LESCOL® (fluvastatin* sodium) 20 mg and 40 mg capsules.

*INN rec..

One 20mg capsule contains 21.06 mg fluvastatin sodium corresponding to 20 mg fluvastatin free acid.

One 40mg capsule contains 42.12 mg fluvastatin sodium corresponding to 40 mg fluvastatin free acid.

For excipients, see Section 6.1.

Capsule, hard

20 mg capsules are No. 3 size hard gelatine capsules with a strong reddish brown opaque cap with a pale yellow opaque body with XU 20 mg imprinted in red.

Capsule, hard

40 mg capsules are No. 1 size hard gelatine capsules with a strong reddish brown opaque cap with a moderate orange yellow body with XU 40 mg imprinted in red.

LESCOL is indicated as an adjunct to diet for the reduction of elevated total-C, LDL-C, apo B and TG levels in patients with primary hypercholesterolaemia and mixed dyslipidaemia (Fredrickson types IIa and IIb).

LESCOL is also indicated to slow the progression of coronary atherosclerosis in patients with primary hypercholesterolaemia and concomitant coronary heart disease who do not adequately respond to dietary control.

LESCOL is also indicated in patients with coronary heart disease for the secondary prevention of coronary events after percutaneous coronary intervention, see Section 5.1.

Prior to initiating LESCOL, secondary causes of hypercholesterolaemia should be excluded, and the patient placed on a standard cholesterol-lowering diet. Dietary therapy should be continued during treatment.

• Dose recommendations for lipid lowering effect

The recommended starting dose is 40 mg (1 capsule LESCOL 40 mg) once daily in the evening, although a dose of 20 mg fluvastatin (1 capsule LESCOL 20 mg) once daily may be adequate in mild cases. Most patients will require a dose of 20 mg to 40 mg once daily but the dose may be increased to 80 mg daily (1 tablet LESCOL XL 80 mg or 1 capsule LESCOL 40 mg twice daily), individualised according to baseline LDL-C levels and the recommended goal of therapy to be accomplished. The maximum recommended daily dose is 80 mg.

The maximum lipid-lowering effect with a given dose of the drug is achieved within 4 weeks. Doses should be adjusted according to the patient's response and dose adjustment made at intervals of 4 weeks or more. The therapeutic effect of LESCOL is maintained with prolonged administration.

For patients requiring a dose of 40 mg twice daily, a calendar pack of 56 LESCOL Capsules 40 mg is available containing morning and evening doses in marked blister strips

LESCOL is efficacious in monotherapy or in combination with bile acid sequestrants. When LESCOL is used in combination with cholestyramine or other resins, it should be administered at least 4 hours after the resin to avoid a significant interaction due to binding of the drug to the resin. Minimal data exist to support the efficacy and safety of LESCOL in combination with nicotinic acid or fibrates (see Section 4.5 Interactions with other medicaments and other forms of interaction).

• Dose recommendations for slowing the progression of coronary atherosclerosis

In a study in patients with primary hypercholesterolaemia and concomitant coronary heart disease 40 mg daily slowed the progression of coronary atherosclerosis.

• Dose recommendations for the secondary prevention of coronary events after percutaneous coronary intervention

In patients with coronary heart disease after percutaneous coronary intervention, the dose is 80 mg daily.

Patients with impaired kidney function

Fluvastatin is cleared by the liver, with less than 6% of the administered dose excreted into the urine. The pharmacokinetics of fluvastatin remain unchanged in patients with mild to severe renal insufficiency (creatinine > 260 µmol/L). No dose adjustments are therefore necessary in these patients.

Patients with impaired liver function

LESCOL/LESCOL XL is contraindicated in patients with active liver disease, or unexplained, persistent elevations in serum transaminases (see 4.3 Contraindications and 4.4 Special warnings and special precautions for use).

Use in the elderly

There is no evidence of reduced tolerability or altered dosage requirements in elderly patients.

Children and adolescents with heterozygous familial hypercholesterolemia

Prior to initiating treatment with Lescol in children and adolescents aged 9 years and older with heterozygous familial hypercholesterolaemia, the patient should be placed on a standard cholesterol-lowering diet. Dietary therapy should be continued during treatment.

