Updated clinical safety experience with fluvastatin

Updated Clinical Safety Experience with Fluvastatin Leonard A. Jokubaitis,

Clinkal experience wlth fluvastatin in > 1,800 North Amerkan patients treated for an average

of6lweekshasshownlttobesafeandwelltolerated. Frequencies of transamhmse and we= atlne klnase elevations compare favorably with those observed during long&rm admlnlstratlon ofother3-hydroxy-3-methyl@utaryl-coenzymeA (HMG-CoA) reductase lnhlbt&ors. Further, whereas frank rhabdomyolysls has been encountered with treatment with all other HMG-CoA reductase inhlbltors, this syndrome has not been observed to date wfth fluvastatln In studies here or abroad; a single case of myopathy, which was probably related to physkal exertlon, was reported In a patlent recelvlngflwastatln. Atthough dyspepsla was observed more commonly In fluvastatln patients, the lncldence, along wlth that of other ad= verse events (e.g,, headache), and the number of treatment dlscontlnuatlons proved statistkally lndlstlngulshablefrom those of placebo controls. Whetherthefavarablesafetyproflleoffluvastatln ls related to this synthetic agent’s unique blopharmaceutkal proflle ls a matter of ongoing long-term Inquiry. (Am J Cardloll~73:18~24D)

MD

T

he beneficial effectsof lipid-lowering therapy in patients with primary (type II) hypercholesterolemia refractory to dietary intervention are predicated on robust associated improvements in cardiovascular morbidity’” and mortality,’ as well as a more modest but statistically significant decline in all-cause mortality.4 Such treatment, particularly that directed toward reducing cholesterol in the low density lipoprotein (LDL) fraction, is further credited with diminishing atherosclerotic plaque progression aswell as inducing angiographitally demonstrable regression of such lesions.5-11 The demonstrated requirement for effective clinical management of serum lipoprotein abnormalities has been met in large part by reversible inhibitors of 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate during cholesterol biosynthesis. The remarkable efficacy and tolerability of HMG-CoA reductase inhibitors in large multicenter studies12-l6support their central role among agents of first choice in the management of hypercholesterolemia.17 Until recently, the HMG-CoA reductase inhibitor classhas been limited to 3 closely related fungal metabolites isolated from Aspergillus ten-em: the methyl compactin analogue lovastatin, the hydroxy acid derivative pravastatin, and the dimethylsubstitutedvariant simvastatin(Figure 1). An extensive program designed to assessa wider array of related structures18has culminated in the development of fluvastatin, the first entirely synthetic HMG-CoA reductase inhibitor. Preliminary clinical data indicate that this agent displays the proven efficacy of its class and also exhibits a unique set of pharmacologic properties, which together may confer safety advantagesfor long-term use.19T2o BlOPtlARMACEUTlCAL PRORLE

From the Department of Cardiology/Diabetes Clinical Research, Sandoz Research Institute, East Hanover, New Jersey. Address for reprints: Leonard A. Jokubaitis, MD, Sandoz Research Institute, 59 Route 10, East Hanover, New Jersey 07936-1080. l8D

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73

Unlike the prodrugs lovastatin and simvastatin, whose activity depends on in vivo hydrolysis of a 6-member lactone ring, fluvastatin contains this reactive moiety as an open-ring acid. This configuration mimics the structure of a key reduced MAY 26, 1994

TABLE I Biopharmaceutical Inhibitors

Dose

Fluvastatin

Profile of HMG-CoA Reductase

Fluvastatin

Lovastatin

Pravastatin

Simvastatin

ZO-40mg

20-80mg

20-40mg

1 O-40 mg

Pharmacologically active as supplied

Yes

No

Yes

No

Effect of food on absorption

No

Yes

No

No

Actwe plasma metabolites

No

Yes

98%

95%

45%

No

Yes

No

95% Yes

1.2 hr

15 hr

2 hr

15.6 hr

95%

70%

50%

<87%

Crosses bloodbrain barrier Exposure duration (tld Liver excretion (% of absorbed dose)

Yes

Yes (l/10)

Adapted with permiwon from Circulation.lg HMG-CoA = 3.hydroxy-3.methylglutaryl-coenzyme A.

