Fluvastatin and fluvastatin extended release: a clinical and safety profile

Drug Profile

© Future Drugs Ltd. All rights reserved. ISSN 1477-9072 641

CONTENTS

Introduction tothe compound

Pharmacodynamics

Pharmacokinetics& metabolism

Clinical efficacy

Safety & tolerability

Conclusion

Expert opinion

Five-year view

Key issues

References

Affiliations

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Fluvastatin and fluvastatin extended release: a clinicaland safety profileAnders Åsberg and Hallvard Holdaas†

Cardiovascular diseases due to atherosclerosis are the leading causes of mortality in the Western world. Cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has demonstrated a reduction in cardiovascular morbidity and mortality in diverse populations. Fluvastatin (Lescol®, Novartis Pharmaceuticals) was the first totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on the market and has recently become available in an extended-release formulation (Lescol XL®, Novartis Pharmaceuticals). Data from several clinical outcome trials have shown substantial benefits from fluvastatin treatment in diverse populations. Fluvastatin exists primarily in its acid form and as inactive metabolites in vivo, while active metabolites as well as the lactone form are only present in small amounts. The demonstration of the safe use of fluvastatin in a wide range of patients may be associated with the predominant acid form of the drug in vivo, as well as its predominant metabolism via the cytochrome P450 2C9 pathway.

Expert Rev. Cardiovasc. Ther. 2(5), 641–652 (2004)

†Author for correspondenceMedical Department, National Hospital, 0027 Oslo, NorwayTel.: +47 23 071 246Fax: +47 23 071 [email protected]

KEYWORDS:cardiovascular disease, drug safety, fluvastatin, hypercholesterolemia, pleiotropic effects, statins

Clinical atherosclerosis represents the majorcause of death in Western societies. Cardiovas-cular diseases due to atherosclerosis remainthe leading cause of mortality in men over 45and women over 65 years of age throughoutEurope, although there are differences bothbetween countries and within countries overtime [1,2].

In Europe cardiovascular mortality isincreasing, particularly in Eastern Europe.Conversely, cardiovascular disease hasdeclined in the countries from both Northernand Southern European regions [3]. Observa-tional studies in different populations indicatea continuous positive relationship betweencholesterol and cardiovascular diseases [4,5].

Hydroxymethylglutaryl coenzyme A(HMG-CoA) reductase inhibitors (statins)represent a breakthrough in the treatment ofhigh-serum cholesterol. Recent observationsalso suggest that some of the clinical benefitsof statins may be independent of their choles-terol-lowering effect – the so called pleiotropiceffects. The efficacy of statins in reducing car-diovascular morbidity and mortality has beendemonstrated in large clinical trials [6–14].

According to the recommendations of theNational Cholesterol Education Program(NCEP) expert panel, low-density lipoproteincholesterol (LDL-C) should be lowered to 2.6or 3 mmol/l for patients with or without addi-tional risk factors [15]. These recommendationshave been reinforced by the recent publicationof the NCEP guidelines [16]. Similar guidelineshave been published for the prevention of cor-onary heart disease in clinical practice, by theSecond Joint Task Force of European andother societies on coronary prevention [1].

There are six statins available: simvastatin(Zocor®, Merck Sharpe and Dohme), lovasta-tin (Mevacor®, Merck Sharpe and Dohme),pravastatin (Lipostat®, Bristol–Myers Squibb),atorvastatin (Lipitor®, Pfizer Ltd), fluvastatin(Lescol®, Novartis Pharmaceuticals) and rosu-vastatin (Crestor®, AstraZeneca), all of whichlower LDL-C. Fluvastatin is the first statinavailable as an extended-release formulation(Lescol XL®, Novartis Pharmaceuticals).

In general, statins are well-tolerated.There is an associated small risk for myo-pathy (which may progress to fatal or non-fatal rhabdomyolysis); however, the potential

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Åsberg & Holdaas

642 Expert Rev. Cardiovasc. Ther. 2(5), (2004)

for drug–drug interactions is known to increase in specifichigh-risk groups. The incidence of myopathy associated withstatin therapy may be partly dose related, and is increasedwhen statins are used in combination with agents that sharecommon metabolic pathways. Of particular concern is thepotential for interactions with other lipid-lowering agents suchas fibrates (e.g., gemfibrozil [Lopid®, Pfizer Ltd]), which maybe used in patients with mixed hyperlipidemia, and withimmunosuppressive agents (e.g., cyclosporin A) that are com-monly used in post-transplant patients. Clinicians should beaware of the potential for drug–drug interactions in order tominimize the risk of myopathy during long-term statin ther-apy in patients at risk of cardiovascular diseases. From a safetypoint of view, fluvastatin may offer an advantage due to itspredominant acid configuration in plasma.

Introduction to the compoundMechanisms of actionFluvastatin (XU 62-320) is the first totally syntheticHMG-CoA reductase inhibitor on the market and is admin-istered orally as its sodium salt: (±)-(3R*,5S*,6E)-7-(3-[4-fluorophenyl]-1-isopropylindol-2-yl)-3,5-dihydroxy-6-hep-tenoate. Fluvastatin has the molecular formulaC24H25FNO4•Na and its molecular weight is 433.4 g/mol.It is a relatively hydrophilic (octanol/water partition coeffi-cient of 20 at pH7), weak acid with an ionization constant(pKa) of 5.5. Instant-release fluvastatin has been on the mar-ket under different names around the world (i.e., Lescol®,Canef®, Cardiol® and Vastin® all Novartis Pharmaceuti-cals), and has been commercially available since 1994.Recently, the extended-release formulation of fluvastatin hasbeen approved for use.

In general, the β-hydroxy side chain of statins exists in bothan active open acid form as well as in a closed lactone formthat shows relatively low HMG-CoA reductase inhibitoryeffect [17]. Some statins, such as lovastatin and simvastatin, areadministered in the inactive lactone form and interconvertin vivo to the active acid form, while others, such as atorvasta-tin, are administered in the acid form, and interconvert to theinactive lactone form following administration. The lactoneand acid forms exist in equilibrium in vivo, and for many stat-ins the lactone form is at least as abundant as the acid form inplasma [18–21]. Fluvastatin, pravastatin and cerivastatin show asomewhat different pattern [18,22] – the systemic exposure oflactone in plasma is less than 5% of that of fluvastatin and itsother metabolites [23]. It has previously been hypothesizedthat the lactone form of statins may, in part, be responsiblefor the myotoxicity of statins [24]. Since fluvastatin lactoneonly exists in vivo in plasma in a negligible amount, thismight explain the few cases of severe myotoxic side effects, forinstance rhabdomyolysis reported for fluvastatin, especially inpatients on cyclosporine therapy where a transport interactionmay be of importance [25]. Another explanation may be lowerpharmacokinetic interaction risk via cytochrome P450 (CYP)2C9 in patients on polypharmacy.