The recommended starting dose is 40 mg (1 capsule Lescol 40 mg) or 80 mg (one capsule Lescol 40 mg twice daily). The dose of 20 mg fluvastatin (1 capsule Lescol 20 mg) may be adequate in mild cases. 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 fibrates in children and adolescents has not been investigated.

Known hypersensitivity to any component of LESCOL.

Patients with active liver disease, hepatic impairment, or unexplained, persistent elevations in serum transaminases.

HMG-CoA reductase inhibitors, including LESCOL, are unlikely to be of benefit in patients with rare homozygous familial hypercholesterolaemia.

As with other lipid-lowering drugs, it is recommended that liver function tests be performed before the initiation of treatment and at 12 weeks following initiation of treatment or elevation in dose and periodically thereafter in all patients. Should an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) exceed 3 times the upper limit of normal and persist, therapy should be discontinued. In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.

Caution should be exercised when LESCOL is administered to patients with a history of liver disease or heavy alcohol ingestion.

Since fluvastatin is eliminated primarily via the biliary route and is subject to significant pre-systemic metabolism, the potential exists for drug accumulation in patients with hepatic insufficiency.

The use of fluvastatin in combination with glibenclamide should be avoided whenever possible (see Section 4.5 Interactions with other medicaments and other forms of interaction).

Skeletal muscle:

With LESCOL, myopathy has rarely been reported, whereas myositis and rhabdomyolysis have been reported very rarely. In patients with unexplained diffuse myalgias, muscle tenderness or muscle weakness, and/or marked elevation of creatine kinase (CK) values, myopathy, myositis or rhabdomyolysis have to be considered. Patients should therefore be advised to report promptly unexplained muscle pain, muscle tenderness or muscle weakness, particularly if accompanied by malaise or fever.

Creatine kinase measurement:

There is no current evidence to require routine monitoring of plasma total creatine kinase or other muscle enzyme 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 the value interpretation difficult.

Before the treatment:

As with all other statins physicians should prescribe fluvastatin with caution in patients with pre-disposing factors for rhabdomyolysis and its complications. A creatine kinase level should be measured before starting fluvastatin treatment in the following situations:

• Renal impairment

• Hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse

• In elderly (age> 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis.

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 (> 5xULN), levels should be re-measured within 5 to 7 days later to confirm the results. If CK-levels are still significantly elevated (> 5xULN) at baseline, treatment should not be started.

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).

If muscular symptoms are severe and cause daily discomfort, even if CK-levels are elevated to 5 x ULN, treatment discontinuation should be considered.

Should the symptoms resolve and CK-levels return to normal, then re-introduction of fluvastatin or another statin may be considered at the lowest dose and under close monitoring.

The risk of myopathy is known to be increased in patients receiving immunosuppressive drugs (including ciclosporin), fibrates, nicotinic acid or erythromycin together with other HMG-CoA reductase inhibitors. Minimal data exist to support the efficacy or safety of LESCOL in combination with nicotinic acid, its derivatives, fibrates or ciclosporin. Isolated cases of myopathy have been reported post-marketing for concomitant administration of fluvastatin with colchicine. LESCOL should be used with caution in patients receiving such concomitant medication (see Section 4.5).

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Children and adolescents with heterozygous familial hypercholesterolemia

In patients aged <18 years, 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. The long-term efficacy of Lescol therapy in childhood to reduce morbidity and mortality in adulthood has not been established. (see Section 5.1).

Fluvastatin has only been investigated in children of 9 years and older with heterozygous familial hypercholesterolaemia (for details see section 5.1). In the case of pre-pubertal children, as experience is very limited in this group, the potential risks and benefits should be carefully evaluated before the initiation of treatment.

Fluvastatin is substantially metabolised by cytochrome P450 (CYP2C9). Other substrates or inhibitors of CYP2C9 administered concomitantly may therefore potentially result in increased plasma levels of fluvastatin, with a consequent increased risk of myopathy (see section 4.4).

Food interactions

Although AUC and C_max were lowered and t_max prolonged when LESCOL was taken with food, there was no apparent difference in the lipid-lowering effects whether LESCOL was taken with food or not.

