Date of Revision: August 28, 2008

Control Number: 122195

*LESCOL is a registered trademark

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3

CONTRAINDICATIONS 5

WARNINGS AND PRECAUTIONS 5

DRUG INTERACTIONS 17

DOSAGE AND ADMINISTRATION 23

OVERDOSAGE 26

ACTION AND CLINICAL PHARMACOLOGY 27

STORAGE AND STABILITY 31

SPECIAL HANDLING INSTRUCTIONS 31

DOSAGE FORMS, COMPOSITION AND PACKAGING 31

PART II: SCIENTIFIC INFORMATION 33

PHARMACEUTICAL INFORMATION 33

CLINICAL TRIALS 34

DETAILED PHARMACOLOGY 43

MICROBIOLOGY 48

TOXICOLOGY 49

REFERENCES 55

PART III: CONSUMER INFORMATION. 58

PrLESCOL *

Fluvastatin sodium capsules 20 and 40 mg

Pr

LESCOL * XL

Fluvastatin sodium extended release tablets 80 mg

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

• LESCOL */LESCOL * XL (fluvastatin sodium) are contraindicated in patients with known hypersensitivity to any component of this medication (see DOSAGE FORMS, COMPOSITION AND PACKAGING).

• LESCOL */LESCOL * XL are contraindicated in patients with active liver disease or unexplained, persistent clinically relevant elevations in serum transaminases (see WARNINGS AND PRECAUTIONS - Hepatic).

• As with other drugs of this class, LESCOL */LESCOL * XL are contraindicated during pregnancy and in nursing mothers (see WARNINGS AND PRECAUTIONS - Special Populations - Pregnant Women / Nursing Women). Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). LESCOL */LESCOL * XL should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the possible harm. If the patient becomes pregnant while taking LESCOL */LESCOL * XL, the drug should be discontinued immediately and the patient apprised of the potential harm to the fetus. Atherosclerosis being a chronic process, discontinuation of lipid metabolism regulating drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia (see WARNINGS AND PRECAUTIONS - Special Populations - Pregnant Women / Nursing Women).

WARNINGS AND PRECAUTIONS

General

Before instituting therapy with LESCOL */LESCOL * XL (fluvastatin sodium), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see INDICATIONS AND CLINICAL USE). The patient should be advised to inform subsequent physicians of the prior use of LESCOL */LESCOL * XL or any other lipid metabolism regulator.

Muscle Effects

Effects on skeletal muscle such as rare cases of myalgia, myopathy and, very rarely, rhabdomyolysis have been reported in patients treated with LESCOL */LESCOL * XL.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with LESCOL */LESCOL * XL and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine phosphokinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or a marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. LESCOL */LESCOL * XL therapy should be discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected.

Creatine kinase measurement:

There is no current evidence to require routine monitoring of plasma total creatine kinase levels in asymptomatic patients on statins. If creatine kinase has to be measured it should not be done following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes interpretation difficult.

Pre-disposing Factors for Myopathy/Rhabdomyolysis:

LESCOL */LESCOL * XL, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

• Personal or family history of hereditary muscular disorders

• Previous history of muscle toxicity with another HMG-CoA reductase inhibitor

• Concomitant use of a fibrate or niacin

• Hypothyroidism

• Alcohol abuse

• Excessive physical exercise

• Age >70 years

• Renal impairment

• Hepatic impairment

• Diabetes with hepatic fatty change

• Surgery and trauma

• Frailty

• Situations where an increase in plasma levels of active ingredient may occur

In such situations, the risk of treatment should be considered in relation to the possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (> 5 x Upper Levels of Normal [ULN]), levels should be re-measured within 5 to 7 days later to confirm the results. If CK levels are still significantly elevated (> 5 x ULN) at baseline, treatment should not be started. LESCOL */LESCOL * XL therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or predisposing to the development of rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic endocrine and electrolyte disorders, or uncontrolled seizures).

Whilst on treatment:

If muscular symptoms like pain, weakness or cramps occur in patients receiving fluvastatin, their CK levels should be measured. Treatment should be stopped, if these levels are found to be significantly elevated (> 5xULN). LESCOL */LESCOL * XL withdrawal should be considered if muscular symptoms are severe and cause daily discomfort, even if CK levels are not significantly elevated (i.e. <= 5 x ULN). Should the symptoms resolve and CK levels return to normal, then reintroduction of fluvastatin or another statin may be considered at the lowest dose and under close monitoring. An increased risk of myopathy has been reported with HMG-CoA reductase inhibitors which are predominantly CYP3A4 substrates when administered concomitantly with other drugs metabolized by the CYP3A4 isoenzymes such as immunosuppressive drugs, including cyclosporine, colchicines, fibrates, macrolide antibiotics, azole antifungal agents, selective serotonine reuptake inhibitors, or niacin at lipid lowering doses. Since LESCOL */LESCOL * XL are predominantly metabolized by the CYP2C9 subclass of the P450 cytochromes and not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4, it is not expected to increase the risks of myopathy when co-administered with other drugs metabolized by the P450 isoenzyme system. The benefits and risks of using HMG-CoA reductase inhibitors concomitantly with immunosuppressive drugs, erythromycin, or other drugs metabolized by the P450 enzyme system, fibrates or lipid-lowering doses of niacin should nevertheless be carefully considered (see WARNINGS AND PRECAUTIONS - Pharmacokinetic Interactions, and DRUG INTERACTIONS - Cytochrome P450). Experience to date with the use of fluvastatin together with cyclosporine consists of 3 pharmacokinetics studies (fluvastatin doses of 20 mg, 40 mg), 17 clinical trials of small-medium size and short-, medium- term duration (fluvastatin doses of 20 mg, 40 mg, 40 mg BID) in renal and heart transplant recipients, and one large prospective placebo-controlled trial in 2,102 renal transplant recipients followed up for 5 to 6 years (fluvastatin doses of 40 mg and 40 mg BID). Published data indicate that the trough concentration of cyclosporine A was not changed (see DETAILED PHARMACOLOGY - Pharmacokinetics, DRUG INTERACTIONS - Drug-Drug Interactions - Immunosuppressive Drugs, and REFERENCES). No correlation between systemic fluvastatin levels and musculoskeletal adverse events or biochemical markers of musculoskeletal damage or renal function impairment have been observed in clinical trials conducted to date. In post-marketing experience, isolated cases of myopathy have been reported when fluvastatin was co-administered with cyclosporine. Myopathy has not been observed in clinical trials involving small numbers of patients who were treated with LESCOL * together with niacin at lipid lowering doses. The use of fibrates alone or in combination with HMG-CoA reductase inhibitors has been occasionally associated with myopathy. In short-term studies involving a small number of patients, myopathy was not reported during administration of bezafibrate and LESCOL * at doses of 40 mg/day and 60 mg/day. To date, the 80 mg/day dose has not been evaluated with bezafibrate. Interruption of therapy with LESCOL */LESCOL * XL should be considered in any patient with an acute serious condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure or rhabdomyolysis, such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disorders and uncontrolled seizures.

Pediatric population

Fluvastatin has only been investigated in children of 9 years and older with heterozygous familial hypercholesterolemia (see CLINICAL TRIALS: Pediatrics) and efficacy and safety have not been studied for treatment periods longer than two years. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. No data are available about the physical, intellectual and sexual maturation for prolonged treatment period. Adolescent females should be counselled on appropriate contraceptive methods while on fluvastatin therapy (see CONTRAINDICATIONS). No specific drug-drug interaction studies were conducted in the pediatric patient population (See DRUG INTERACTIONS).

Pharmacokinetic Interactions

The use of HMG-CoA reductase inhibitors has been associated with rhabdomyolysis, which may be more frequent when they are co-administered with drugs that inhibit the same cytochrome P450 isoenzyme system particularly the CYP3A4. The various HMG-CoA reductase inhibitors differ with respect to the P450 isoenzyme involved in their metabolism. LESCOL */LESCOL * XL are predominantly metabolized by the CYP2C9 subclass of the P450 cytochromes and therefore is not expected to interact with drugs known to be CYP3A4 substrates, such as immunosuppressants, macrolide antibiotics, selective serotonine reuptake inhibitors, azole antifungal agents, or grapefruit juice. It may interact, however, with CYP2C9 substrates, e.g. nonsteroidal anti-inflammatory drugs or oral anticoagulants. These potential interactions may be less clinically relevant due to the overlap between the different CYP2C isoenzymes (see WARNINGS AND PRECAUTIONS - Muscle Effects, and DRUG INTERACTIONS). For more information, please refer to REFERENCES - Drug Interactions.