PharmacodynamicsLipid-lowering effectApproximately two-thirds of the total cholesterol pool in thebody is derived from de novo biosynthesis in the liver [26]. Inhi-bition of hepatic cholesterol biosynthesis is therefore an effec-tive target for intervention in patients with elevated cholesterollevels. The rate-limiting step in cholesterol biosynthesis is theconversion of HMG-CoA to mevalonate, mediated by theenzyme HMG-CoA reductase (FIGURE 1). Fluvastatin, as well asall other statins, performs its effect by inhibiting this rate-limit-ing step in the cholesterol synthesis pathway. The structure offluvastatin is partly similar to HMG-CoA (FIGURE 2), the naturalsubstrate of HMG-CoA reductase, and its intermediate formsin the conversion to mevalonate. The bicyclic ring system offluvastatin is thought to mimic the structure of coenzyme A,even though this is not immediately obvious from the chemicalstructures of molecules. The coenzyme A structure anchors themolecule to the HMG-CoA reductase while the β-dihydroxyfive-carbon side chain (mimicking the 3-hydroxy-3-methyl-glutaryl side chain of HMG-CoA) actively blocks the activity ofHMG-CoA reductase [17]. Furthermore, the low-density lipo-protein (LDL)-receptors in the liver are upregulated to com-pensate for the lower intrahepatic concentration of cholesterolfollowing inhibition of the de novo biosynthesis of cholesterolby statins. The clearance of both LDLs and very low-density

Dolichol

Acetyl-CoA

HMG-CoA

Mevalonate

Isopentenyl-PP

Geranyl-PP

Farnesyl-PP

Squalene

Lanosterol

Cholesterol Ubiquinone

Geranylgeranyl-PP

HMG-CoA reductase

Figure 1. Cholesterol biosynthesis pathway.CoA: Coenzyme A; HMG: Hydroxymethylglutaryl; PP: Pyrophosphate.

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lipoproteins (VLDLs) from the plasma is increased due to thisadaptive upregulation of the LDL-receptors and hence bothplasma total cholesterol and LDL-C is decreased [27,28].

Pleiotropic effectIt has been hypothesized that statins in general may also havenonlipid-lowering effects that can improve cardiovascular risk,such as improvement of endothelial function and stabilizationof plaque, as well as inhibition of proliferation of both smoothmuscle cells and myocytes, inhibited platelet function, and ageneral decreased vascular inflammation [29]. The mechanismfor these hypothesized effects is not clear, but geranylgeranylpyrophosphate is a promising candidate since it serves as animportant lipid attachment for a variety of proteins involved inintracellular signaling, including different γ-subunits of G-pro-teins (FIGURE 1) [30]. It is not clear if potential pleiotropic effectsare a class effect of statins or are specific to each.

Fluvastatin has shown potentially antiatherogenic effectsin a number of experimental studies [31]. It has been shownthat fluvastatin exhibits antioxidative properties and con-tributes to the prevention of atherosclerosis in cholesterol-fed rabbits [32,33]. Fluvastatin also reduced macrophage accu-mulation in carotid lesions in rabbits [34]. Furthermore,treatment with fluvastatin significantly attenuated leuko-cyte–endothelial cell adhesion responses to platelet-activat-ing factor and leukotrene B4 in postcapillary venules ofhypercholesterolemic rats [35]. Fluvastatin has been found toreduce interleukin-6 in vitro in human vascular smoothmuscle cells [36], and to inhibit proliferation of vascularsmooth muscle cells [37].

The effect of fluvastatin on endothelial function in renaltransplant recipients further elucidates this. Hausberg andcolleagues performed a double-blind, placebo-controlled

trial in renal transplant recipients, 4 to5 years after transplantation [38]. A totalof 36 patients were randomized toreceive either placebo or 40 mg fluvasta-tin per day. Endothelial function in thebrachial artery was significantly betterin the fluvastatin group compared withplacebo at 6 months. This effect wasconserved at 3 years, as shown inanother publication from the samegroup [39]. The authors performed asimilar, double-blind study, randomiz-ing renal transplant patients at the timeof transplantation to either 40 mg fluv-astatin per day or placebo. The endothe-lial function in small-resistance arteri-oles was no different between the twotreatment groups at 3 months posttransplant [40]. Fluvastatin has beenshown to improve microcirculation inpatients with hyperlipidemia [41], and tohave a beneficial effect on myocardial

blood flow in patients with coronary artery disease [42]. Theclinical benefits of fluvastatin were independent of baselinecholesterol in the Lipoprotein and Coronary AtherosclerosisStudy (LCAS) [43], the Lescol Intervention Prevention Study(LIPS) [11], and the Assessment of LEscol in Renal Trans-plantation (ALERT) study [13], indicating that nonlipideffects could be involved.

In addition to these potential nonlipid effects of statinsthat may directly benefit those with cardiovascular disease, ithas also been hypothesized that statins may have immuno-modulating effects in solid organ transplant recipients. Ithas been shown in vitro that the statin compactin (mevasta-tin, AG Scientific) inhibits natural killer cells [44]. Furtherin vitro evidence of the immunomodulating effects of statinshave recently been reviewed by Mach [45].

Findings reported by Katznelson and colleagues in renaltransplant patients [46], and Wenke and colleagues andKobashigawa and coworkers in heart transplant patients,have also indicated an effect on acute rejections [47,48]. How-ever, a sufficiently powered (n = 364) prospective, double-blind, placebo-controlled study of the incidence of acuterejection in renal transplant patients showed no effect of flu-vastatin 40 mg/day on the incidence of acute rejection [49].A recent review by Holdaas and Jardine stated that the mostlikely explanation is that statins do not have any relevantimmunomodulating effects that result in clinically relevantinfluence on acute rejection episodes in transplantpatients [50].

Pharmacokinetics & metabolismPharmacokinetics of the different statins have been reviewedthoroughly by several authors [28,51–54], so this review will focuson the pharmacokinetics of fluvastatin only.

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O S

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OHO

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H3C

Hydroxymethylglutaryl coenzyme A

Fluvastatin

Figure 2. Hydroxymethylglutaryl coenzyme A and fluvastatin.