Drug interactions

Effects of other drugs on fluvastatin:

Ciclosporin - In an interaction study concomitant administration of fluvastatin (up to 40 mg/day) and ciclosporin resulted in an increase in the bioavailability of fluvastatin by a factor of 1.9. The results from another study wherein LESCOL XL (80 mg fluvastatin) was administered to renal transplant patients who were on stable ciclosporin regimen showed that fluvastatin exposure (AUC) and maximum concentration (Cmax) were increased by 2 fold compared to historical data in healthy subjects. The combination of fluvastatin and ciclosporin should be used with caution due to the potential for an increased risk of myopathy and/or rhabdomyolysis (see section 4.4 Special warnings and special precautions for use).

Fibric acid derivatives (fibrates) and nicotinic acid:

Bezafibrate - An interaction study between 20 mg o.d. fluvastatin and 200 mg t.d.s. bezafibrate showed that mean AUC and C_max 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.

Gemfibrozil - In an interaction study the concomitant administration of fluvastatin and gemfibrozil had no effect on the pharmacokinetics of either drug. The combination should be used with caution however, due to reports of an increased risk of myopathy and/or rhabdomyolysis when other HMG-CoA reductase inhibitors have been combined with fibrates.

Ciprofibrate - Concomitant administration of fluvastatin and ciprofibrate has no effect on the bioavailability of fluvastatin. However, the combination should be used with caution due to reports of an increased risk of myopathy and/or rhabdomyolysis when ciprofibrate is used in combination with other HMG-CoA reductase inhibitors.

Nicotinic acid - Concomitant administration of fluvastatin and nicotinic acid has no effect on the bioavailability of fluvastatin. However, the combination should be used with caution due to reports of an increased risk of myopathy and/or rhabdomyolysis when nicotinic acid is used in combination with other HMG-CoA reductase inhibitors.

Erythromycin - There are reports of an increased risk of myopathy and/or rhabdomyolysis when other HMG-CoA reductase inhibitors have been combined with erythromycin. The results from an interaction study with a small number of healthy volunteers suggested that erythromycin and fluvastatin were not metabolised by the same isoenzyme, however caution should be exercised when these two drugs are given in combination in view of the interaction seen with other HMG-CoA reductase inhibitors.

Fluconazole - Administration of fluvastatin to healthy volunteers pre-treated with fluconazole (CYP 2C9 inhibitor) resulted in an increase in the exposure (AUC) and mean peak concentration (Cmax) of fluvastatin by about 84% and 44% respectively. Caution should be exercised when fluvastatin is administered concomitantly with fluconazole.

Itraconazole - No interactions have been seen with itraconazole. Nevertheless patients should be closely monitored.

Antipyrine - Administration of LESCOL does not influence the metabolism and excretion of antipyrine. As antipyrine is a model for drugs metabolised by the microsomal hepatic enzyme systems, interactions with other drugs metabolised by these systems are not expected.

Propranolol - Concomitant administration of LESCOL with propranolol has no effect on the bioavailability of LESCOL.

Bile-acid sequestering agents - Administration of LESCOL 4 hours after cholestyramine results in a clinically significant additive effect compared with that achieved with either drug alone. LESCOL should be administered at least 4 hours after the resin (e.g. cholestyramine) to avoid a significant interaction due to drug binding to the resin.

Digoxin - Concomitant administration of LESCOL with digoxin has no effect on digoxin plasma concentrations.

Amlodipine - No clinically significant pharmacokinetic interactions occur when fluvastatin is concomitantly administered with amlodipine.

Cimetidine/ranitidine/omeprazole - Concomitant administration of LESCOL with cimetidine, ranitidine or omeprazole results in an increase in the bioavailability of LESCOL, which, however, is of no clinical relevance.

Rifampicin - Administration of LESCOL to subjects pre-treated with rifampicin resulted in a reduction of the bioavailability of LESCOL by about 50%. Although at present there is no clinical evidence that fluvastatin efficacy in lowering lipid levels is altered, for patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis), appropriate adjustment of fluvastatin dosage may be warranted to ensure a satisfactory reduction in lipid levels.

Phenytoin - In an interaction study concomitant administration of fluvastatin and phenytoin resulted in an increase of fluvastatin mean AUC and Cmax values by 40% and 27% respectively. This combination should be used with caution due to the increased risk of developing myopathy and/or rhabdomyloysis.

Effects of fluvastatin on other drugs:

Ciclosporin - Both LESCOL and LESCOL XL had no effect on ciclosporin bioavailability when co-administered (see also Effects of other drugs on fluvastatin).