Pravastatin 0

Lovastatin

Simvastatin

Compactin

tln(bottom).Theope4n4nghydroxyddmo&tybseefnIn fhw&aUn and pravadath. kwadatln. and slmvartstln exhtasckbsd-Wgmevalonolactone~and mustundergoInvhwhydrolyslstotheopen-rlngstwcture.

intermediary substrate of HMG-CoA during endogenous mevalonate formation and potently inhibits this process. By blocking this early rate-limiting metabolic step, treatment with fluvastatin, as with therapy with other HMG-CoA reductase inhibitors, is thought to up-regulate hepatocellular LDLreceptor expression and thus enhance receptormediated clearance and catabolism of LDL cholesterol (LDL-C). To maximize hepatic cholesterol turnover and limit any possible untoward effects of diminished cholesterol availability in skeletal muscle or peripheral organs, HMG-CoA reductase inhibitors should ideally be targeted to the liver. Of the available agents in this category, fluvastatin possesses a biopharmaceutical profile most consistent with hepatoselectivity (i.e., low systemic or extrahepatic exposure). In addition to having a high absorption rate that is unaffected by food intake, fluvastatin exhibits a very short plasma half-life and a high degree of protein binding, a high first-pass hepatic extraction and biliary excretion, and no circulating active metabolites (Table I). Finally, owing to its relatively hydrophilic character, fluvastatin does not cross the blood-brain barrier. To date, data with fluvastatin appear favorable with respect to key criteria of HMG-CoA reductase inhibitor safety: l Hepatic effects, namely, elevations in serum alanine aminotransferase and aspartate aminotransferase l Myopathy, as indicated by symptoms such as muscle weakness or diffuse myalgia in conjunction with marked elevations in creatine kinase l Rates of patient complaints and treatment discontinuations attributable to lipid-lowering therapy l Drug interactions, especially those involving A SYMPOSIUM:

HMG-CoA

REDUCTASE

INHIBITORS

m

FL 40 mg bid* CME FL 20 mg bid+ CME

b b

FL 20 mg bid

b

FL20mgqpm

6

0

12

48

24

Weeks

Number: 918 entered Entry criteria: Completion of one of three phase III trials

The safety profile of fluvastatin reported here pertains to doses of 20 mg/day and 40 mg/day, which have been shown to be effective clinically.21 The largest randomized controlled study of fluvaPATIENT POPULATION statin has shown that a dosage of 20 mg/day The aggregate North American experience with produced a mean decrease in LDL-C of 22.2%. fluvastatin encompasses some 38 trials involving Th’is response is comparable to the 20-25% reduc> 2,700 patients, of whom 1,881 were allocated to tion in LDL-C previously observed with starting fluvastatin treatment. Included in this population doses of the other available HMG-CoA reductase are 941 patients treated with fluvastatin for r 1 inhibitors.22>23 year and 506 patients for 2 2 years. A total of 918 patients with severe primary hypercholesterolemia (mean baseline LDL-C, 227 mg/dL) who completed one of 3 phase III trials on fluvastatin were then enrolled in the multicenter Fluvastatin Long-Term Extension Trial (FLUENT).21 Initially designed as a 48-week investigation but now extended into a third year, FLUENT used an open-label, free-titration design. In addition to a low-fat diet, therapy with increasing doses of fluvastatin was instituted along with the bile acid-binding resin cholestyramine as needed to restore LDL-C to < 130 mg/dL (Figure 2). At week 48 of the FLUENT study, doses of 20 mglday and 40 mglday of fluvastatin produced reductions in LDL-C of 26.0% and 29.5%, respec40 mg/d 20 mgld fluvastatin fluvastatin tively (Figure 3). agents that may be frequently used in conjunction with lipid-lowering agents.