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Åsberg & Holdaas


Fluvastatin is rapidly and completely absorbed with anabsolute bioavailability of only 29%, but the first-pass metabo-lism is saturable and the bioavailability therefore increases whendoses higher than 20 mg/day are given [55,56]. In order to bypassthis saturable first-pass metabolism, a sustained-release formu-lation was developed, and this shows linear pharmacokinetics atdoses up to 320 mg/day [57]. Increasing the dose to 640 mg/dayresults in a severe, nonproportional increase in systemic expo-sure. Fluvastatin is highly bound to plasma albumin (99%) andthe volume of distribution is relatively low, 0.42 l/kg, mainlyconsisting of distribution to the liver [55,58]. The excretion offluvastatin is primarily via feces (90%) and less than 1% isfound unchanged in the urine [55]. Fluvastatin and its hydroxy-lated metabolites are active, while the most prominent metabo-lite, N-des-isopropyl-propionic acid, does not show pharmaco-logic activity to any relevant degree [17,23]. The interval tomaximum concentration (Tmax) is short for the instant-releaseformulation of fluvastatin, between 0.5 and 1.5 h, while theextended-release formulation has a Tmax of between 3 and4 h [55,57,59]. Terminal half-life of the instant-release formula-tion of fluvastatin is short, only 0.5 to 1.0 h [55], and the drug ischaracterized as a high extraction drug. The apparent terminalhalf-life is longer in the sustained-release formulation – in therange of 3 to 9 h [57].

Age and sex does not seem to influence fluvastatinpharmacokinetics, neither does renal impairment, but inpatients with hepatic impairment, a significant reduction inboth clearance and volume of distribution has beenshown [60,61]. Administration of fluvastatin with food mightreduce the maximum concentration (Cmax) and overall sys-temic exposure with a concomitant increase in Tmax [62].Chronic alcohol consumption also shows similar effects onfluvastatin pharmacokinetics [63]. These effects probably haveno clinical relevance.

Fluvastatin differs from the other statins in that it is theonly statin that is mainly metabolized by CYP2C9 [62,64]. Themetabolic pattern for fluvastatin and a selection of its metabo-lites in humans are shown in FIGURE 3. Other metabolites havealso been described but are only present in minor amounts inhumans [23]. The lactone form of fluvastatin is also onlypresent in small amounts in humans, a pattern not seen formost other statins [23]. Fluvastatin is not only a substrate forCYP2C9 but has also been shown to be an inhibitor ofCYP2C9 in vitro [24,56,64]. There are some case reports indi-cating a possible interaction between fluvastatin andwarfarin [65], but in a controlled study there was no significantchange in either bleeding time or plasma concentrations ofwarfarin [66].

However, in a recent study, fluvastatin has been shown to bevulnerable in the inhibition of its CYP2C9 metabolism – sev-eral-fold higher systemic exposure was present in both hetero-zygous and homozygous CYP2C9*3 genotypes [67]. TheCYP2C9*2 genotypes, on the other hand, did not contributeto any important degree to the variability of fluvastatin sys-temic exposure. Fluconazole (Diflucan®, Pfizer Ltd), a known

inhibitor of CYP2C9 [24], has also been shown to increasefluvastatin systemic exposure by 1.8-fold [68]. In cyclosporine(Sandimmun®, Novartis)-treated renal transplant patients,the systemic exposure of fluvastatin was also approximately1.9-fold higher than in healthy controls [69], and in hearttransplant recipients the area under the fluvastatin concentra-tion–time curve (AUC) was 3.1 to 3.5-fold higher [70]. Sincecyclosporines do not interfere with CYP2C9 activity, an alter-native mechanism may be responsible for this specific interac-tion and both the authors and others have speculated that itmight be due to an interaction via the liver-specific organicanion transporter polypeptide (OATP)-C that mediates statintransport into the liver [51]. Interaction with organic aniontransporter (OAT)-3, present in skeletal muscle, kidney andbrain tissue, may be relevant with regard to myotoxicity butprobably not to the pharmacokinetic interaction with statins.Fluvastatin has been shown to inhibit this transporter, but sofar only pravastatin has been shown to be a substrate of thetransporter itself [71].

Gemfibrozil is known to interact with several statins,resulting in a several-fold increase in the systemic exposureof the statins [24]. There has been speculation regarding themechanism of this interaction, and CYP2C8, as well as urid-ine diphosphate glucuronyl transferase (UGT) inhibition,are possible candidates [72,73]. However, no increase in fluv-astatin AUC was shown with concomitant administration ofgemfibrozil [74]. This is in accordance with the hypothesizedinvolvement of UGTs in the lactonization of statins [75], andthe low level of fluvastatin lactone in humans comparedwith many other statins.

Omeprazole (Losec®, AstraZeneca), a CYP2C19 inhibitor,and other gastric acid-regulating agents such as cimetidine(Tagamet®, GlaxoSmithKline) and ranitidine (Zantac®,GlaxoSmithKline) have been shown to increase fluvastatinCmax by 50% [62]. The mechanism may be indirect via anincreased pH, such as decreased degradation in the gastro-intestinal tract. Cholestyramine (Questran®, Bristol–MyersSquibb) given concomitantly with fluvastatin has been shownto reduce the Cmax and AUC of fluvastatin, as well as toincrease the Tmax [60]. When the intake of these drugs is sepa-rated by 4 h, the interaction is of no clinical relevance.Rifampicin (a CYP2C9 inducer), on the other hand, reducesbioavailability by approximately 50% [76].

Clinical efficacyThe average reduction from baseline LDL-C levels in the majorstatin clinical trials has ranged between 25 and 35%. In the largeprospective trial ALERT, LDL-C was lowered by 32% with80 mg fluvastatin, and there was a LDL difference between thetreatment and placebo arms of 1 mmol/l, as seen in other majorclinical trials (TABLE 1) [13]. The extended-release formulationmay be even more potent; treatment (80 mg) led to medianreductions in LDL-C of 38% at 4 weeks in a pooled analysis ofclinical trial data; a reduction of more than 40% was achieved in40% of these patients [77]. Fluvastatin in the extended-release



formulation was also effective in raising high-density lipoproteincholesterol (HDL-C) with a mean increase of 8.7%; and in asubset of patients with baseline triglyceride levels above3.4 mmol/l, HDL-C was increased by 21%. Mediandecreases in triglyceride levels were 19%, but the decreasewas 31% in the subset of patients with baseline triglyceridelevels of above 3.4 mmol/l. In a multicenter, placebo-con-trolled trial in patients with Type 2 diabetes, fluvastatin inthe extended-release formulation decreased LDL-C by 29%and triglycerides by 18% following 8 weeks of treatment [78].