Colchicine - No information is available on the pharmacokinetic interaction between fluvastatin and colchicine. However, myotoxicity, including muscle pain and weakness and rhabdomyolysis, have been reported anecdotally with concomitant administration of colchicines.

Phenytoin - Co-administration of fluvastatin (40 mg b.i.d. for 5 days) increased the mean C_max of phenytoin by 5% whereas the mean AUC was increased by 22%. Patients on phenytoin should be carefully monitored when fluvastatin therapy is initiated or when the dose is increased.

Warfarin and other coumarin derivatives - Co-administration of fluvastatin with warfarin may commonly cause significant increases in prothrombin time. This has resulted very rarely in serious haemorrhage. It is recommended that prothrombin times are monitored when fluvastatin therapy is initiated, discontinued or the dosage changed in patients receiving warfarin or other coumarin derivative.

Glibenclamide - An interaction study between fluvastatin 40 mg b.i.d. and glibenclamide was done in diabetic patients stabilised on 5-20 mg of glibenclamide. The AUC for glibenclamide increased on average by 1.7 times (range: 0.9 – 3.5), Cmax increased on average by 1.6 times (range: 0.9 -3.0) and the mean t1/2 of glibenclamide increased from 8.5 to 18.8 hours when taken with fluvastatin. In this study there were no significant changes in glucose levels but in view of the increases seen in glibenclamide levels there remains a potential for serious hypoglycaemia and this combination should be avoided whenever possible.

Other concomitant therapy - In clinical studies in which LESCOL was used concomitantly with angiotensin converting enzyme (ACE) inhibitors, beta-blockers, calcium channel blockers, salicylic acid, H₂-blockers and non-steroidal anti-inflammatory drugs (NSAIDs), no clinically significant adverse interactions occurred.

Animal studies have indicated that fluvastatin is devoid of embryotoxic and teratogenic potential. However, since HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in women of childbearing potential not taking adequate contraceptive precautions. If a patient becomes pregnant while taking this class of drug, therapy should be discontinued. As small amounts of fluvastatin have been found in rat milk, LESCOL is contraindicated in nursing mothers.

No data exist on the effects of LESCOL on the ability to drive and use machines.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000) very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

The most commonly reported adverse drug reactions are minor gastrointestinal symptoms, insomnia and headache.

Table 1

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares

• Memory loss

• Sexual dysfunction

• Depression

• Exceptional cases of interstitial lung disease, especially with long-term therapy (see section 4.4)

Laboratory Findings

Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid-lowering agents. Confirmed elevations of transaminase levels to more than 3 times the upper limit of normal (ULN) developed in a small number of patients (less than or equal to 1%). Marked elevations of CK levels to more than 5 x ULN developed 0.3 - 1.0% of patients receiving licensed doses of fluvastatin in clinical trials.

Children and adolescents with heterozygous familial hypercholesterolemia

The safety profile of fluvastatin in children and adolescents with heterozygous familial hypercholesterolemia assessed in 114 patients aged 9-17 years treated in two open non-comparative clinical trials was similar to the one observed in adults. In both clinical trials no effect was observed on growth and sexual maturation. The ability of the trials to detect any effect of treatment in this area was however low.

The experience with overdoses of LESCOL is very limited. Should an accidental overdosage occur, administration of activated charcoal is recommended. In the case of a very recent oral intake gastric lavage may be considered. Treatment should be symptomatic.

LESCOL, a fully synthetic cholesterol-lowering agent, is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. LESCOL exerts its main effect in the liver. 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 cholesterol concentration.

A variety of clinical studies has demonstrated that elevated levels of total cholesterol (total-C), 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. Epidemiologic 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). The overall cholesterol profile is improved with the principal effects being the reduction of total-C and LDL-C. LESCOL also produces a moderate reduction in triglycerides and a moderate increase in HDL-C.

In a pooled analysis of all placebo-controlled studies, patients with primary mixed dyslipidaemia (Type IIb) defined as baseline TG levels 200 mg/dL, treatment with LESCOL in daily doses ranging from 20 mg to 80 mg (40 mg b.i.d.) demonstrated consistent and significant decreases in total-C, LDL-C, and apo-B, TG, and a modest increase in HDL-C.