Carcinogenesis and Mutagenesis

See TOXICOLOGY

Cardiovascular

Effect on CoQ10 levels (ubiquinone)

A significant decrease in plasma CoQ10 levels in patients treated with fluvastatin sodium and other statins has been observed in short-term clinical trials. The clinical significance of a potential long-term statin- induced deficiency of CoQ10 has not yet been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure (see REFERENCES).

Endocrine and Metabolism

Homozygous familial hypercholesterolemia

LESCOL */LESCOL * XL has not been evaluated in patients with rare homozygous familial hypercholesterolemia. Most HMG-CoA reductase inhibitors are less or not effective in this subgroup of hypercholesterolemic patients (see REFERENCES). For heterozygous familial hypercholesterolemia (FH) see CLINICAL TRIALS.

Effect on lipoprotein(A) [Lp(a)]

In some patients the beneficial effect of lowered total cholesterol and LDL cholesterol levels may be partly blunted by a concomitant increase in the Lp(a) levels. Until further experience is obtained from controlled clinical trials, it is suggested, where feasible, that Lp(a) measurements be carried out in patients placed on therapy with LESCOL */LESCOL * XL (see REFERENCES).

Endocrine function

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such could theoretically blunt adrenal and/or gonadal steroid production. Fluvastatin sodium exhibited no effect upon non-stimulated cortisol levels, FSH (males only) or thyroid metabolism as assessed by TSH. Small declines in total testosterone have been noted in treated groups, but no commensurate elevation in LH occurred. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in an adequate number of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Patients treated with fluvastatin sodium who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones.

Hepatic

LESCOL */LESCOL * XL, as well as other HMG-CoA reductase inhibitors should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

Active liver disease or unexplained transaminase elevations are contraindications to the use of LESCOL */LESCOL * XL; if such condition develops during therapy, the drug should be discontinued. Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid-lowering agents. Overall, 25 of 2373 patients (1.1%) treated with LESCOL * capsules in worldwide controlled clinical trials developed marked persistent elevations (to more than 3 times the upper limit of normal) in transaminase levels requiring discontinuation of treatment in 14 (0.6%) patients. The incidence of such elevations varied from 0.9% at 20 mg/day to 1.9 % at 80 mg/day. In all clinical trials (controlled and uncontrolled) with LESCOL * capsules, ranging from 28 to 71.2 weeks of exposure, 33 of 2969 (1.1%) patients had persistent transaminase elevations requiring discontinuation of treatment in 19 (0.6%) patients. In the majority of patients, these abnormal biochemical findings were asymptomatic. In a retrospective pooled analysis of all placebo-controlled studies of at least 6 weeks and up to 130 weeks with LESCOL * capsules, all patients with transaminase elevations >3 times the upper limit of normal were evaluated. A total of 1814 patients received daily either 20 mg, 40 mg or 80 mg (40 mg b.i.d.) fluvastatin sodium. All patients with persistent (two consecutive occasions) transaminase elevations > 3 times the upper limit of normal had abnormal transaminase elevations at either baseline (before initiation of therapy) and/or by 8 weeks after the start of therapy or dose increase. In a pooled analysis of three 24-week controlled trials in 854 patients, persistent transaminase elevation occurred in 1.9% of patients treated with LESCOL * XL 80 mg, and in 13 of 16 patients the abnormality occurred within 12 weeks of initiation of treatment with LESCOL * XL 80 mg. It is recommended that liver function tests be performed at baseline and 8 weeks after initiation of treatment as well as after an increase in the dose. Particular attention should be paid to patients who develop abnormal serum transaminase levels or signs and symptoms of liver disease. In these patients, measurements should be repeated promptly to confirm the finding and then performed more frequently until the abnormality(ies) returns to normal. If the transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal and are persistent, the drug should be discontinued.

Immune

Rare cases of hypersensitivity reactions, such as rash, urticaria, eczema and other skin reactions (e.g. dermatitis, bullous exanthema), thrombocytopenia, angioedema, face edema, vasculitis and lupus erythematosus syndrome have been reported during post-marketing experience with LESCOL * capsules. If hypersensitivity is suspected, LESCOL */LESCOL * XL should be discontinued. Patients should be advised to report to their doctors promptly any signs of hypersensitivity such as rash, angioedema, urticaria, photosensitivity, polyarthralgia, fever and malaise.

Ophthalmologic

Current data from long-term clinical trials do not indicate an adverse effect of LESCOL */LESCOL * XL on the human lens.

Renal

Because fluvastatin sodium does not undergo significant renal excretion modification of dosage should not be necessary in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). As there is no experience with LESCOL */LESCOL * XL in patients with severe renal insufficiency (creatinine > 260 mmol/L, i.e. creatinine clearance < 30 mL/min), its use cannot be recommended in this patient population.

Special Populations

Pregnant Women

LESCOL */LESCOL * XL are contraindicated during pregnancy

(see CONTRAINDICATIONS). Data on the use of LESCOL */LESCOL * XL in pregnant women is limited. A few reports have been

received of congenital anomalies in infants whose mothers were treated during a critical period of pregnancy with other HMG-CoA reductase inhibitors. During the clinical program, a total of 5 women who were receiving LESCOL * capsules became pregnant and were discontinued from the studies. Of these 5 women, 3 gave birth to healthy babies, one experienced an ectopic pregnancy which was attributed to a severely scarred fallopian tube and one spontaneously aborted. Atherosclerosis is a chronic process and discontinuation of lipid metabolism regulators during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. LESCOL */LESCOL * XL should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued and the patient apprised of the potential hazard to the fetus (see CONTRAINDICATIONS).

Nursing Women

It is not known whether fluvastatin sodium is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fluvastatin sodium, women receiving LESCOL */LESCOL * XL should not breast-feed (see CONTRAINDICATIONS).

Pediatrics (10-17 years of age)

(see WARNINGS AND PRECAUTIONS - General- Pediatric Population)

Geriatrics

The effect of age on the pharmacokinetics of immediate release fluvastatin sodium capsules was evaluated. Results indicate that for the general patient population plasma concentrations of fluvastatin sodium do not vary either as a function of age or gender (see ACTIONS AND CLINICAL PHARMACOLOGY: Pharmacokinetics). Elderly patients may be more susceptible to myopathy (see WARNINGS AND PRECAUTIONS - Muscle Effects - Pre-disposing Factors for Myopathy/Rhabdomyolysis).

DRUG INTERACTIONS

Overview

Pharmacokinetic and pharmacodynamic studies conducted with drugs in healthy subjects may not detect the possibility of potential drug interactions in some patients due to differences in underlying disease(s), age or renal function (see WARNINGS AND PRECAUTIONS - Renal, Special Populations - Geriatrics; and DRUG INTERACTIONS - Patients with Severe Hypercholesterolemia).

Concomitant Therapy with other Lipid Metabolism Regulators

Information on combination drug therapy from controlled studies is limited. Based on post-marketing surveillance, gemfibrozil, fenofibrate, other fibrates and lipid lowering doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see WARNINGS AND PRECAUTIONS - Muscle Effects). Therefore, combined drug therapy should be approached with caution.

Drug-Drug Interactions

No specific drug-drug interaction studies were conducted in the pediatric patient population. A drug interactive effect (pharmacokinetic and/or clinical) has been shown for the following drugs in combination with fluvastatin sodium:

Cholestyramine

The cholesterol-lowering effects of LESCOL */LESCOL * XL and the bile acid sequestrant, cholestyramine, are additive. Administration of immediate release fluvastatin sodium concomitantly 2 to 4 hours after cholestyramine, results in fluvastatin decreases of more than 50% for the fluvastatin AUC and 50-80% for the fluvastatin Cmax. However, administration of immediate release fluvastatin sodium 4 hours after cholestyramine resulted in a clinically significant additive effect in reducing Total-C and LDL-C compared with that achieved with either component drug.

Gemfibrozil/Fenofibrate/Niacin

Myopathy, including rhabdomyolysis, has occurred in patients who were receiving co-administration of HMG-CoA reductase inhibitors with fibric acid derivatives and niacin (in lipid lowering doses), particularly in subjects with pre-existing renal insufficiency (see WARNINGS AND PRECAUTIONS - Muscle Effects). LESCOL * capsules have been safely administered concomitantly with nicotinic acid, gemfibrozil and bezafibrate in clinical studies. In short-term studies involving a small number of patients, myopathy was not reported during administration of bezafibrate and LESCOL * capsules at doses of 40 mg/day and 60 mg/day. To date, the 80 mg/day dose has not been evaluated with bezafibrate. An additional interaction study between 20mg o.d. fluvastatin and 200mg t.d.s. bezafibrate showed that mean AUC and Cmax values of fluvastatin were increased on average by about 50-60%. No effect was seen on bezafibrate pharmacokinetics. This combination should be used with caution, however, due to the increased risk of developing myopathy and/or rhabdomyolysis when HMG-CoA reductase inhibitors including fluvastatin have been combined with fibrates. Any patient complaining of myalgia should be carefully evaluated.