Another randomized, controlled trial assessed the efficacy andsafety of the extended-release formulation of fluvastatin in1229 elderly (aged 70–85 years) men and women. The meanLDL reduction after 6 months was 31% [79]. Overall, thelipid-lowering effect of fluvastatin extended release is compa-rable to that achieved with other statins in large randomized,controlled trials (TABLE 1).

Data from several clinical outcome trials have demonstratedthe clinical benefits of fluvastatin therapy in diverse popula-tions. These include the LCAS [43], the study of Lescol® in

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Fluvastatin

Figure 3. Metabolic pattern of fluvastatin and its main metabolites.CYP: Cytochrome P450.


Åsberg & Holdaas


Severe Atherosclerosis (LiSA) [80], the FLuvastatin AngioplastyREstenosis (FLARE) trial [81], and the study of FLuvastatin OnRIsk reDuction after Acute myocardial infarction(FLORIDA) [82]. Recently, two large, randomized clinical trialshave demonstrated that fluvastatin is effective for the secondaryprevention of cardiac events in patients following coronaryintervention procedures (LIPS) [11], and for the primary pre-vention of cardiac events in renal transplant recipients(ALERT) [13].

Patients recruited to LCAS (n = 429) had coronary heartdisease with documented angiographic lesions and moderateelevation of LDL-C [43]. Over the follow-up period of2.5 years, fluvastatin-treated patients showed a LDL-Creduction of 24%. Assessed by quantitative coronary angio-graphy, fluvastatin-treated patients showed significantly lessprogression of the qualifying lesion. There was a nonsignifi-cant reduction of 24% of clinical events (myocardial infarc-tion, revascularization, unstable angina requiring hospitali-zation or death) in a subset of patients with baseline HDLlevels below 0.4 mmol/l. In addition to significantly reduc-ing lesion progression, fluvastatin also significantly loweredclinical events compared with placebo [83]. In LiSA(n = 365), patients had elevated LDL-C (>4.1 mmol/l) andsymptomatic ischemic cardiac disease. Treatment with fluv-astatin (40–80 mg/day) resulted in a significantly lower inci-dence of cardiac events over 12 months of follow-up, com-pared with placebo-treated patients [80]. The FLARE trialwas a study of the prevention of restenosis. Patients weregiven fluvastatin, 40 to 80 mg, 2 to 4 weeks prior to aplanned percutaneous coronary intervention by balloonangioplasty. Treatment with fluvastatin did not influence therate of restenosis, but resulted in a statistically significant

reduction in the combined outcomes of overall death andmyocardial infarction at 40 weeks. In the FLORIDA trial,540 patients post myocardial infarction were randomized toreceive fluvastatin or placebo [82]. Primary end points in thestudy were 48-h ambulatory electrocardiogram monitoringand clinical events. The trial was underpowered since resid-ual ischemia was observed less frequently in the study popu-lation than had been reported in other studies, and thereforefailed to show any benefit on the primary end point.

LIPS was the first large, prospective, randomized trial toinvestigate the effects of statin therapy on clinical outcomes fol-lowing a successful percutaneous coronary intervention [81].The primary outcome of the study was the incidence of majoradverse cardiac events (MACE), defined as cardiac death, non-fatal MI, or a cardiac intervention procedure. A total of1677 patients were enrolled in LIPS, and the patients were ran-domized to fluvastatin (80 mg) or placebo within days of suc-cessful completion of their first percutaneous coronary inter-vention. Fluvastatin significantly reduced LDL-C by a medianof 27%. Over a median follow-up period of 3.9 years, fluvasta-tin therapy resulted in a significant risk reduction of 22% in theincidence of MACE compared with placebo (p = 0.01). Theclinical benefits were independent of baseline cholesterol levels.The results from LIPS suggest that treating 19 patients for4 years with fluvastatin would prevent one fatal or nonfatalmajor cardiac event.

Holdaas and colleagues recently published the first large,randomized, controlled trial to study cardiac outcomes inrenal transplantation [13]. The intent-to-treat populationcomprised 2102 patients with cholesterol levels between4 and 9 mmol/l. The patients were randomly assigned toreceive either fluvastatin (n = 1050) or placebo (n = 1052).

Table 1. Low-density lipoprotein-cholesterol levels and coronary heart disease event rates in major statin trials.

Study Sample size(n)

Follow-up(years)

Baseline LDL(mmol/l)

LDL-C netchange

(mmol/l)

LDL-C netchange

(%)

CHD% risk

reduction

Ref.

4S 4444 5.4 4.9 1.7 35 34 [7]

WOSCOPS 6595 4.9 5.0 1.3 26 32 [9]

CARE 4159 5.0 3.6 1.0 28 24 [12]

HPS 20536 5.0 3.4 1.0 30 27 [6]

PROSPER 5804 3.2 3.8 1.0 27 19 [8]

ASCOT–LLA 10305 3.3 3.4 1.0 29 36 [10]

ALERT 2102 5.1 4.1 1.0 32 35 [13]

LIPID 9014 6.1 3.9 0.9 25 24 [14]

LIPS 1677 3.9 3.4 0.9 27 31 [11]

CHD, cardiac death or nonfatal myocardial infarction. Annual rates expressed in percent for the untreated group.4S: Scandinavian Simvastatin Survival Study; ALERT: Assessment of LEscol in Renal Transplantation study; ASCOT–LLA: Anglo–Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm; CARE: Cholesterol And Recurrent Events trial; CHD: Coronary heart disease; HPS: Heart Protection Study; LDL: Low-density lipoprotein; LDL-C: LDL cholesterol; LIPID: Long-term Intervention with Pravastatin in Ischemic Disease study; LIPS: Lescol Intervention Prevention Study; PROSPER: PROSpective study of Pravastatin in the Elderly at Risk; WOSCOPS: West Of Scotland COronary Prevention Study.