In the Lescol Intervention Prevention Study (LIPS), the effect of fluvastatin on major adverse cardiac events (MACE) was assessed in patients with coronary heart disease who had first successful transcathether therapy (TCT). The study included male and female patients (18-80 years old) and with baseline total cholesterol levels ranging from 3.5-7.0 mmol/L.

In this randomised, double-blind, placebo-controlled trial, a total of 1677 patients were recruited (844 in fluvastatin group and 833 in placebo group). The MACE was defined as cardiac death, non fatal MI and re-intervention (including CABG, repeat TCT, or TCT of a new lesion). The dose of fluvastatin used in this study was 80 mg daily over 4 years. Although the overall composite endpoint showed significant reduction in MACE (22%) compared to placebo (p=0.013), the individual components (cardiac death, non fatal MI and re-intervention) failed to reach statistical significance. There was however a trend in favour of fluvastatin. Therapy with fluvastatin reduced the risk of cardiac death and/or myocardial infarction by 31% (p=0.065).

Children and adolescents with heterozygous familial hypercholesterolemia

The safety and efficacy of Lescol in children and adolescent patients aged 9 - 16 years of age with heterozygous familial hypercholesterolemia has been evaluated in 2 open label, uncontrolled clinical trials of 2 years' duration. 114 patients (66 boys and 48 girls) were treated with fluvastatin administered as either Lescol capsules 20 mg - 40 mg bid or Lescol 80 mg extended release tablets using a dose-titration regimen based upon LDL-C response.

The first study enrolled 29 pre-pubertal boys, 9-12 years of age, who had an LDL-C level > 90th percentile for age 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 equivalent to 5.8 mmol/L (range: 137 - 354 mg/dL equivalent to 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 to 123.7 mg/dL (2.5 mmol/L to 3.2 mmol/L).

The second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C 190 mg/dL (equivalent to 4.9 mmol/L) or LDL-C 160 mg/dL (equivalent to 4.1 mmol/L) and one or more risk factors for coronary heart disease, or LDL-C 160 mg/dL (equivalent to 4.1 mmol/L) and a proven LDL-receptor defect. The mean baseline LDL-C was 225 mg/dL equivalent to 5.8 mmol/L (range: 148 - 343 mg/dL equivalent to 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 prolonged release tablet) to achieve an LDL-C goal of 130 mg/dL (3.4 mmol/L).

In the first study, Lescol 20 to 80 mg daily doses decreased plasma levels of total-C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL equivalent to 4.2 mmol/L (range: 74 - 336 mg/dL equivalent 1.9 – 8.7 mmol/L). In the second study, Lescol 20 to 80 mg daily doses decreased plasma levels of total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL equivalent to 4.1 mmol/L (range: 90 - 295 mg/dL equivalent to 2.3 – 7.6 mmol/L).

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 (3.4 mmol/L).

LESCOL is a racemate of the two erythro enantiomers of which one exerts the pharmacological activity. LESCOL is absorbed rapidly and completely (98%) following oral administration to fasted volunteers. In a fed state, the drug is absorbed at a reduced rate. Fluvastatin exerts its main effect in the liver, which is also the main organ for its metabolism. The absolute bioavailability assessed from systemic blood concentrations is 24%. The apparent volume of distribution (V_zf) for the drug is 330 L. More than 98% of the circulating drug is bound to plasma proteins, and this binding is unaffected by drug concentration.

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.

The hepatic metabolic pathways of fluvastatin in humans have been characterised. There are multiple, alternative cytochrome P₄₅₀ (CYP₄₅₀) pathways involved. However, the major pathway is mediated by CYP2C9 and this pathway is subject to potential interactions with other CYP2C9 substrates or inhibitors. In addition there are several minor pathways (e.g. CYP3A4).

Several detailed in vitro studies have addressed the inhibitory potential of fluvastatin on common CYP isoenzymes. Fluvastatin inhibited only the metabolism of compounds that are metabolized by CYP2C9.

Following administration of ³H-fluvastatin to healthy volunteers, excretion of radioactivity is about 6% in the urine and 93% in the faeces, and fluvastatin accounts for less than 2% of the total radioactivity excreted. The plasma clearance (CL/f)for fluvastatin in man is calculated to be 1.8 ± 0.8 L/min. Steady-state plasma concentrations show no evidence of fluvastatin accumulation following administration of 40 mg daily. Following oral administration of 40 mg of LESCOL, the terminal disposition half-life for fluvastatin is 2.3 ± 0.9 hours.