Cimetidine/Ranitidine/Omeprazole

Concomitant administration of LESCOL * capsules with cimetidine, ranitidine and omeprazole results in a significant increase in the fluvastatin Cmax (43%, 70% and 50%, respectively) and AUC (24 to 33%), with an 18 to 23% decrease in apparent oral plasma clearance (Cl/F).

Digoxin

In a crossover study involving 18 patients chronically receiving digoxin, concomitant administration of a single 40 mg dose of LESCOL * capsule had no effect on digoxin AUC and small but clinically insignificant increases in the digoxin Cmax and urinary clearance were noted.

Rifampicin

Administration of LESCOL * capsules to subjects pre-treated with rifampicin results in significant reduction in Cmax (59%) and AUC (51%) of fluvastatin, with a large increase (95%) in plasma clearance.

Antipyrine

Administration of fluvastatin sodium does not influence the metabolism and excretion of antipyrine, either by induction or inhibition.

Cardiovascular agents

Concomitant administration of propranolol has no effect on the bioavailability of fluvastatin sodium. No clinically significant pharmacokinetic interactions occur when fluvastatin is concomitantly administered with losartan or amlodipine, although mild to moderate adverse events were reported upon concomitant administration of fluvastatin and amlodipine (see ADVERSE REACTIONS).

Warfarin and other coumarin derivatives

In vitro

protein binding studies demonstrated no interaction at therapeutic concentrations. In a drug interaction study, the concomitant use of LESCOL * capsules and warfarin did not alter the plasma levels and prothrombin times compared to warfarin alone. However, isolated incidences of bleeding episodes and/or increased prothrombin times have been reported very rarely in patients on fluvastatin receiving concomitant warfarin or other coumarin derivatives. It is recommended that prothrombin times are monitored when fluvastatin treatment is initiated, discontinued, or the dosage changed in patients receiving warfarin or other coumarin derivatives.

Cytochrome P450

Fluvastatin is predominantly metabolized by the hepatic microsomal CYP2C9 subclass of the P450 cytochromes. It is not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4. The clearance of drugs which are also CYP2C9 substrates may decrease when co-administered with fluvastatin. However, for those CYP2C9-metabolized drugs which have been studied directly, including diclofenac, tolbutamide, and warfarin, the effect on clearance is small and no clinically significant drug interactions of fluvastatin with other CYP2C9 substrates have been demonstrated. Caution should nevertheless be exercised with concomitant use of drugs metabolized by the CYP2C9 subclass of the P450 cytochromes such as phenytoin, oral anticoagulants (e.g. warfarin), oral hypoglycemic agents (e.g. tolbutamide, chlorpropamide) and nonsteroidal anti-inflammatory drugs (e.g. diclofenac) (see WARNINGS AND PRECAUTIONS - Muscle Effects). Since LESCOL */LESCOL * XL are predominantly metabolized by the CYP2C9 subclass of the P450 cytochromes and not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4, it is not expected to increase the risks of drug interactions when combined with drugs or common agents such as grapefruit juice that inhibit this enzyme (immunosuppressants, azole-type antifungal agents, macrolide antibiotics or antidepressants) (see WARNINGS AND PRECAUTIONS - Pharmacokinetics Interactions, Muscle Effects, and REFERENCES).

Itraconazole and erythromycin

Concomitant administration of fluvastatin with the potent cytochrome P450 (CYP) 3A4 inhibitors itraconazole and erythromycin has minimal effects on the bioavailability of fluvastatin. Given the minimal involvement of this enzyme in the metabolism of fluvastatin, it is expected that other CYP3A4 inhibitors (e.g. ketoconazole, cyclosporin) are unlikely to affect the bioavailability of fluvastatin (see WARNINGS AND PRECAUTIONS - Muscle Effects).

Fluconazole

Administration of fluvastatin to healthy volunteers pre-treated with fluconazole (CYP2C9 inhibitor) resulted in a significant increase in the exposure, elimination half life and peak concentration of fluvastatin by about 84%, 80% and 44%, respectively. Although there was no clinical evidence that the safety profile of fluvastatin was altered in patients pre-treated with fluconazole for 4 days, caution should be exercised when fluvastatin is administered concomitantly with fluconazole.

Oral Antidiabetic Agents

For patients receiving oral sulfonylureas (glibenclamide [glyburide], tolbutamide) for the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycemic control. In glyburide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean Cmax, AUC, and t1/2 of glyburide approximately 50%, 69% and 121%, respectively. Glyburide (5 to 20 mg daily) increased the mean Cmax and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in glucose, insulin and C-peptide levels. However, patients on concomitant therapy with glyburide (glibenclamide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 80 mg per day.

Phenytoin

The overall magnitude of the changes in phenytoin pharmacokinetics during co-administration with fluvastatin are relatively small and not clinically significant. Thus, routine monitoring of phenytoin plasma levels is sufficient during co-administration with fluvastatin. The minimal effect of phenytoin on fluvastatin pharmacokinetics indicates that dosage adjustment of fluvastatin is not warranted when co- administered with phenytoin.

Colchicines

Myotoxicity, including muscle pain and weakness and rhabdomyolysis, has been reported anecdotally with concomitant administration of fluvastatin and colchicine during acute exacerbation of gouty arthritis.

Patients with severe hypercholesterolemia

Higher dosages (80 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma levels of fluvastatin. Caution should be exercised in such patients who are also significantly renally impaired, elderly, or are also concomitantly being administered digoxin, or CYP 450 inhibitors (see WARNINGS AND PRECAUTIONS - Pharmacokinetic Interactions, and Muscle Effects; and DRUG INTERACTIONS). Although specific interaction studies were not performed with all drugs listed below, in clinical studies, LESCOL * capsules was used concomitantly with angiotensin-converting enzyme (ACE) inhibitors, beta blockers, calcium-channel blockers, oral sulphonylureas, antacids, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence to date of clinically significant interactions.

Immunosuppressive Drugs

In a pharmacokinetic study conducted in 19 stable renal transplant patients receiving cyclosporine A concomitantly with fluvastatin 20 mg/day, the AUC for fluvastatin was increased by 1.9 times. Similarly, in a pharmacokinetic study conducted in 19 stable renal transplant patients on stable cyclosporine A regimen who received fluvastatin extended release 80 mg/day for 1 week, both the AUC and Cmax for fluvastatin were increased by two fold as compared with data from historical controls treated with the same fluvastatin regimen. The trough concentration of cyclosporine A was not changed. In heart transplant patients treated with fluvastatin 40 mg/day and cyclosporine A for four weeks, AUC for fluvastatin was increased 3.5 times and 3.1 times in patients than in the age-matched healthy controls on study days 1 and 28, respectively (see DETAILED PHARMACOLOGY - Pharmacokinetics, and REFERENCES). In post-marketing experience, isolated cases of myopathy have been reported when fluvastatin was co-administered with cyclosporine (see WARNINGS AND PRECAUTIONS: Muscle Effects).

Drug-Food Interactions

There were no apparent differences in the lipid-lowering effects of fluvastatin when administered with the evening meal or four (4) hours after the evening meal (see ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics - Absorption). Based on the lack of interaction of fluvastatin with other CYP3A4 substrates, fluvastatin is not expected to interact with grapefruit juice.

Drug-Laboratory Interactions

The HMG-CoA reductase inhibitors may cause elevation of transaminase levels (see WARNINGS AND PRECAUTIONS). Marked elevations of CK levels to more than 5 x ULN developed in a very small number (0.3-1.0%) of patients on fluvastatin sodium. In the differential diagnosis of chest pain in a patient on LESCOL */LESCOL * XL, cardiac and noncardiac fractions of these enzymes should be determined.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Patients should be placed on a standard cholesterol-lowering diet (at least equivalent to the Adult Treatment Panel III [ATP III TLC diet]) before receiving LESCOL */LESCOL * XL, and should continue on this diet during treatment with LESCOL */LESCOL * XL. If appropriate, a program of weight control and physical exercise should be implemented. Prior to initiating therapy with LESCOL */LESCOL * XL, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of LESCOL * capsule or LESCOL * XL tablet if cholesterol levels fall below the targeted range, such as that recommended by current guidelines.