Treatment with fluvastatin significantly reduced total cholesteroland LDL-C levels. From a mean baseline LDL-C level of4.1 mmol/l, fluvastatin-treated patients showed sustainedreductions throughout the study; the mean LDL-C level was2.7 mmol/l at the end of the study. Thus, most patients wereable to achieve target LDL-C levels as recommended by con-sensus bodies for the prevention of coronary heartdisease [1,10]. The 35% risk reduction for cardiac death andnonfatal myocardial infarction, and the absolute net reduc-tion in LDL-C (1 mmol/l between groups) are similar tothose observed in other major statin outcome trials (TABLE 1).The incidence of cardiovascular or renal end points did notdiffer between groups. No significant difference was seen forthe incidence of cardiac intervention procedures comparedwith placebo, thus the primary end point of first MACE wasnonsignificant with fluvastatin (17%, p = 0.139). However,fluvastatin use significantly reduced the risk of cardiac deathby 38% (p = 0.031) and of cardiac death or first definite non-fatal myocardial infarction by 35% compared with placebo(p = 0.005). These data indicate that the number that wouldneed to be treated in order to prevent one cardiac death ornonfatal myocardial infarction would be 31 patients over5 years, representing a relatively small cost of overall care forthis population.

Safety & tolerabilityIn general, statins are well-tolerated; and as a rule for all thelarge prospective clinical trials, the side-effect profile has beenno different between the active-treatment and placebo arms. Aconcern during statin therapy is the risk for myopathy andrhabdomyolysis. While rare, both have been reported for allstatins [25]. Cerivastatin (Baycol®) was voluntarily withdrawnfrom the global market by Bayer in 2001 [84], raising concernsregarding the safety of the entire class. Relative to other statins,cerivastatin had a higher reporting rate for rhabdomyolysis,including fatalities, particularly at the highest recommendeddose (0.8 mg/day) or when it was taken in combination withgemfibrozil [85]. In approximately 50% of all cases of statin-related rhabdomyolysis, a drug–drug interaction wassuspected [25].

The patients who will benefit most from statin therapyare, at the same time, patients who may be at the greatestrisk of myopathy. Patients at highest risk for coronary heartdisease – regardless of their lipid profiles – include olderindividuals, post-transplant patients, and patients withhypertension, diabetes or multivessel atherosclerotic disease.These individuals are also the most likely to need multiplemedications and thus are at greatest risk for drug–druginteractions while on statin therapy. As a class, the reportedrates of serious adverse events among statins have been verylow, and include a slight risk for elevation of liver enzymesand myopathy [86]. The risk for reversible elevation of livertransaminases (defined by alanine aminotransferase and/oraspartate aminotransferase levels over three-times the upperlimit of normal) is approximately 1% for all statins [87]. At

doses investigated in clinical trials, these rates were notfound to be significantly different than those forplacebo [88]. Safety data were pooled from all Novartis-spon-sored research clinical trials (RCTs) between 1987 and 2001and included 8951 patients receiving placebo or fluvastatin20 to 80 mg/day. There were no cases of rhabdomyolysis ormyopathy, and the frequency of elevated creatinine kinaselevels was similar to that of placebo [89]. Potential side effectsof statins are more likely to occur when statins are adminis-tered in combination with other drugs. Of special concernhas been the interaction of statins with fibrates. Safety datawere also pooled from ten Novartis-sponsored studies inwhich fluvastatin was administered in combination withbezafibrate (Bezalip®, Roche), fenofibrate (Lipantil®,Fournier Pharmaceuticals Ltd) or gemfibrozil. The creati-nine kinase elevation for the combined use of of fluvastatinand a fibrate did not differ from placebo or fluvastatinalone [90]. In a RCT in 1229 elderly patients (who are moreprone to side effects), the overall safety of extended releasefluvastatin was similar to that of the placebo.

The ALERT trial recruited a population of high-riskpatients. The use of any cardiovascular drugs over the totalduration of follow-up was 95% in both groups, demonstrat-ing the cardiovascular complexity of this population. Allpatients were on immunosuppressive drugs and conse-quently the risk was high for side effects of drug–drug inter-actions. However, there were no differences in the incidenceof critical elevations of alanine aminotransferase, aspartateaminotransferase or creatinine kinase levels between the twogroups. None of the instances of critical creatinine kinaseabnormalities were accompanied by musculoskeletal symp-toms. There were two cases of nonfatal rhabdomyolysis dur-ing the trial, one in the fluvastatin group and one in the pla-cebo group. On investigation, neither of these cases weredrug related but were due to recent trauma. After the epi-sodes resolved, both patients restarted allocated drug treat-ments and completed the trial. Another concern for long-term survivors of renal transplantation is an increased risk ofinfectious disease [91]. Reassuringly, there was no increase ininfections in the population treated with fluvastatin.

A major concern has been an increased incidence of cancerduring statin therapy. An increased incidence of cancer wasobserved in the PROSpective study of Pravastatin in the Eld-erly at Risk (PROSPER) trial and an increased incidence ofbreast cancer in the Cholesterol And Recurrent Events(CARE) study, both trials using pravastatin in the activearm [8,12]. However, a pooled analysis of all large trials withpravastatin could not confirm the increased cancer risk [8].Renal transplant patients experience a substantial increasedcancer incidence due to long-term immunosuppressive medi-cation. In the ALERT trial, the patients were exposed toimmunosuppressive medication for a mean period of12 years. Although the incidence of cancer was several timeshigher in the ALERT trial than in other statin trials due to theimmunosuppressive therapy, there was no difference in cancer


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incidence between the placebo arm and the fluvastatin arm(TABLE 2). Reassuringly, fluvastatin did not seem to cause anyconcern for cancer risk in this population at high risk ofneoplasm. The safety profile of fluvastatin is perhaps themost remarkable aspect of the ALERT trial. Fluvastatin alsohas the potential to be an appropriate drug for HIV-infectedpatients receiving highly active antiretroviral drugs, whichare metabolized by CYP3A4 and therefore show potentialpharmacokinetic interaction problems with most statins [92].However, fluvastatin, with its CYP2C9 profile, bypasses thispotential problem to a certain degree in polypharmacy. Arecent meta-analysis by Ballantyne and colleagues has alsostressed the clinical benefits of fluvastatin in thispopulation [93].

ConclusionSeveral landmark trials over the past 10 years have demonstratedthat statins can substantially reduce both morbidity andmortality from cardiovascular disease in diverse populations.Statins are becoming a mainstay in cholesterol-loweringmanagement of patients with dyslipidemia, both for primaryand secondary prevention. Populations in need of statintreatment encompass a sizeable portion of individuals whoare also at high risk for drug–drug interactions due to theirneed for multiple medications. Fluvastatin is the firstHMG-CoA reductase inhibitor in an extended-release for-mulation, which may help bypass saturable bioavailablility.Its atypical metabolic profile for a statin, being metabolizedmainly by CYP2C9, also contributes to the possibility of amore flexible and individualized pharmacotherapy with stat-ins. The clinical benefits of fluvastatin have been demon-strated in randomized, controlled trials in a variety of high-risk patients, with an excellent safety profile even in patientswith complex treatment regimens. The lipid-lowering effectof fluvastatin and the reduction in cardiac end points are

consistent with the beneficial effects of statins in large clinicaltrials. The clinical trial evidence suggests a highly favorablebenefit-to-risk profile for fluvastatin.