(n=84)

(n=460)

HEPAllC EFFECTS * pcO.001,

compared

with baseline

FIDURE3. Mean percent change from basellne ln Un-C at

week48, FLUENT study.= 20D

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73

Mild asymptomatic increasesin serum transaminase levels have been observed in patients treated with various lipid-altering regimens, including niaMAY 26, 1994

tin, gemfibrozil, and clofibrate, as well as the HMG-CoA reductase inhibitors.24 The mechanism underlying these modest elevations is not as yet clearly elucidated; however, cholestatic or hypersensitivity effects are 2 phenomena that have essentially been ruled out by clinical experience to date. Among the HMG-CoA reductase inhibitors, frequencies of persistent, marked elevations of transaminase levels to at least 3 times the upper limit of normal on 22 occasions are 1.0% for simvastatin, 1.3% for pravastatin, and 1.9% for lovastatin.14,25-28When these liver function test anomalies occur, they are usually encountered within the first 12 and 18 months on lovastatin and pravastatin, respectively; are not accompanied by increases in alkaline phosphatase levels; and either subside on discontinuation or elicit negative rechallenges, some of which may be attributable to subsequent reductions in alcohol consumption.14 The clinical experience with fluvastatin to date compares favorably with these data. Among 1,881 patients treated with fluvastatin for a mean of 61 weeks, the incidence of persistent transaminase elevations was 1.3%, as against 0.5% among 747 placebo controls. 29Of the 918 patients treated for > 23 months on average in FLUENT, therapy was discontinued as a result of transaminase elevations in 6 cases; of these, 2 showed a viral etiology, 1 was observed in association with acute glomerulonephritis, a fourth was related to increased alcohol intake, and the remaining 2 were either of small magnitude or uncertain origin.21 Although statistically significant, the mild increases in alanine and aspartate aminotransferases from baseline are not considered clinically relevant (Table II). Although remote, the prospect of liver injury on treatment with HMG-CoA reductase inhibitors warrants periodic monitoring, with discontinuation of therapy if aspartate or alanine aminotransferase levels are persistently 23 times the upper limit of normal. For patients on fluvastatin, those liver enzyme abnormalities that occur are generally observed within the first 3 months of therapy; liver function tests should be carried out at baseline (pretreatment), 6 and 12 weeks after initiation of therapy or dose elevation, and periodically (e.g., semiannually) thereafter. 30A more rigorous schedule is advised for the first year of therapy with other HMG-CoA reductase inhibitors in that liver function tests must be conducted every 8 weeks after the first 3 months.27-29 Caution should be exercised when any HMGCoA reductase inhibitor is administered to a patient with a history of heavy alcohol ingestion. Both

TABLE II Effects of Long-Term Fluvastatin Treatment on Primary Biochemical Safety Parameters in FLUENT Percentile Median

Baseline*

Change at Week 48

p Valuet

Aspartate aminotransferase FL 20 mg 83 FL 40 mg 468 FL 40 mg + CME 286 Tota I a37

15.0 15.0 14.0 15.0

1.0 2.0 2.0 2.0


Alanine aminotransferase FL 20 mg FL 40 mg FL 40 mg + CME Total

83 468 286 a37

13.0 13.0 13.0 13.0

1.0 3.0 4.0 3.0

< < < <

Creatine FL 20 FL 40 FL 40 Total

a3 468 286 837

65.0 57.0 60.0 59.0

4.0 3.0 2.0 3.0


Parameter (U/liter)

kinase mg mg mg + CME

No. Patients

*Value of last lead-in phasevisit after completion of short-term

0.001 0.001 0.001 0.001

study or last avallable

data. tP

values from W~lcoxonsigned-ranktest for median change equal to zero. CME = cholestyramine; FL = fluvastatin: FLUENT = Fluvastatin Long-Term

Extenslan Tr~al.~~

active liver disease and unexplained baseline transaminase elevations are contraindications to such therapy. MYOPAlHY A small proportion (generally < 1%) of persons treated with HMG-CoA reductase inhibitors develop myopathy. This syndrome should be considered in any patient presenting with diffuse myalgias, muscle tenderness or weakness, and markedly elevated creatine kinase values on the order of at least 10 times the upper limit of normal. So defined, this syndrome has been reported in approximately O.l-0.2% of patients on lovastatin13,28 and pravastatin. 25,27Between 5 and 9% of patients treated with simvastatin have sustained creatine kinase elevations of at least 50 U/liter; moreover, case reports of myopathy exist,31 although no drug-related musculoskeletal symptoms occurred in 1 multicenter study15 of 252 simvastatin recipients. Drug-related myopathy has not been reported with fluvastatin. However, a single case has been reported in a fluvastatin-treated patient but was related to physical exertion. An additional case was reported in a patient receiving placebo. In addition to equivalent rates of therapy discontinuations, the frequencies of asymptomatic creatine kinase elevations in excess of 2 10 times the upper limit of normal were similar in both fluvastatin (0.5%) and placebo control (0.4%) patients. Of special concern when administering HMGA SYMPOSIUM:

HMG-CoA

REDUCTASE

INHIBITORS

2m

TllBLE 111 Frequencies of Adverse Events Attributable to Drug in Core Phase III Trials Fluvastatin (%) (n = 620)

Placebo (%) (n = 411)

Dyspepsia

6.6

3.6

Headache

3.5

3.6

Abdominal pain

3.9

2.4

Diarrhea

3.2

3.2

Nausea

2.7

1.5

Fatigue

2.3

2.9

Rash

2.1

2.9

Adverse Event

TABLE IV Drug Interactions Involving HMG-CoA Reductase Inhibitors Fluvastatin

Pravastatin

Lovastatin

Simvastatin

Waffarin

No

No

Yes

Yes

Digoxin

No

No

No

Yes

Niacin

No

No

Yes

No

Erythromycin

No

No

Yes

No

Propranolol

No

No

No

Yes

ADMRSE EVENT PROFILES AND TREAIMENT DISCONflNUAllONS The frequency of therapy terminations due to adverse events in 1,524 fluvastatin patients (3.3%) after a mean duration of 21 weeks was not statistically distinguishable from the 3.5% rate among 974 control patients over approximately the same follow-up interval. The total 7.3% discontinuation rate in all fluvastatin patients also compares favorably with that recorded among controls (9.0%). Three deaths (0.2%) among patients randomly allocated to fluvastatin were attributed to cardiovascular disease but not to the drug per se. Although dyspepsia and abdominal pain were recorded somewhat more frequently in the fluvastatin group, these were not statistically distinguishable from comparable proportions of placebo patients (Table III).

DRUG INTERACTIONS AND OTHER PHENOMENA Compared with drug interactions characteristic of the other HMG-CoA reductase inhibitors, fluvaCoA reductase inhibitors is the prospect of frank statin exhibits a favorable profile (Table IV).*” rhabdomyolysis with acute renal failure secondary 28,30,31 In addition, although specific interaction to myoglobinuria. The likelihood of this syndrome studies were not performed, fluvastatin has been on treatment with other HMG-CoA reductase administered along with angiotensin converting inhibitors is increased when they are administered enzyme inhibitors, P-adrenergic blockers, calcium in conjunction with agents that may potentially channel antagonists, diuretics, and nonsteroidal compromise renal and/or hepatic function,32,33 anti-inflammatory drugs without evidence of clininamely, cyclosporine, erythromycin, niacin (particu- cally significant adverse interactions.30 Because larly at high dosages and with sustained-release fluvastatin treatment does not influence the mepreparations),34 and fibric acid derivatives.14Z5-37 tabolism or excretion of antipyrine either by inhibiThe 5-8% rate of myopathy recorded with lova- tion or induction, it is not expected to interact with statin-gemfibrozil treatment,35,37together with the other agents metabolized by the microsomal heoccasional association of clofibrate with myopathy, patic enzyme system.30 has resulted in the recommendation that concomiAdministration of cholestyramine concomitant HMG-CoA reductase inhibitor-fibrate treat- tantly with or ~4 hours before fluvastatin treatment should generally be avoided.26-28p30 ment diminishes the latter’s area under the curve Therapy with any HMG-CoA reductase inhibi(AUC) by 50% and maximal plasma concentration tor should be discontinued or temporarily withheld (C,,,) by 50-80%; these parameters are also signifiin any patient with an acute, serious condition cantly reduced by rifampicin (by 51 and 59%, suggestive of myopathy or predisposing to the respectively). Concomitant administration of the development of renal failure secondary to rhabdo- antiulcer medications cimetidine, ranitidine, or myolysis: sepsis; hypotension; major surgery; omeprazole significantly increases both the AUC trauma; severe metabolic, endocrine, or electrolyte and C,, of fluvastatin, presumably because of disorders; or uncontrolled epilepsy.262*,30 inhibition of gastric acid, which can hydrolyze the Unlike the experience with the 3 other available drug. This kinetic interaction has not demonHMG-CoA reductase inhibitors, it should be noted strated any correlated clinical sequelae. that rhabdomyolysis has never been observed with A final area of theoretical concern, given fluvastatin treatment.29 This includes short-term fluvastatin’s cholesterol-depleting effects, involves adrenal and gonadal steroid reserves. With respect studies in which regimens involving concomitant to the former, the expected 2- to 2.5-fold increase niacin38 or fibrates were instituted. HMG-CoA = 3-h)ldroxy-3-methylglutarlcoenzyme A. Data from Physlclans’ Desk Reference, 6-z Sandoz,30 and C/m Pharmacokinet.31