Recommended Dose and Dosage Adjustment

Adults

Hypercholesterolemia and Mixed Hyperlipidemia

For patients requiring LDL-C reduction of less than 25%, a starting dose of 20 mg LESCOL * capsule taken once daily is recommended. For patients requiring LDL-C reduction of at least 25%, the recommended starting dose is 40 mg daily of LESCOL * capsule taken once daily. If necessary, the dosage of fluvastatin may then be increased to 80 mg of LESCOL * XL tablet, taken once daily at any time, or alternatively, 80 mg of LESCOL * capsule, taken in divided doses of 40 mg twice daily. LESCOL * capsules may be taken consistently with or without food, in the evening or at bedtime. LESCOL * capsules must be swallowed whole with a glass of water. A single dose of LESCOL * XL tablets can be administered at any time of the day with or without food. LESCOL * XL tablets must be swallowed whole with a glass of water. Since maximal reduction in LDL-C is seen within 4 weeks of administration of a given dose of LESCOL * capsule or LESCOL * XL tablet, periodic lipid level determination should be performed with dosage adjusted to a maximum of 80 mg of fluvastatin daily, according to patient response.

Pediatric population

Prior to initiating treatment with LESCOL */LESCOL * XL, the patient should be placed on a standard cholesterol-lowering diet for 6 months. Dietary therapy should be continued during treatment. The recommended starting dose is 20 mg daily of LESCOL * capsule taken once daily. If the patients did not achieve an LDL-C level of 3.4 mmol/L (130 mg/dL) or less, the dosage of fluvastatin may then be increased in a step-wise fashion at approximately 6-week intervals to a maximum daily dose of 80 mg. The patient may take 80 mg of LESCOL * XL tablet, once daily at any time of the day , or alternatively, 80 mg of LESCOL * capsule, in divided doses of 40 mg twice daily. Starting doses should be individualized according to baseline LDL-C levels and the recommended goal of therapy to be accomplished. The use of fluvastatin in combination with nicotinic acid, cholestyramine, or fibrate in children and adolescents has not been investigated.

Severe Hypercholesterolemia

In patients with severe hypercholesterolemia, higher dosages (80 mg/day) may be required (see WARNINGS AND PRECAUTIONS - Pharmacokinetic Interactions and Muscle Effects and DRUG INTERACTIONS).

Secondary Prevention of Cardiovascular Events (See Hypercholesterolemia and Mixed Hypercholesterolemia)

During the LESCOL * Intervention Prevention Study (LIPS), patients were initiated on fluvastatin treatment at 40 mg twice a day with no titration from a lower dose level. This daily dose was proven to be as well tolerated as placebo. Therefore, in patients with coronary heart disease who have undergone a percutaneous intervention procedure, the appropriate dose of LESCOL * is 40 mg twice a day.

Concomitant Therapy

See DRUG INTERACTIONS

Dosage in Patients with Renal Impairment

See WARNINGS AND PRECAUTIONS - Renal

Dosage in Patients with Hepatic Impairment

See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS - Hepatic

Use in the Elderly

See WARNINGS AND PRECAUTIONS - Geriatrics

Use in Children

See WARNINGS AND PRECAUTIONS - Pediatrics The dosage of LESCOL */LESCOL * XL should be individualized according to baseline LDL-C, total- C/HDL-C ratio and/or TG levels to achieve the recommended target lipid values at the lowest possible dose (see Recommendations for the Management of Dyslipidemia and the Prevention of Cardiovascular Disease [Canada] summarized below in Table 2, and/or the Third Report of the U.S. National Cholesterol Education Program [NCEP Adult Treatment Panel III]) and the patient response. Lipid levels should be monitored periodically and, if necessary, the dose of LESCOL */LESCOL * XL adjusted based on target lipid levels recommended by guidelines.

Table 2: Canadian Recommendations for Target Lipid Values Based on Level of Risk

Note: LDL-C = low-density lipoprotein cholesterol.

1. Apolipoprotein B can be used as an alternative measurement, particularly for follow-up of patients treated with statins. An optimal level of apolipoprotein B in a patient at high risk is < 0.9 g/L, in a patient at moderate risk <

1.05 g/L and in a patient at low risk < 1.2 g/L.

Includes patients with chronic kidney disease and those undergoing long-term dialysis.

In the 'very low' risk stratum, treatment may be deferred if the 10-year estimate of cardiovascular disease is < 5% and the LDL-C level is <5.0 mmol/L.

OVERDOSAGE

The maximum single oral dose of LESCOL * (fluvastatin sodium) capsules received by healthy volunteers was 80 mg. No clinically significant adverse experiences were seen at this dose. The maximum dose administered with an extended release formulation was 640 mg for two weeks. This dose was not well tolerated and produced a variety of GI complaints and an increase in transaminase values (i.e., ALT and AST). There has been a single report of two children, one 2 year old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems. Should an overdose occur, treatment should be symptomatic and supporting measures should be undertaken as required. The dialysability of LESCOL */LESCOL * XL and its metabolites in man is not known at present.

ACTION AND CLINICAL PHARMACOLOGY

LESCOL * (fluvastatin sodium) is a fully synthetic HMG-CoA reductase inhibitor and is hydrophilic. Fluvastatin sodium is a racemate of two erythro enantiomers of which one exerts the pharmacological activity.

Mechanism of Action

Fluvastatin sodium is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. Fluvastatin exerts its main effect in the liver and is mainly a racemate of the two erythro enantiomers of which the 3R,5S enantiomer exerts the pharmacological activity. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The ultimate result of these mechanisms is a reduction of the plasma total cholesterol (Total-C) and low density lipoprotein cholesterol (LDL-C) concentrations. Epidemiologic and clinical studies have associated the risk of coronary artery disease (CAD) with elevated levels of Total-C, LDL-C and decreased levels of HDL-C. These abnormalities of lipoprotein metabolism are considered as major contributors to the development of the disease. Other factors, e.g. interactions between lipids/lipoproteins and endothelium, platelets and macrophages, have also been incriminated in the development of human atherosclerosis and of its complications. Effective treatment of hypercholesterolemia/dyslipidemia in long-term clinical trials has consistently been associated with a reduced risk of CAD.

Pharmacodynamics

A variety of clinical studies has demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (a membrane transport complex for LDL- C) promote human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. In multicentre clinical trials, those pharmacologic and/or non-pharmacologic interventions that simultaneously lowered LDL-C and increased HDL-C reduced the rate of cardiovascular events (both fatal and non-fatal myocardial infarctions) in high risk males or in males and females with established coronary artery disease. LESCOL */LESCOL * XL reduces total-C, LDL-C, apo-B, and TG, and marginally increases HDL-C in patients with hypercholesterolemia and mixed dyslipidemia. Therapeutic response is well established within 2 weeks, and maximum response is achieved within 4 weeks from treatment initiation and maintained during chronic therapy.

Pharmacokinetics

Table 4 3- Summary of LESCOL */LESCOL * XL's Pharmacokinetic Parameters in Single-Dose and Steady-State Studies

Capsules

Cmax (ng/mL) mean +- SD (range)

t1/2 (h)

mean +- SD (range)

AUC0-4

(ng * h/mL) mean +- SD (range)

Clearance (L/h) mean +- SD (range)

T

max

(h)

mean +- SD (range)

Extended-release 80 mg tablets

80 mg single dose, fasting (n = 24)

126 +- 53

(37-242)

- 579 +- 341

(144-1760)

- 3.2 +- 2.6

(1-12)

80 mg single dose, fed-state high fat meal (n = 24)

183 +- 163

(21-733)

- 861 +- 632

(199-3132)

- 6

(2-24)

80 mg once daily fasting 7 day steady-state (n =

102 +- 42

(43.9-181)

- 630 +- 326

(247-1406)

- 2.6 +- 0.91

(1.5-4)

11)

Absorption

LESCOL * is absorbed rapidly and completely following oral administration of the capsule, with peak concentrations reached in less than 1 hour. Following administration of a 10 mg dose, the absolute bioavailability is 24% (range 9%-50%). Administration with food reduces the rate but not the extent of absorption. At steady-state, administration of fluvastatin with the evening meal results in a two-fold decrease in Cmax and more than two-fold increase in Tmax as compared to administration 4 hours after the evening meal. No significant differences in extent of absorption or in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in higher-than-expected plasma fluvastatin concentrations. Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form. In vivo studies showed that stereo-selective hepatic binding of the active form occurs during the first pass resulting in a difference in the peak levels of the two enantiomers, with the active to inactive peak concentration ratio being about 0.7. The approximate ratio of the active to inactive approaches unity after the peak is seen and thereafter the two enantiomers decline with the same half-life. After an intravenous administration, bypassing the first-pass metabolism, the ratios of the enantiomers in plasma were similar throughout the concentration-time profiles. Fluvastatin administered as LESCOL * XL 80 mg tablets reaches peak concentration in approximately 3 hours under either: fasting conditions; or immediately after a low-fat meal; or 2.5 hours after a low fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range: 9%-66%) compared to that of the LESCOL * immediate release capsule administered under fasting conditions. Administration of a high fat meal delayed the absorption (Tmax: 6 hours) and increased the bioavailability of the XL tablet by approximately 50%. Once LESCOL * XL begins to be absorbed, fluvastatin concentrations rise rapidly. The maximum concentration seen after a high fat meal is much less than the peak concentration following a single dose or twice-daily dose of the 40 mg LESCOL * capsule. Overall variability in the pharmacokinetics of LESCOL * XL is large (42%-64% CV for Cmax and AUC), and especially so after a high fat meal (63%-89% for Cmax and AUC). Intrasubject variability in the pharmacokinetics of LESCOL * XL under fasting conditions (about 25% for Cmax and AUC) tends to be much smaller as compared to the overall variability. Multiple peaks in plasma fluvastatin concentrations have been observed after LESCOL * XL administration.