Expert opinionThe established indication for use of statins today is to lowerLDL-C in patients in order to reduce the risk for cardiac, cere-bral or vascular morbidity and mortality in patients with a widerange of LDLs. However, statins seem to have promise for ben-eficial effects beyond their lipid-lowering ability. Statins do notonly affect lipid metabolism via their cholesterol synthesisinhibitory effect via HMG-CoA reductase inhibition, but mayalso affect inflammatory and immunomodulatory mechanismsin additional ways, such as inhibited prenylation (FIGURE 1) [94].The clinical implication of these mechanisms is that statins maywiden their therapeutic use beyond traditional cardiovascularindications. The authors have already seen small trial/cohortstudies examining potential beneficial effects in a wide varietyof diseases such as Alzheimer’s disease and dementia, osteoporo-sis, multiple sclerosis and neoplasms. Clearly, extensive addi-tional clinical trials are needed before the indications of statinscan be expanded beyond the established areas.

Five-year viewStatins are now established as the LDL lowering drugs ofchoice. The future will determine to what level LDL shouldbe reduced. Several major trials are now underway to examinethe hypothesis that ‘the lower the better’. Even if ongoingstudies do demonstrate this for LDL-C, the future use of stat-ins will focus increasingly on the safety aspect of the drugs.The price to pay by increasing the dose of statins might not beworth paying. In the future, therefore, combined treatmentmodalities, beyond todays options of combining a statin withniacin, fibrates or cholesterol absorption inhibitors, will be anemerging field.

Table 2. Cancer incidence in major statin trials.

Study Follow-up Statin Placebo Ref.

(years) Cancer incidence % Cancer incidence %

4S 5.4 90/2221 4.1 96/2223 3.4 [7]

WOSCOPS 4.9 116/3302 3.5 106/3293 3.2 [9]

CARE 5.0 172/3302 8.3 161/2078 8.9 [12]

HPS 5.0 814/10269 7.9 803/10267 7.8 [6]

PROSPER 3.2 245/2891 8.5 119/2913 4.1 [8]

ALERT 5.1 296/1050 28.3 316/1052 30.1 [13]

LIPID 6.1 379/4512 8.4 399/4502 8.9 [14]

LIPS 3.9 14/844 1.7 18/833 2.2 [11]

4S: Scandinavian Simvastatin Survival Study; ALERT: Assessment of LEscol in Renal Transplantation study; CARE: Cholesterol And Recurrent Events trial; HPS: Heart Protection Study; LIPID: Long-term Intervention with Pravastatin in Ischemic Disease study; LIPS: Lescol Intervention Prevention Study; PROSPER: PROSpective study of Pravastatin in the Elderly at Risk; WOSCOPS: West Of Scotland COronary Prevention Study.



DisclosureHallvard Holdaas has served as a consultant for and receivedtravel expenses, payment for lecturing, or funding forresearch from pharmaceutical companies marketing lipid-low-ering drugs, including Novartis, Merck Sharpe and Dohme,

Bristol–Myers Squibb, AstraZeneca, Schering, Bayer and PfizerLtd. Anders Åsberg has served as a consultant for and receivedtravel expenses, payment for lecturing, or funding for researchfrom pharmaceutical companies marketing lipid-loweringdrugs, including Novartis, Pfizer Ltd and Bayer.

Key issues

• Fluvastatin lowers low-density lipoprotein cholesterol (LDL-C) comparable to the net reduction of LDL-C levels demonstrated in other major statin trials.

• Two large controlled trials have demonstrated that fluvastatin reduces cardiovascular morbidity and mortality to the same extent as other statin trials have shown in diverse populations.

• The tolerability and pharmacokinetic profiles of fluvastatin allow its use in most patient groups.

• Fluvastatin has the potential for fewer drug interactions than other 3-hydroxy-3-methylglutaryl coenzyme A inhibitors.

• Fluvastatin in the extended-release formulation bypasses the saturable bioavailablility that is present with high doses using the instant-release formulation.

• Fluvastatin appears to be a cost-effective therapy for hypercholesterolemia in a variety of patients.

References

1 Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and other Societies on coronary prevention. Eur. Heart J. 19, 1434–1503 (1998).

2 Tyroler HA. Coronary heart disease epidemiology in the 21st century. Epidemiology Rev. 22, 7–13 (2000).

3 Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, Tolonen H, Ruokokoski E, Amouyel P. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. MONitoring trends and determinants In CArdiovascular disease. Lancet 353, 1547–1557 (1999).

4 Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16, 434–444 (1993).

5 Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart disease in a population with low cholesterol concentrations. Br. Med. J. 303, 276–282 (1991).

6 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized, placebo-controlled trial. Lancet 360, 7–22 (2002).

7 Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).

8 Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 360, 1623–1630 (2002).

9 Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333, 1301–1307 (1995).

10 Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo–Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT–LLA): a multicenter, randomized controlled trial. Lancet 361, 1149–1158 (2003).

11 Serruys PW, de Feyter P, Macaya C et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. J. Am. Med. Assoc. 287, 3215–3222 (2002).

12 Sacks FM, Pfeffer MA, Moye LA et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol And Recurrent Events trial investigators. N. Engl. J. Med. 335, 1001–1009 (1996).

13 Holdaas H, Fellström B, Jardine AG et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial. Lancet 361, 2024–2031 (2003).

14 Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N. Engl. J. Med. 339, 1349–1357 (1998).

15 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). J. Am. Med. Assoc. 285, 2486–2497 (2001).

16 Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110, 227–239 (2004).

17 Kathawala FG. HMG-CoA reductase inhibitors: an exciting development in the treatment of hyperlipoproteinemia. Med. Res. Rev. 11, 121–146 (1991).

18 Lilja JJ, Kivistö KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin. Pharmacol. Ther. 66, 118–127 (1999).

19 Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active


Åsberg & Holdaas


lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin. Pharmacol. Ther. 69, 340–345 (2001).

20 Backman JT, Kyrklund C, Kivistö KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin. Pharmacol. Ther. 68, 122–129 (2000).