Food: Although AUC and C_max were lowered and t_max prolonged when LESCOL was taken with food, there was no apparent difference in the lipid-lowering effect whether LESCOL was taken with food or not.

Plasma concentrations of fluvastatin do not vary as a function of either age or gender in the general population.

Children and adolescents with heterozygous familial hypercholesterolemia

No pharmacokinetic data in children are available.

The safety of fluvastatin was extensively investigated in toxicity studies in rats, dogs, monkeys, mice and hamsters. A variety of changes were identified that are common to HMG-CoA reductase inhibitors, viz. hyperplasia and hyperkeratosis of the rodent non-glandular stomach, cataracts in dogs, myopathy in rodents, mild liver changes in most laboratory animals with gall bladder changes in dog, monkey and hamster, thyroid weight increases in the rat and testicular degeneration in the hamster. Fluvastatin is devoid of the CNS vascular and degenerative changes recorded in dogs with other members of this class of compound.

A carcinogenicity study was performed in rats at dose levels of 6, 9 and 18 mg/kg a day (escalated to 24 mg/kg a day after 1 year) to establish a clear maximum tolerated dose. These treatment levels yielded plasma drug levels approximately 9, 13 and 26 to 35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and one carcinoma of the forestomach was observed at the 24 mg/kg a day dose level. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded in male rats treated with 18 to 24 mg/kg a day.

The forestomach neoplasms observed in rats and mice reflect chronic hyperplasia caused by direct contact exposure to fluvastatin rather than a genotoxic effect of the drug. The increased incidence of thyroid follicular cell neoplasms in male rats given fluvastatin appears to be consistent with species-specific findings with other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no treatment-related increases in the incidences of hepatic adenomas or carcinomas were observed.

The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg a day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg a day and in females at 15 mg/kg a day. These treatment levels yielded plasma drug levels approximately 0.2, 10 and 21 times the mean human plasma drug concentration after a 40 mg oral dose.

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.

In a study in rats at dose levels in females of 0.6, 2 and 6 mg/kg a day and in males of 2, 10 and 20 mg/kg a day, fluvastatin had no adverse effects on the fertility or reproductive performance. Teratology studies in rats and rabbits showed maternal toxicity at high dose levels, but there was no evidence of embryotoxic or teratogenic potential. A study in which female rats were dosed at 12 and 24 mg/kg a day during late gestation until weaning of the pups resulted in maternal mortality at or near term and post partum accompanied by fetal and neonatal lethality. No effects on the pregnant females or fetuses occurred at the low dose level of 2 mg/kg a day.

A second study at levels of 2, 6, 12 and 24 mg/kg a day during late gestation and early lactation showed similar effects at 6 mg/kg a day and above caused by cardiotoxicity. In a third study, pregnant rats were administered 12 or 24 mg/kg a day during late gestation until weaning of pups with or without the presence of concurrent supplementation with mevalonic acid, a derivative of HMG-CoA that is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the cardiotoxicity and the maternal and neonatal mortality. Therefore, the maternal and neonatal lethality observed with fluvastatin reflects its exaggerated pharmacologic effect during pregnancy.

Capsule content:

Magnesium stearate

Sodium hydrogen carbonate

Talc

Cellulose microcrystalline, fine powder

Cellulose microcrystalline, granular powder

Maize starch, physically modified

Calcium carbonate

Capsule shell:

Iron oxide red E172

Iron oxide yellow E172

Gelatin

None

3 years.

Do not store above 25°C.

Alu/alu blister consisting of an aluminium coating foil and an aluminium covering foil.

HDPE bottle with a tight closure consisting of a polyethylene container (high density polyethylene, grey pigmented) and a closure.

The 20 mg capsules are contained in calendar packs of 28.

The 40 mg capsules are contained in calendar packs of 28 capsules and available in calendar packs of 56 capsules for twice daily dosing.

None

Novartis Pharmaceuticals UK Ltd

Trading as Sandoz Pharmaceuticals

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

20 mg capsules: PL 00101/0360

40mg capsules: PL 00101/0361

30 June 2004

3 December 2009

Legal Category: POM