Distribution

Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. The parent drug is targeted to the liver and no active metabolites are present systemically. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.

Metabolism

Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5 and 6- positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Both enantiomers of fluvastatin are metabolized in a similar manner. In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20%) (see DRUG INTERACTIONS).

Excretion

Fluvastatin is primarily (about 90%) eliminated in the feces as metabolites, with less than 2% present as unchanged drug. Urinary recovery is about 5%. After a radiolabeled dose of fluvastatin, the clearance was 0.8 L/h/kg. Following multiple oral doses of radiolabeled compound, there was no accumulation of fluvastatin; however, there was a 2.3 fold accumulation of total radioactivity. Steady-state plasma concentrations show no evidence of accumulation of fluvastatin following immediate release capsule administration of up to 80 mg daily, as evidenced by a beta-elimination half-life of less than 3 hours. However, under conditions of maximum rate of absorption (i.e., fasting) systemic exposure to fluvastatin is increased 33% to 53% compared to a single 20 mg or 40 mg dose of the immediate release capsule. Following once daily administration of the 80 mg LESCOL * XL tablet for 7 days, systemic exposure to fluvastatin is increased (20%-30%) compared to a single dose of the 80 mg LESCOL * XL tablet. Terminal half-life of LESCOL * XL was about 9 hours as a result of the slow-release formulation.

Special Populations and Conditions Pediatrics (10-17 years of age):

Pharmacokinetic data in the pediatric population are not available.

STORAGE AND STABILITY

LESCOL * capsules: Store between 15 and 30oC in a tight container. Protect from light and humidity. LESCOL * XL tablets: Store between 15 and 25oC.

SPECIAL HANDLING INSTRUCTIONS

Not applicable

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition

Active Ingredient:

fluvastatin sodium

Capsules:

Inactive Ingredients: Capsule shell and printing ink:

sodium bicarbonate, calcium carbonate, microcrystalline cellulose, pregelatinized starch, talc, magnesium stearate.

gelatin, iron oxide red, iron oxide yellow, titanium dioxide,.sodium laurel sulphate, benzyl alcohol, sodium propionate, edetate calcium disodium, carboxymethyl cellulose sodium, butyl paraben, propyl paraben, methyl paraben.

Extended Release Tablets:

Inactive Ingredients

: microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, potassium bicarbonate, povidone, magnesium stearate, iron oxide yellow, titanium dioxide and polyethylene glycol 8000.

Dosage Forms and Packaging

LESCOL * Capsules 20 mg -

Each strong reddish brown opaque cap and pale yellow opaque body capsule contains 20 mg fluvastatin (from 21.06 mg fluvastatin sodium). "XU 20MG" printed in red ink on the body.

Available in bottles of 100.

LESCOL * Capsules 40 mg

- Each strong reddish brown opaque cap and orange yellow opaque body capsule contains 40 mg fluvastatin (from 42.12 mg fluvastatin sodium). "XU 40MG" printed in red ink on the body.

Available in bottles of 100.

LESCOL * XL (fluvastatin sodium) Extended Release Tablets 80 mg

- Each yellow, round, slightly biconvex film-coated tablet with bevelled edges debossed with "LESCOL * XL" on one side and "80" on the other contains 80 mg fluvastatin (from 84.24 mg fluvastatin sodium). Available in blister packs of 28 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: fluvastatin sodium Chemical Name: [R *,S *-(E)]-(+-)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5- dihydroxy-6-heptenoic acid, monosodium salt Molecular formula: C24H25FNO4 *Na Molecular mass: 433.46 Structural formula:

F

racemic

-

O Na+

N

H3C CH3

O O O H H Physicochemical properties: Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. The pKa value is approximately 5.5. The pH of a 1% solution (w/v) varies between 8.2- 10.0 due to trace amounts of residual sodium hydroxide or carbonates. The octanol/water partition coefficient is 6.8.

CLINICAL TRIALS

Hypercholesterolemia

LESCOL */LESCOL * XL (fluvastatin sodium) are highly effective in reducing Total-C and LDL-C in patients with hypercholesterolemia. A marked response is seen within one week, and the maximum therapeutic response usually occurs within four weeks. The response is maintained during extended periods of therapy. In a multicenter, double-blind, placebo-controlled, dose-response study in patients with familial and non- familial hypercholesterolemia, LESCOL * capsules, given as a single dose at bedtime or on a twice daily basis for 12 weeks, resulted in similar lipid lowering effect. However, in patients with heterozygous familial hypercholesterolemia (FH), optimal reduction in total and LDL cholesterol necessitates combination drug therapy in the majority of patients (see REFERENCES). For homozygous FH, see WARNINGS AND PRECAUTIONS, Homozygous Familial Hypercholesterolemia). In a large multicenter, double-blind, placebo-controlled study, the administration of LESCOL * capsules at doses of 40 mg b.i.d. (N=266 patients) resulted in a mean LDL-C reduction of 35 % after 8 weeks of exposure and a mean LDL-C reduction of 32% at endpoint (28 weeks of exposure). Similarly, in another double blind study, the administration of LESCOL * at a dose of 80 mg/day resulted in statistically significant (p < 0.001) percent reductions in TC (-21 to -30.1), LDL-C (-30 to -37.2) and LDL/HDL ratio (-33 to -37.7). LESCOL * XL has been studied in eight controlled studies of patients with Type IIa or IIb hyperlipoproteinemia, involving over 1300 patients in a daily dose regimen of 80 mg in trials of 26 weeks in duration. In the two pivotal studies (n = 406), patients randomized to treatment with LESCOL * XL resulted in a significant mean decrease in LDL-C in the range of 31.0% (SE = 1.24) to 33.1% (SE = 1.07), TG decrease in the range of 12.8% (SE = 2.22) to 15.4% (SE = 2.19) and mean increase in HDL-C in the range of 2.6% (SE = 1.01) to 3.3% (SE = 1.05) after 26 weeks of treatment. Therapeutic response is well established within 2 weeks, and a maximum response is achieved within 4 weeks of initiation of treatment. In the other three supportive non-pivotal clinical studies (n=849), patients randomized to treatment with LESCOL * XL resulted in a significant mean decrease in LDL-C of 32.2% (SE = 0.51), TG decrease of 13.5% (SE = 0.97) and mean increase in HDL-C of 8.3% (SE = 0.47) after 24 weeks of treatment. In patients with primary mixed dyslipidemia (Fredrickson Type IIb) as defined by baseline plasma triglycerides levels = 200 mg/dL from the two pivotal studies (n = 406), LESCOL * XL 80 mg produced a mean reduction in triglycerides in the range of 17.5% (SE = 4.65) to 19.3% (SE = 3.13). In these patients, LESCOL * XL 80 mg produced increases in HDL-C (in the range of + 4.8 (SE = 1.38) to + 5.2 (SE = 1.87)). Significant decrease in LDL-C was also achieved. In these studies, patients with triglycerides > 400 mg/dL were excluded. The concomitant administration of LESCOL * and cholestyramine results in a clinically significant additive effect in reducing Total-C, LDL-C compared with that achieved with either component drug. The results of a randomized, double-blind, parallel-group, placebo-controlled study which investigated the concomitant administration of fluvastatin capsules 20 mg and open-label cholestyramine 4 g/day resulted in LDL-C reductions up to -30.6% .