21 Schneck DW, Birmingham BK, Zalikowski JA et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin. Pharmacol. Ther. 75, 455–463 (2004).

22 Kantola T, Kivistö KT, Neuvonen PJ. Effect of itraconazole on cerivastatin pharmacokinetics. Eur. J. Clin. Pharmacol. 54, 851–855 (1999).

23 Dain JG, Fu E, Gorski J, Nicoletti J, Scallen TJ. Biotransformation of fluvastatin sodium in humans. Drug Metab. Dispos. 21, 567–572 (1993).

24 Molden E. Variability in cytochrome P450-mediated metabolism of cardiovascular drugs: clinical implications and practical attempts to avoid potential problems. Heart Drug 4, 55–79 (2004).

25 Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann. Pharmacother. 36, 288–295 (2002).

26 Brown MS, Kovanen PT, Goldstein JL. Regulation of plasma cholesterol by lipoprotein receptors. Science 212, 628–635 (1981).

27 Hayashi K, Kurokawa J, Nomura S, Kuga Y, Ohkura Y, Kajiyama G. Effect of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the induction of low-density lipoprotein receptor in HepG2 cells. Biochem. Biophys. Acta 1167, 223–225 (1993).

28 Desager JP, Horsmans Y. Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin. Pharmacokinet. 31, 348–371 (1996).

29 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler. Thromb. Vasc. Biol. 21, 1712–1719 (2001).

30 Van Aelst L, D’Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev. 11, 2295–2322 (1997).

31 Corsini A. Fluvastatin: effects beyond cholesterol lowering. J. Cardiovasc. Pharmacol. Ther. 5, 161–175 (2000).

32 Rikitake Y, Kawashima S, Takeshita S et al. Antioxidative properties of fluvastatin, an HMG-CoA reductase

inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits. Atherosclerosis 154, 87–96 (2001).

33 Yasuhara M, Suzumura K, Tanaka K et al. Fluvastatin, an HMG-CoA reductase inhibitor, protects LDL from oxidative modification in hypercholesterolemic rabbits. Biol. Pharm. Bull. 23, 570–574 (2000).

34 Baetta R, Camera M, Comparato C, Altana C, Ezekowitz MD, Tremoli E. Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering. Arterioscler. Thromb. Vasc. Biol. 22, 692–698 (2002).

35 Kimura M, Kurose I, Russell J, Granger DN. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats. Arterioscler. Thromb. Vasc. Biol. 17, 1521–1526 (1997).

36 Ito T, Ikeda U, Shimpo M et al. HMG-CoA reductase inhibitors reduce interleukin-6 synthesis in human vascular smooth muscle cells. Cardiovasc. Drugs Ther. 16, 121–126 (2002).

37 Corsini A, Pazzucconi F, Pfister P, Paoletti R, Sirtori CR. Inhibitor of proliferation of arterial smooth-muscle cells by fluvastatin. Lancet 348, 1584 (1996).

38 Hausberg M, Kosch M, Stam F et al. Effect of fluvastatin on endothelium-dependent brachial artery vasodilation in patients after renal transplantation. Kidney Int. 59, 1473–1479 (2001).

39 Kosch M, Barenbrock M, Suwelack B, Schaefer RM, Rahn KH, Hausberg M. Effect of a 3-year therapy with the 3-hydroxy-3-methylglutaryl coenzyme A reductase-inhibitor, fluvastatin on endothelial function and distensibility of large arteries in hypercholesterolemic renal transplant recipient. Am. J. Kidney Dis. 41, 1088–1096 (2003).

40 Åsberg A, Holdaas H, Jardine AG, Edvardsen C, Hartmann A. Fluvastatin reduces atherogenic lipids without any effect on native endothelial function early after kidney transplantation. Clin. Transplant. 17, 385–390 (2003).

41 Haak E, Abletshauser C, Weber S et al. Fluvastatin therapy improves microcirculation in patients with hyperlipidemia. Atherosclerosis 155, 395–401 (2001).

42 Eichstädt HW, Abletshauser CB, Stork T, Weidinger G. Beneficial effects of fluvastatin on myocardial blood flow at

two time-points in hypercholesterolemic patients with coronary artery disease. J. Cardiovasc. Pharmacol. 35, 735–740 (2000).

43 Herd JA, Ballantyne CM, Farmer JA et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am. J. Cardiol. 80, 278–286 (1997).

44 Cutts JL, Scallen TJ, Watson J, Bankhurst AD. Role of mevalonic acid in the regulation of natural killer cell cytotoxicity. J. Cell. Physiol. 139, 550–557 (1989).

45 Mach F. Statins as novel immunomodulators: from cell to potential clinical benefit. Thromb. Haemost. 90, 607–610 (2003).

46 Katznelson S, Wilkinson AH, Kobashigawa JA et al. The effect of pravastatin on acute rejection after kidney transplantation – a pilot study. Transplantation 61, 1469–1474 (1996).

47 Wenke K, Meiser B, Thiery J et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a 4-year randomized trial. Circulation 96, 1398–1402 (1997).

48 Kobashigawa JA, Katznelson S, Laks H et al. Effect of pravastatin on outcomes after cardiac transplantation. N. Engl. J. Med. 333, 621–627 (1995).

49 Holdaas H, Jardine AG, Wheeler DC et al. Effect of fluvastatin on acute renal allograft rejection: a randomized multicenter trial. Kidney Int. 60, 1990–1997 (2001).

50 Holdaas H, Jardine A. Acute renal allograft rejections, a role for statins? Minerva Urol. Nefrol. 55, 111–119 (2003).

51 Åsberg A. Interactions between cyclosporin and lipid-lowering drugs: implications for organ transplant recipients. Drugs 63, 367–378 (2003).

52 Garcia MJ, Reinoso RF, Sanchez Navarro A, Prous JR. Clinical pharmacokinetics of statins. Methods Find. Exp. Clin. Pharmacol. 25, 457–481 (2003).

53 Williams D, Feely J. Pharmacokinetic–pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin. Pharmacokinet. 41, 343–370 (2002).

54 Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol. Ther. 80, 1–34 (1998).



55 Tse FL, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J. Clin. Pharmacol. 32, 630–638 (1992).

56 Transon C, Leemann T, Vogt N, Dayer P. In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (+/-)- fluvastatin. Clin. Pharmacol. Ther. 58, 412–417 (1995).

57 Sabia H, Prasad P, Smith HT, Stoltz RR, Rothenberg P. Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia. J. Cardiovasc. Pharmacol. 37, 502–511 (2001).

