces total and LDL cholesterol and increases HDL cholesterol, the addition of a gestagen, in particular when the gestagen is taken continuously, has a deleterious effect on HDL cholesterol. However, the leucocyte count increased. In a previous study conducted amongst women with diabetes, the leucocyte count did not change during treatment with conjugated equine oestrogen plus medroxyprogesterone acetate for 6 months [2]. Differences between trials may be due to the type of HRT that is used, subject characteristics or other variables. Our finding may be the result of chance as the number of participants was low. However, the relationship between HRT use and leucocyte count warrants further investigation. No conflict of interest was declared. This study was supported by a research grant from Novo Nordisk.

Statin Safety: An Appraisal from the Adverse Event Reporting System

The adverse event (AE) profiles of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) agents are of great interest, in particular the most recently approved statin, rosuvastatin. The forwarding of reports of AEs has been shown to be influenced by several reporting biases, including secular trend, the new drug reporting effect, product withdrawals, and publicity. Comparative assessments that use AE reporting rates are difficult to interpret under these circumstances, because such effects can themselves lead to marked increases in AE reporting. Consequently, many comparative reporting rate analyses are best carried out in conjunction with other metrics that put reporting burden into context, such as report proportion. All-AE reporting rates showed a temporal profile that resembled those of other statins when marketing cycle and secular trend were taken into account. A before-and-after cerivastatin withdrawal comparison showed a substantial increase in the reporting of AEs of interest for the statin class overall. Report proportion analyses indicated that the burden of rosuvastatin-associated AEs was similar to that for other statin agents. Analyses of monthly reporting rates showed that the reporting of rosuvastatin-associated rhabdomyolysis and renal failure have increased following AE-specific mass media publicity. Postrosuvastatin AE reporting patterns were comparable to those seen with other statins and did not resemble cerivastatin.

Controversies in cardiology

HomeCirculationVol. 112, No. 8Controversies in cardiology Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBControversies in cardiology Originally published23 Aug 2005https://doi.org/10.1161/circ.112.8.ivCirculation. 2005;112:ivThere are several areas of therapeutics where current practice differs between the United States and Europe. In the case of nesiritide, the use of this drug is undoubtedly controversial. This recombinant human brain natriuretic peptide is given to tens of thousands of patients in the United States every week at a cost of about $500 for each dose, and many physicians there are extremely enthusiastic about this new treatment for acute decompensated heart failure (ADHF).Aggressive marketing by the manufacturer, Scios Inc, has been suggested as one reason for its increasing use1 while many cardiologists in Europe are far less enthusiastic and have questioned whether nesiritide offers any improvement over current optimal management. Also the European Agency for the Evaluation of Medicinal Products has still not approved nesiritide and awaits the results of a trial involving 1900 patients before it will even consider doing so. In the UK, the assessment of nesiritide by the National Institute for Clinical Excellence is going at a snail’s pace and will not make any recommendations until August 2007.One recent meta-analysis published in March this year has suggested that nesiritide significantly increases the risk of worsening renal function in patients with ADHF,2 and another published a month later concluded that nesiritide may be associated with an increased risk of death after treatment for ADHF.3Scios Inc have stated in a letter to physicians and patient advocates dated 6 May 2005 that they remain confident in the safety profile of nesiritide and the benefits it offers to patients with acute decompensated heart failure. Differences of opinion on either side of the Atlantic appear set to continue.In the case of rosuvastatin, Europe and the US again seem at variance. Concerns were expressed in correspondence in a UK journal4 that rosuvastatin has an as yet unproven safety record, but family doctors and specialists are keen to prescribe it, even to individuals with no previous experience with lipid-lowering drugs, and to some who have predisposing risk factors for a potentially lethal side-effect. This was followed in June 2005 by new research that suggested that this drug, which has not been used in end-point trials, caused more kidney and muscle problems than rival medications although the rate of these complications was low.5The US Food and Drug Administration has contended that rosuvastatin’s risks are no greater than its competitors and rejected consumer efforts to remove the drug from sale, but did order a label warning that serious muscle problems and kidney damage could occur, especially among Asians.Manufacturer AstraZeneca strongly disagreed with the conclusions of the Circulation study and said the higher reports of side-effects may have been the result of heightened awareness of the problems following the withdrawal of cerivastatin in 2001. But in the UK, the Medicines and Healthcare Product Regulatory Agency issued advice as long ago as May 2004 that all patients start on 10 mg daily, and that the40- dose is contraindicated in patients with predisposing risk factors for muscle toxicity.Future issues of Circulation: European perspectives in cardiology will follow forthcoming developments and look at other variations in practice.References1 Topol EJ. Nesiritide—;not verified. N Engl J Med. 2005; 353 (2): 113–;6.CrossrefMedlineGoogle Scholar2 Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005; 111 (12): 1487–91.LinkGoogle Scholar3 Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005; 293 (15): 1900–5.CrossrefMedlineGoogle Scholar4 Florentinus SR, Heerdink ER, Klungel OH, de Boer A. Should rosuvastatin be withdrawn from the market?. Lancet. 2004; 364 (9445): 1577.CrossrefGoogle Scholar5 Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation. 2005; 111 (23): 3051–7.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails August 23, 2005Vol 112, Issue 8 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.112.8.iv Originally publishedAugust 23, 2005 PDF download Advertisement