Primary Mixed Hyperlipidemia

In a retrospective pooled analysis of all placebo controlled studies, patients with primary hypercholesterolemia treated with LESCOL * capsules in daily doses ranging from 20 mg to 80 mg (40 mg b.i.d.) demonstrated consistent and significant median decreases (percent change) in total-C (16.6 to 27.0%), LDL-C (22.2 to 35.9%), TG (11.9 to 17.8%) and Apo B (18.3 to 28.4%) and modest median increases (percent change) in HDL-C (3.3 to 5.6%). In patients with primary combined (mixed) hyperlipidemia (Type IIb) defined as baseline TG levels 200 mg/dL, treatment with LESCOL * capsules in daily doses ranging from 20 mg to 80 mg (40 mg b.i.d.) demonstrated consistent and significant median decreases (percent change) in total-C (16.4 to 26.8%), LDL-C (21.6 to 34.6%), TG (17.3 to 23.2%) and Apo B (18.3 to 28.1%) and modest median increases (percent change) in HDL-C (5.8 to 9.0%).

Secondary Prevention of Cardiovascular Events

LESCOL * Intervention Prevention Study:

The LESCOL * Intervention Prevention Study (LIPS) assessed the effect of LESCOL * 80 mg daily in 1,677 patients with coronary heart disease who had undergone their first percutaneous coronary intervention (PCI) procedure in the preceding 6 months. Patients in this multicenter, randomized, double- blind, placebo-controlled study were treated with dietary/lifestyle counseling and either LESCOL * 40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years. Patients were eligible for enrollment in the study if they had a total cholesterol level between 135 and 270 mg/dL (3.5 - 7.0 mmol/L), with fasting triglycerides levels of less than 400 mg/dL (4.5 mmol/L) before the index procedure. The upper total cholesterol limit for eligibility was 212 mg/dL (5.5 mmol/L) for patients whose baseline lipids were measured from blood drawn 24 hours to 4 weeks following MI and 232 mg/dL (6.0 mmol/L) for patients with type 1 or 2 diabetes mellitus. Exclusion criteria included sustained systolic blood pressure of more than 180 mm Hg and diastolic blood pressure of more than 100 mm Hg despite medical therapy, left ventricular ejection fraction of less than 30%, a history of previous PCI or CABG, severe valvular disease, idiopathic cardiomyopathy or congenital heart disease, severe renal dysfunction (defined as serum creatinine level > 1.8 mg/dL [160 umol/L]), obesity (defined as a body mass index > 35 kg/m2), and the presence of malignant or other disease with a life expectancy of less than 4 years. The primary endpoint of the LIPS study was time from randomization to the first occurrence of a major adverse cardiac endpoint, defined as either cardiac death, nonfatal myocardial infarction or re-intervention procedure. Secondary endpoints included cardiac death, combined cardiac death/nonfatal myocardial infarction, all death, combined all death/nonfatal myocardial infarction, noncardiac death and major adverse cardiac endpoints excluding repeat procedures of the index lesion, within the first 6 months of follow-up. The mean time between randomization and index procedure was 2.7 days in both groups. LESCOL * significantly reduced the risk of major adverse cardiac events by 22% (p=0.013, 181 events in the LESCOL * group versus 222 in the placebo group). The risk reduction in major cardiac events observed with LESCOL * was irrespective of baseline LDL-C levels or previous history of myocardial infarction. Greater risk reductions were observed in patients with diabetes (47%, p=0.041), patients >65 years of age (38%, p=0.006) and patients with multivessel coronary disease (34%, p=0.011). Secondary endpoints, cardiac death, noncardiac death, all death, combined cardiac death/MI and combined all death/MI, failed to reach statistical significance. Over the course of the study, treatment with LESCOL * led to median reductions in total cholesterol, LDL-C, triglycerides of 18%, 26% and 14%, and an increase in HDL-C of 10%. Outcome data for the LESCOL * Intervention Prevention Study are shown in Figure 1.

Figure 1 - MACE-Free Survival Time

Table 4 presents the incidence and risk of primary and secondary outcome end points in the intent-to-treat population.

Table 4- Incidence and Risk of Primary and Secondary Outcome End Points in the Intent-to- Treat PopulationP

Incidence, No. (%) Fluvastatin vs Placebo

Fluvastatin

Placebo P P

(n = 844) (n = 833) Value + RR (95% CI) Value ++

P

RR indicates relative risk; CI, confidence interval; and MACE, major adverse cardiac event (composite end point of cardiac death, nonfatal myocardial infarction [MI], or intervention procedure).

+ By Cochran - Mantel - Haenszel test.

++ Based on Cox proportional hazards model.

SS MACE excluding reinterventions (surgical or percutaneous coronary reintervention) occurring in the first 6 months of follow-up for lesions treated at the index procedure.

Atherosclerosis

LESCOL */LESCOL * XL were also found to reduce the rate of progression of atherosclerosis in patients with coronary artery disease and mild to moderate elevations of cholesterol as part of a treatment strategy to lower total and LDL cholesterol to target levels. In a placebo controlled trial including such patients, LESCOL * monotherapy reduced the rate of progression of atherosclerosis as evaluated by quantitative coronary angiography (QCA). In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of LESCOL * (fluvastatin sodium) therapy on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with coronary artery disease and mild to moderate hypercholesterolemia (baseline LDL-C range 3 - 5 mmol/L). In this randomized, double blind, placebo controlled trial, 429 patients were treated with conventional measures (step I AHA diet) and either LESCOL * capsule 40 mg/day or placebo. In order to provide treatment to patients with LDL-C >= 4.1 mmol/L at baseline receiving placebo, adjunctive therapy with cholestyramine was added after week 12 to all patients in the study with baseline LDL-C values >= 4.1 mmol/L. These baseline levels were present in 25% of the study population. The primary endpoint, assessed by QCA, was within-patient per-lesion change in minimum lumen diameter (MLD) of qualifying lesions. QCA were evaluated at baseline and 2.5 years. LESCOL * significantly slowed the progression of coronary atherosclerosis. Primary endpoint analysis showed significantly less progression in the all LESCOL * (+- cholesterolamine) versus all placebo patients (change in MLD -0.028 mm versus -0.100 mm, p<0.01) and for fluvastatin alone versus placebo alone (change in MLD -0.024 versus -0.094 mm, p< 0.02). Beneficial trends with treatment were consistently seen in clinical event rates (new occurrence or worsening of angina, coronary revascularization procedures [PTCA] or CABG surgery, myocardial infarction [MI] and total mortality) within the 2.5 years treatment, but were not statistically significant. This trial was however not designed to demonstrate a reduction in the risk of coronary morbidity and mortality.

Pediatrics (10-17 years of age)

Fluvastatin sodium was studied in two open-label, uncontrolled, dose-titration studies which enrolled pediatric patients (9 years and older) with heterozygous familial hypercholesterolemia. The first study (Study ZA01) enrolled 29 pre-pubertal boys (9-12 years of age), who had primary hypercholesterolemia above the 90th percentile of their age group and one parent with primary hypercholesterolemia and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226 mg/dL or 5.8 mmol/L (range: 137 - 354 mg/dL or 3.6 - 9.2 mmol/L). All patients were started on LESCOL * capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg bid) to achieve an LDL-C goal of 96.7 - 123.7 mg/dL (2.5 - 3.2 mmol/L). Endpoint analyses were performed at Year 2. In the first study (Study ZA01), the mean achieved LDL-C was 161 mg/dL or 4.2 mmol/L (range: 74 - 336 mg/dL or 1.9 - 8.7 mmol/L). The second study (Study B2301) enrolled 85 male and female patients, 9 to 17 years of age (includes one 9-year old and one 17-year old subject), who had an LDL-C >= 190 mg/dL (4.9 mmol/L) or LDL-C >= 160 mg/dL (4.1 mmol/L) and one or more risk factors for coronary heart disease, or LDL-C > 160 mg/dL (4.1 mmol/L) and a proven LDL-receptor defect. The main exclusion criteria were patients with homozygous familial hypercholesterolemia; secondary forms of dyslipoproteinemia; ALAT, ASAT and creatinine levels greater than 1.5 x ULN; serum CK and serum TSH levels > 2 x ULN; body mass index (BMI) greater than 32 kg/m2. The mean baseline LDL-C was 225 mg/dL or 5.8 mmol/L (range: 148 - 343 mg/dL or 3.8 - 8.9 mmol/L). All patients were started on LESCOL * capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (LESCOL * 80 mg XL tablet) to achieve an LDL-C goal of < 130 mg/dL (3.4 mmol/L). Endpoint analyses were performed at Week 114. In the second study (Study B2301), the mean achieved LDL-C was 159 mg/dL or 4.1 mmol/L (range: 90 - 295 mg/dL or 2.3 - 7.6 mmol/L). At the end of the study, mean reductions of 20.7% was observed in Apo B concentrations. In both studies, no statistically significant reduction of Triglycerides was noted (see Table 5).