58 Tse FL, Smith HT, Ballard FH, Nicoletti J. Disposition of fluvastatin, an inhibitor of HMG-COA reductase, in mouse, rat, dog, and monkey. Biopharm. Drug Dispos. 11, 519–531 (1990).

59 Kivistö KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br. J. Clin. Pharmacol. 46, 49–53 (1998).

60 Smith HT, Jokubaitis LA, Troendle AJ, Hwang DS, Robinson WT. Pharmacokinetics of fluvastatin and specific drug interactions. Am. J. Hypertens. 6, S375–S382 (1993).

61 Lintott CJ, Scott RS, Bremer JM, Shand BI. Fluvastatin for dyslipoproteinemia, with or without concomitant chronic renal insufficiency. Am. J. Cardiol. 76, A97–A101 (1995).

62 Scripture CD, Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin. Pharmacokinet. 40, 263–281 (2001).

63 Smit JW, Wijnne HJ, Schobben F, Sitsen A, de Bruin TW, Erkelens DW. Effects of alcohol consumption on pharmacokinetics, efficacy, and safety of fluvastatin. Am. J. Cardiol. 76, A89–A96 (1995).

64 Fischer V, Johanson L, Heitz F et al. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P450 and implications for metabolic drug interactions. Drug Metab. Dispos. 27, 410–416 (1999).

65 Trilli LE, Kelley CL, Aspinall SL, Kroner BA. Potential interaction between warfarin and fluvastatin. Ann. Pharmacother. 30, 1399–1402 (1996).

66 Jokubaitis LA. Fluvastatin in combination with other lipid-lowering agents. Br. J. Clin. Pract. Suppl. 77A, 28–32 (1996).

67 Kirchheiner J, Kudlicz D, Meisel C et al. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin. Pharmacol. Ther. 74, 186–194 (2003).

68 Kantola T, Backman JT, Niemi M, Kivisto KT, Neuvonen PJ. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur. J. Clin. Pharmacol. 56, 225–229 (2000).

69 Goldberg R, Roth D. Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporin. Transplantation 62, 1559–1564 (1996).

70 Park JW, Siekmeier R, Lattke P et al. Pharmacokinetics and pharmacodynamics of fluvastatin in heart transplant recipients taking cyclosporin A. J. Cardiovasc. Pharmacol. Ther. 6, 351–361 (2001).

71 Takeda M, Noshiro R, Onozato ML et al. Evidence for a role of human organic anion transporters in the muscular side effects of HMG-CoA reductase inhibitors. Eur. J. Pharmacol. 483, 133–138 (2004).

72 Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab. Dispos. 30, 1352–1356 (2002).

73 Prueksaritanont T, Subramanian R, Fang X et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab. Dispos. 30, 505–512 (2002).

74 Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am. J. Cardiol. 76, A80–A83 (1995).

75 Prueksaritanont T, Zhao JJ, Ma B et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J. Pharmacol. Exp. Ther. 301, 1042–1051 (2002).

76 Jokubaitis LA. Updated clinical safety experience with fluvastatin. Am. J. Cardiol. 73, D18–D24 (1994).

77 Ballantyne CM, Pazzucconi F, Pinto X et al. Efficacy and tolerability of fluvastatin extended-release delivery system: a pooled analysis. Clin. Ther. 23, 177–192 (2001).

78 Winkler K, Abletshauser C, Hoffmann MM et al. Effect of fluvastatin slow-release on low density lipoprotein (LDL)

subfractions in patients with Type 2 diabetes mellitus: baseline LDL profile determines specific mode of action. J. Clin. Endocrinol. Metab. 87, 5485–5490 (2002).

79 Bruckert E, Lievre M, Giral P et al. Short-term efficacy and safety of extended-release fluvastatin in a large cohort of elderly patients. Am. J. Geriatr. Cardiol. 12, 225–231 (2003).

80 Riegger G, Abletshauser C, Ludwig M et al. The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during 1 year of treatment. Atherosclerosis 144, 263–270 (1999).

81 Serruys PW, Foley DP, Jackson G et al. A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; final results of the FLuvastatin Angiographic REstenosis (FLARE) trial. Eur. Heart J. 20, 58–69 (1999).

82 Liem AH, van Boven AJ, Veeger NJ et al. Effect of fluvastatin on ischemia following acute myocardial infarction: a randomized trial. Eur. Heart J. 23, 1931–1937 (2002).

83 Ballantyne CM, Herd JA, Ferlic LL et al. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 99, 736–743 (1999).

84 SoRelle R. Baycol withdrawn from market. Circulation 104, E9015–E9016 (2001).

85 Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N. Engl. J. Med. 346, 539–540 (2002).

86 Bottorff M, Hansten P. Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors: the role of metabolism-monograph for physicians. Arch. Intern. Med. 160, 2273–2280 (2000).

87 Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 101, 207–213 (2000).

88 Farmer JA, Torre-Amione G. Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Saf. 23, 197–213 (2000).

89 Benghozi R, Bortolini M, Jia Y, Isaacsohn JL, Troendle AJ, Gonasun L. Frequency of creatine kinase elevation during treatment with fluvastatin. Am. J. Cardiol. 89, 231–233 (2002).

90 Farnier M, Bortolini M, Salko T et al. Frequency of creatine kinase elevation


Åsberg & Holdaas


during treatment with fluvastatin in combination with fibrates (bezafibrate, fenofibrate, or gemfibrozil). Am. J. Cardiol. 91, 238–240 (2003).

91 Patel R, Paya CV. Infections in solid-organ transplant recipients. Clin. Microbiol. Rev. 10, 86–124 (1997).

92 Green ML. Evaluation and management of dyslipidemia in patients with HIV infection. J. Gen. Intern. Med. 17, 797–810 (2002).

93 Ballantyne CM, Riegger G, Moore N, Saia F, Serruys PW. Fluvastatin reduces cardiac mortality in patients with coronary heart disease. Cardiovasc. Drugs Ther. 18, 67–75 (2004).

94 Palinski W, Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis. J. Am. Soc. Nephrol. 13, 1673–1681 (2002).

Affiliations• Anders Åsberg, PhD

Department of Pharmacology, School of Pharmacy, University of Oslo, NorwayTel.: +47 22 856 559Fax: +47 22 854 [email protected]

• Hallvard Holdaas, MD, PhD

Medical Department, National Hospital, Oslo, NorwayTel.: +47 23 071 246Fax: +47 23 071 [email protected]

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Fluvastatin and fluvastatin extended release: a clinical and safety profile