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administered to a patient receiving other agents that tend to diminish endogenous steroid hormone levels (e.g., ketoconazole, spironolactone, cimetidine).30

Mean plasma cortisol (mglml) 50

CONCUJSlON

FL 40 mg q pm (N=28)

201 lo-

0

I 30

0

I 60

90

Minutes post-ACTH Mean plasma cortisol (mg/ml) 60

I

4030201

FL 40 mg bid (N=74)

lo-

0

I 30

0

I 60

90

Minutes post-ACTH

50s

Mean plasma cortisol (mg/ml)

201

Placebo (N=28)

lo0

I 30

+ +

I

60 Minutes post-ACTH

0

i

90

Baseline Week28

I FIGURE 4. Mean plaqna codsol levels after swhnocoltlcotropkhomlone(Acln)stimulatknQaphstirfluvastatln (FL)-treated patbnts and placebo controls are essentlally superlmpesabk. b/d = twice dally; q = evey *Y.

Clinical studies have shown fluvastatin to be an effective lipid-lowering agent that is safe and well tolerated. Fluvastatin possessesa biopharmaceutical profile consistent with hepatoselectivity (i.e., low systemic or nonhepatic exposure), including a short plasma half-life and a high degree of protein binding. The incidence of laboratory abnormalities (elevations in serum transaminases and creatine kinase levels) seen in patients receiving fluvastatin compares favorably with those observed with other HMG-CoA reductase inhibitors. The limited recommendations for liver enzyme testing with fluvastatin may result in a lower cost for monitoring. Liver enzyme tests can cost between $25-40. Assuming an averagecost of $33 per test, the recommended first year’s liver enzyme testing for a patient on fluvastatin would total $132. This includes the initial test, the tests taken at 6 and 12 weeks, and the first semiannual test at week 38. For all other HMG-CoA reductase inhibitors, liver enzyme testing is currently recommended just prior to initiation of therapy, every 6 weeks for the first 3 months, and every 8 weeks for the remainder of the first year on therapy. A total of 7 tests would therefore be warranted during the first year, at a cost of $231. In later years, liver enzyme tests would cost $66/year (2 tests annually) for patients receiving any of the HMG-CoA reductase inhibitors. Discontinuation rates due to adverse events among patients receiving fluvastatin are similar to those of patients receiving placebo. In certain respects, fluvastatin appears to have a safety profile superior to other agents of its class. Drug-related myositis or rhabdomyolysis, reported with other HMG-CoA reductase inhibitors, has not been observed with fluvastatin. Certain drug interactions characteristic of HMG-CoA reductase inhibitors also have not been reported during clinical trials of fluvastatin. These attributes suggest that fluvastatin may prove to be an important addition to the treatment armamentarium of hypercholesterolemia.

in mean plasma co&o190 minutes after adrenocorticotropic hormone (ACTH) stimulation has been observed in > 100 patients tested over a 24- to 28-week period, as indicated by the superimposable graphs displayed in Figure 4.29 Similarly, although patients treated with fluvastatin 40 mg every evening show slight, statistically nonsignificant blunting of basal testosterone levels, changes in mean testosterone concentrations after stimulation with human chorionic gonadotropin prove REFERENCES l. Lipid Researchclinics Program.The Lipid Cliiics Coronary Primaly Prevensimilar to those in placebo recipients.29Caution is tion Trial results: I. reduction in incidence of coronary heart disease.JAM4 advisedwhen any HMG-CoA reductase inhibitor is 19&1;251:351-364.

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