Table 5:

Lipid lowering effect of fluvastatin in children and adolescents with heterozygous familial hypercholesterolemia

The majority of patients in both studies (83% in the first study and 89% in the second study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26 to 30% of patients in both studies achieved a targeted LDL-C goal of <= 130 mg/dL. The long-term efficacy of LESCOL * or LESCOL * XL therapy in childhood to reduce morbidity and mortality in adulthood has not been established. In both studies, all patients continued with their normal growth and sexual maturation. However, efficacy and safety have not been studied for treatment periods longer than two years. No data are available about the physical, intellectual and sexual maturation for prolonged treatment period. These studies were not designed to assess cardiovascular outcomes of early initiation of statin therapy in children.

DETAILED PHARMACOLOGY

Human pharmacology

LESCOL * capsules have been studied in 19 controlled trials worldwide involving patients with Type IIa and IIb hyperlipoproteinemia. LESCOL * alone was administered to 2326 patients in daily dose regimens of 20 mg, 40 mg and 80 mg (40 mg b.i.d.) for periods ranging from 6 weeks up to 36 weeks. At doses of 20 mg/day to 80 mg/day (40 mg b.i.d. ), LESCOL * resulted in highly significant decreases in LDL-C from 22.2% to 35%. Significant reductions of apolipoprotein B, statistically significant reductions of triglycerides (TG) and increased HDL-C were also noted. Fluvastatin had no effect on fibrinogen. The LDL lowering effect of LESCOL * is mediated through the inhibition of cholesterol biosynthesis and the increased catabolism of LDL-C induction of the LDL receptor.

Pharmacokinetics

Fluvastatin sodium is not a pro-drug. It is absorbed rapidly and completely (98%) following oral administration to fasted volunteers. The drug is also completely absorbed, even when administered up to 4 hours post-prandial, but at a reduced rate (Cmax is reduced by 40-70%). Fluvastatin is targeted to, and sequestered by the liver; therefore, absolute bioavailability based on systemic blood concentrations is about 25%. At doses above 20 mg given in the fasted state, absolute bioavailability can be dose dependent. Dose-normalized values at 40 mg were 20-40% higher than at 20 mg in the fasted state. Fluvastatin administered as LESCOL * XL 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions. Similar results were seen under fed conditions when administered immediately after a low-fat meal, or administered 2.5 hours after a low fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range: 9%-66%) compared to that of the LESCOL * immediate release capsule administered under fasting conditions. Administration of a high fat meal delayed the absorption (Tmax: 6 hours) and increased the bioavailability of the XL tablet by approximately 50%. Once LESCOL * XL begins to be absorbed, fluvastatin concentrations rise rapidly. The maximum concentration seen after a high fat meal is much less than the peak concentration following a single dose or twice-daily dose of the 40 mg LESCOL * capsule. Overall variability in the pharmacokinetics of LESCOL * XL is large (42%-64% CV for Cmax and AUC), and especially so after a high fat meal (63%-89% for Cmax and AUC). Intrasubject variability in the pharmacokinetics of LESCOL * XL under fasting conditions (about 25% for Cmax and AUC) tends to be much smaller as compared to the overall variability. Multiple peaks in plasma fluvastatin concentrations have been observed after LESCOL * XL administration. The volume of distribution (VDss) for the drug is calculated to be approximately 30 litres (0.35 L/kg). More than 98% of the circulating drug is bound to plasma albumin, and this binding is unaffected by drug concentration. The parent drug is targeted to the liver and no active metabolites are present systemically. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. Fluvastatin is predominantly metabolized by the hepatic microsomal CYP2C9 subclass of the P450 cytochromes. It is not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4. Interactions between fluvastatin and drugs metabolized by the CYP2C9 or CYP3A4 subclasses of the P450 cytochromes may occur in some patients. Following administration of 3H-fluvastatin sodium to healthy volunteers, excretion of radioactivity was about 5% in the urine and 90% in the feces, and fluvastatin accounted for less than 2% of the total radioactivity excreted. The plasma clearance for fluvastatin in man is calculated to be approximately 40 litres per hour. Steady-state plasma concentrations show no evidence of fluvastatin accumulation following administration of up to 80 mg daily for 25 days. However, under conditions of maximum rate of absorption (i.e. fasting), systemic exposure to fluvastatin is increased 33% to 53% compared to a single 20 or 40 mg dose. This increase in systemic exposure may result from saturation of uptake and sequestration of fluvastatin by the liver when fluvastatin is administered under fasting conditions. After single (or multiple) 20 mg and 40 mg (40 and 80 mg/day) oral doses of fluvastatin sodium, no differences in the fluvastatin elimination half-life are observed. The beta elimination half-life for fluvastatin is 1.2 hours (range of 0.53 to 3.1 hours). The extent of absorption of fluvastatin sodium 20 mg capsules is equivalent to that of a solution of fluvastatin sodium except that the time to peak under fasted conditions is about 0.7 hours following administration of the capsule compared to about 0.4 hours for the solution. Following ingestion of a single 20 mg fluvastatin sodium capsule under fasted conditions, measurable plasma concentrations of fluvastatin appear systemically within 10 minutes after dosing and reach a peak of 147 +- 86 ng/mL at 0.66 +- 0.3 hours. Fluvastatin sodium, like the other HMG-CoA reductase inhibitors, has variable bioavailability. The coefficient of variation (based on the inter-subject variability) was 47 to 57% for AUC, and 58 to 69% for Cmax. Results from an overnight pharmacokinetic evaluation following steady-state (15 weeks) administration of fluvastatin sodium with the evening meal or 4 hours after the evening meal, showed no significant difference in AUC and no apparent difference in the lipid-lowering effects between the two treatment groups. The administration of fluvastatin sodium with the evening meal resulted in a two-fold decrease in Cmax and more than a two-fold increase in Tmax as compared to patients receiving the drug 4 hours after the evening meal. The effects of gender and age on the pharmacokinetics of fluvastatin sodium were evaluated in four patient subgroups; young and elderly, males and females. All patients were administered 20 mg fluvastatin sodium daily, at least two hours after the evening meal, for twenty-one days. Overnight pharmacokinetic evaluations indicate that for the general patient population, plasma concentrations of fluvastatin do not significantly vary either as a function of age or gender. In a single-dose study the kinetics of fluvastatin sodium in subjects with cirrhosis (n=11) and in healthy age-and sex-matched subjects (n = 11) were compared. The mean AUC and Cmax parameters were about 2.5 times higher in the subjects with hepatic insufficiency. There was a 28% decrease in plasma clearance and a 31% smaller volume of distribution. No apparent difference was observed in the plasma elimination half-lives for the two groups. In a study conducted in 14 healthy volunteers, co-administration of diclofenac 25 mg/day and LESCOL * capsules 40 mg/day for 8 days resulted in a significant increase in the fluvastatin AUC(0-9) and Cmax on day 8 when compared to baseline (54% and 77%, respectively). Diclofenac Cmax and AUC were increased (60% and 25%, respectively) and oral clearance decreased by 16% on day 8 when compared to baseline. Dyslipidemia is frequent in organ transplant recipients primarily as a result of immunosuppressive drug treatment. Experience to date with the use of fluvastatin together with cyclosporine consists of 3 pharmacokinetics studies (fluvastatin doses of 20 mg, 40 mg), 17 clinical trials of small-medium size and short-, medium-term duration (fluvastatin doses of 20 mg, 40 mg, 40 mg BID) in renal and heart transplant recipients, and one large prospective placebo-controlled trial in 2,102 renal transplant recipients followed up for 5 to 6 years (fluvastatin doses of 40 mg and 40 mg BID). In a pharmacokinetic study conducted in 19 stable renal transplant patients with hypercholesterolemia receiving cyclosporine A concomitantly with fluvastatin capsules 20 mg/day, the AUC for fluvastatin was increased by 1.9 times compared to that of control subjects from another study who had received the same dose of fluvastatin. The Cmax was increased by 30% but the Tmax remained unchanged. Similarly, in a pharmacokinetic study conducted in 19 stable renal transplant patients on stable cyclosporine A regimen who received fluvastatin extended release 80 mg/day for 1 week, both the AUC and Cmax for fluvastatin were increased by two fold as compared with data from historical controls treated with the same fluvastatin regimen. Published data show that plasma trough concentrations of cyclosporine A are not significantly changed during co- administration with fluvastatin 20 mg/day. In patients receiving cyclosporine A in combination with fluvastatin, liver enzymes and CK levels should be carefully monitored and the dose of fluvastatin adjusted, if necessary. In heart transplant patients treated with fluvastatin 40 mg/day and cyclosporine A for four weeks, AUC for fluvastatin was increased 3.5 times and 3.1 times in patients than in the age- matched healthy controls on study days 1 and 28, respectively. No correlation between systemic fluvastatin levels and musculoskeletal adverse events or biochemical markers of musculoskeletal damage or renal function impairment have been observed in clinical trials conducted to date. Biotransformation pathways for fluvastatin include: a) hydroxylation of the indole ring at the 5- and 6- positions; b) N-dealkylation; and c) beta-oxidation. The major circulating blood components are fluvastatin and the pharmacologically inactive N-desisopropyl-propionic acid metabolite. The hydroxylated metabolites have pharmacological activity but do not circulate systemically. Both enantiomers of fluvastatin are metabolized in a similar manner resulting in only minor differences in systemic exposure.