Safety of High-Dose Atorvastatin Therapy

This article reviews the safety of statins, with emphasis on high-dose atorvastatin (80 mg), the agent with the most efficacy data for clinical outcomes. Although elevated levels of hepatic enzymes were of concern when statins were first introduced, a review of data from large clinical trials shows that elevations in hepatic enzymes are rare and do not lead to clinically significant liver disease. Despite the withdrawal of cerivastatin because of fatal rhabdomyolysis, the risk of this complication with other statins is extremely low. Mild and often transient myalgia is more commonly reported. The safety of high-dose atorvastatin has been evaluated in >11,000 patients, and rates of clinically significant myopathy and elevated hepatic enzymes were extremely low. Simvastatin at doses up to 40 mg is also associated with low rates of elevated hepatic enzymes and myopathy. However, the 80-mg dose of simvastatin carries a risk of myopathy (muscle symptoms and creatine kinase levels >10,000 U/L) of approximately 1 in 250. The clinical benefits of preventing vascular events, myocardial infarction, stroke, and need for revascularization outweigh the low rates of adverse events associated with high-dose statin therapy in high- and intermediate-risk patients.

Atteintes musculaires sévères sous statines : bilan des cas notifiés en France jusqu’à fin février 2002 et données concernant les risques liés à la cérivastatine

Background and methodsAfter the withdrawal of cerivastatin from the market, a survey was performed concerning severe muscular disorders associated with statin treatments that were notified to the French national and pharmaceutical industry pharmacovigilance systems up to February 2002. ResultsAmong the 238 cases analysed, 69 were related to cerivastatin, 86 to simvastatin, 49 to pravastatin, 23 to atorvastatin and 9 to fluvastatin. The reporting rate was six- to ten-times higher for cerivastatin than for other statins. A major risk factor for rhabdomyolysis with cerivastatin was its association with gemfibrozil. ConclusionPostmarketing surveillance appears to be a major tool for early detection of safety problems with a new drug.

Effects of switching pravastatin to cerivastatin on C-reactive protein, butyrylcholinesterase, and lipids

ABSTRACTObjective: C-reactive protein (CRP) concentrations, butyrylcholinesterase (BChE) activity, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) were evaluated in patients switched from pravastatin to cerivastatin. The purpose of this study was to determine whether a more potent statin (cerivastatin) would further affect CRP, whether a relationship between CRP and BChE existed, and if there were any relationships between CRP or BChE and lipids. In view of the withdrawal of cerivastatin from the market, studies considering the effects of conversion of patients from one statin to another are warranted.Research design and methods: Thirty-seven patients actively taking pravastatin (10 mg–40 mg) were switched to cerivastatin (0.2 mg–0.8 mg) at the initial visit in the Lipid Clinic at David Grant Medical Center, Travis Air Force Base. Samples were collected before the conversion (pravastatin phase) and at 6 weeks and 12 weeks post-conversion. Patients were excluded from the study if they were taking gemfibrozil concomitantly. Patients were counseled on the adverse effects of cerivastatin, including rhabdomyolsis.Results: Median CRP levels at the pravastatin phase, 6 weeks of cerivastatin, and 12 weeks of cerivastatin, were 0.380 mg/dL, 0.403 mg/dL, and 0.364 mg/dL ( p = 0.772), respectively. Median BChE activity at the pravastatin phase, 6 weeks of cerivastatin, and 12 weeks of cerivastatin were 0.338 µmol/mL/min, 0.332 µmol/mL/min, 0.33 µmol/mL/min ( p = 0.746), respectively. A negative correlation was observed between CRP and BChE at baseline only (r = –0.353, p = 0.032). There was a significant decline in mean TC ( p < 0.001) and median LDL ( p < 0.001) and a significant increase in mean HDL ( p = 0.017) over the three time points. Numerically TG declined, but it was not statistically significant ( p = 0.649). No correlations were observed between CRP or BChE and any of the lipids. Gender, aspirin use, and the presence of CHD or diabetes did not affect CRP levels or BChE activity.Conclusion: Median CRP remained stable with pravastatin and cerivastatin use, although TC and LDL decreased. The further decline observed with LDL, but not CRP suggests differing effects of statins on LDL and CRP. Limitations include no serum levels prior to statin use and small sample size; thus, future studies are needed to address the relationship between cholesterol and CRP and the mechanism of action of statins on CRP.

Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors

Background The recent withdrawal of cerivastatin by the manufacturer has led to an interest in hydroxymethylglutaryl-coenzyme A (HMG-CoA) inhibitors and the incidence of myopathy. We review the epidemiology, pharmacology, and presumed mechanisms of statin-induced myopathy, with a particular focus on cerivastatin. Methods A MEDLINE search of English-language articles published between 1985 and 2003 was performed. Key words included HMG-CoA inhibitors, statins, myopathy, myotoxicity, rhabdomyolysis, adverse events, drug interactions, and cerivastatin. Results The initial trials, which assessed the efficacy of first-generation HMG-CoA inhibitors, did not show a clinically significant increase in the incidence of myopathy. However, on the basis of Food and Drug Administration post-marketing surveys, the rate of cerivastatin-induced rhabdomyolysis appeared to be 10-fold greater than that of the other statins, despite safe pre-clinical profiles. However, no clinical trials have been performed directly comparing the rates of myotoxicity of all commercially available statins. The mechanism of statin-induced myopathy remains unclear. The prevailing theory is that lipophilic statins lead to depletion of intermediates normally formed after cholesterol synthesis within myocytes. Risk factors for the development of myopathy include drug interactions (especially with fibrates) and the coexistence of conditions known to predispose patients to rhabdomyolysis. Conclusion The cerivastatin experience emphasizes the need for large safety trials before drug approval and for vigilant post-marketing surveillance. Further research and sound clinical judgment may lead to the identification of high-risk individuals in whom statins should be avoided.

The cerivastatin withdrawal crisis: a “post-mortem” analysis

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=1.8–2.9). 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.

Detection and incidence of muscular adverse drug reactions: a prospective analysis from laboratory signals.

The awareness of muscular adverse drug reactions (ADRs) increased since the withdrawal of cerivastatin, a HMG-CoA reductase inhibitor, from the market in August 2001. Our objectives were to assess the detection and incidence of muscular ADRs in a University Hospital using biochemical laboratory data and to evaluate the underreporting rate of drug-induced muscular disorders. A prospective study was undertaken at Toulouse University Hospital, France, for 1 week per month from November 2001 to October 2002. Patients were selected by means of a computerized process using biochemical laboratory data based on serum creatine phosphokinase (CPK) values (over twofold normal). Medical records of all selected patients were then consulted. During the period of the study, 2017 CPK tests were performed, among which 171 values were over twofold normal corresponding to 129 patients. Because of lack of data, 26 patients were excluded. Among these patients ( n=103), 28 cases of muscular ADRs were suspected, 22 of which were detected in outpatient departments. Four patients were totally asymptomatic and five had an increase of CPK over fivefold normal. Nine cases were classified as "serious". Withdrawal of suspected drugs were done in 16 cases with regression of ADRs in 13 cases. According to hospitalization data, the incidence of muscular ADRs was estimated as 7.2 (2.6-15.7) per 10,000 inpatients and 9.3 (5.8-14.1) per 10,000 outpatients over 12 weeks. The involved drugs were mainly: statins (46.4%), fibrates (14.3%), antiretrovirals (14.3%), angiotensin-II receptor antagonists (10.7%), immunosuppressants (7.1%) or hydroxychloroquine (7.1). Only two cases, judged as "serious", were spontaneously reported by physicians during the same period. The results of this survey underline the importance to take into account drug hypothesis in muscular injuries diagnosis.

Cerivastatin withdrawal effect on use of lipid therapy

Cerivastatin withdrawal effect on use of lipid therapy