Animal pharmacology

In vitro

Fluvastatin sodium is a synthetic, hydrophilic, competitive inhibitor of HMG-CoA reductase. The IC50 values for the inhibition of sterol synthesis by fluvastatin sodium are 0.007 mM in rat liver microsomes, 0.03 mM rat hepatoma Fu5AH cells, and 0.05 mM in human hepatoma HepG2 cells. The IC50 for the induction of LDL receptors in the HepG2 cells is 0.05 mM.

In vivo

The administration of fluvastatin sodium resulted in large reductions in serum cholesterol concentrations in rats, hamsters, dogs and Rhesus monkeys demonstrating its significant lipid-lowering effect. In the rats and dogs, the reduction in serum cholesterol resulted primarily from a decrease in the VLDL+LDL fraction with ED50's of 0.09 mg/kg and 2 mg/kg, respectively. In the Rhesus monkey, the ED25 for the reduction in total serum cholesterol was estimated at 24 mg/kg. In the hamster model, which best represents human LDL metabolism, fluvastatin sodium resulted in an increased catabolic removal of LDL as the result of the up-regulation of the LDL receptors. At 6 mg/kg in the hamster, fluvastatin sodium reduced both the VLDL-C and LDL-C while slightly increasing the HDL-C. At oral doses at least 100 times the ED50 for inhibition of sterol synthesis in rats, fluvastatin sodium had no effect on overt behaviour, fasting serum glucose levels, estrogen-like activity in a vaginal response test, anti-inflammatory activity, or cardiovascular activity (with the exception of a mild, reversible reduction in blood pressure) in the rat. At a dose 10 times the ED50 for the reduction of VLDL+LDL-C in dogs, fluvastatin sodium had no effect on blood pressure, heart rate or autonomic responses to norepinephrine, isoproterenol and acetylcholine in anesthetized dogs.

Pharmacokinetics

The pharmacokinetics and disposition of fluvastatin sodium was studied in the mouse, rat, dog and monkey. In all species, absorption of fluvastatin sodium was rapid and essentially complete. Peak plasma concentrations were generally achieved within 0.5 to 3 hours post dose. Distribution of fluvastatin sodium and its metabolites were studied in mice and rats. In both species, the highest concentrations were observed in the liver followed by substantially lower levels in the kidney, heart and adrenals. The permeability of fluvastatin versus lovastatin across the blood-brain barrier was measured using three techniques: the brain uptake index technique, brain perfusion studies in the rat, and an in vitro model consisting of a primary culture of confluent monolayers of bovine brain microvessel endothelial cells. In all three models, lovastatin showed a considerably greater permeability coefficient (0.011 cm/min) than fluvastatin sodium (0.00072 cm/min). Extensive presystemic hepatic extraction followed by direct excretion via the bile occurred with fluvastatin sodium. Biotransformation pathways for fluvastatin include: a) hydroxylation of the indole ring at the 5- and 6-positions; b) N-dealkylation; and c) beta-oxidation. Renal excretion accounted for less than 8% of the dose in all species except the rabbit (ca.30%).

MICROBIOLOGY

Not applicable

TOXICOLOGY

Acute Toxicity

Table 6 - Single Dose Toxicity Studies with Fluvastatin sodium

Signs of toxicity were decreased locomotor activity, ataxia, loss of righting reflex, dehydration, hypothermia, ptosis, shallow breathing, piloerection, soft feces/diarrhea, and/or splayed gait.

Subacute and Chronic Toxicity

The spectrum of effects produced by fluvastatin sodium in mice, rats, hamsters, dogs and monkeys shown in the following table is not unexpected in view of the magnitude of the dosage levels employed.

Table 7 - Multiple Dose Toxicity Studies with Fluvastatin sodium

+ = organ affected in some way by drug treatment

- = no effect was observed in this organ in these species NA = not applicable

E = increased liver enzymes CC = cholesterol calculi

P decedents only

The following table summarizes the significant adverse changes noticed during the long-term toxicology studies with fluvastatin sodium.

Table 8 - Significant Adverse Events During Long-term Toxicology Studies with Fluvastatin Sodium

nd = not determined

P = Seen only in decedents

The fluvastatin-induced hyperplasia/hyperkeratosis was confined to the forestomach epithelial mucosa in mice and rats. This phenomenon did not occur in other species without a non-glandular forestomach (ie. dog, monkey) nor was there evidence of a hyperplastic lesion of the esophagus. Cataract development is a species-specific effect in the dog. The no effect dose level was defined as 8 mg/kg/day in the dog, which is approximately 88 times the mean AUC in man following a 40 mg dose. Evidence of hepatotoxicity in the rat was characterized by elevated serum enzyme activities generally associated with the histopathological diagnosis of hepatocellular change. These changes are classic evidence of the direct hepatotoxic effects of a xenobiotic substance which typically for the rat model were dose- and time-dependent and reversible upon withdrawal of drug treatment. At 8 and 36 mg/kg/day for 26 weeks, gallbladder changes characterized by inflammation and hyperplasia of the mucosa were noted in the dog. However, after two years at 8 mg/kg/day no pathology was apparent and at 16 mg/kg/day only mild hypertrophy of the gallbladder mucosa was noted. In hamsters, dose levels of 5 to 40 mg/kg/day induced the formation of gallbladder cholesterol calculi with a low frequency of bile duct capillary proliferation. In non-human primates, minimal to trace epithelial hyperplasia of the gallbladder epithelium was seen following administration of fluvastatin sodium at doses of 12 mg/kg/day and above for 26 weeks. A large proportion of the drug is excreted in the bile of which approximately 30% is unchanged drug. This may account for the changes encountered in animal studies, whereas man does not appear to excrete the parent drug. Focal hemorrhages were noted in the gallbladder, heart, diaphragm, pancreas, intestines, mesentery and mediastinum. This lesion was probably related to injury of the vascular bed and was considered to be a manifestation of general systemic toxicity in debilitated animals rather than a primary effect of fluvastatin exposure. Hemorrhages have not occurred in the brain or nervous tissue of dogs treated with fluvastatin sodium. The increased incidence of follicular cell neoplasm in the male rats is consistent with species-specific findings from other HMG-CoA reductase inhibitors. No CNS lesions have been observed in any species (mouse, rat, or dog) chronically treated for 2 years with LESCOL *. However, CNS vascular lesions, characterized by perivascular hemorrhages and edema and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other drugs of this class.

Carcinogenicity/Mutagenicity

A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day to establish a clear maximum tolerated dose (determined to be 9 mg/kg/day). These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. An increased incidence of forestomach squamous papillomas and one carcinoma of the forestomach at the 24 mg/kg/day dose level were considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic (genotoxic) effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with species specific findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed. The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.2, 10, and 30 times the mean human plasma drug concentration after a 40 mg oral dose. As with the rat carcinogenicity results, it was concluded that the increased incidence of forestomach squamous papillomas reflected the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a specific (genotoxic) effect of the drug. The carcinogenicity study in mice was repeated at oral dose levels of 50, 150 and 350 mg/kg/day. Reduced body weight gain was recorded at all dose levels, and excessive mortality at the high dose confirmed that the maximum tolerated dose is less than 150 mg/kg/day in the mouse. There was no evidence of increased neoplasia at these doses. No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.

Teratology and Reproductive Studies

In a study in rats at dose levels for females at 0.6, 2 and 6 mg/kg/day and for males at 2, 10 and 20 mg/kg/day fluvastatin sodium had no adverse effects on the fertility or reproductive performance at any of the dose levels studied. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at the low dose level of 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study.

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