Fluvastatin 20 mg and 40mg Capsules

Each 20mg capsule contains 21.06 mg fluvastatin sodium corresponding to 20 mg fluvastatin.

Each 40mg capsule contains 42.12 mg fluvastatin sodium corresponding to 40 mg fluvastatin.

For a full list of excipients, see section 6.1.

Capsule, hard

Brown coloured capsule containing off-white to pale-yellow powder.

Fluvastatin is indicated as an adjunct to diet for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) when response to diet and other non- pharmacological treatments (e.g. exercise, weight reduction) is inadequate in adults with primary hypercholesterolaemia (heterozygous variant) and mixed dyslipidaemia (Fredrickson Types IIa and IIb).

Fluvastatin is also indicated for the secondary prevention of major adverse cardiac events (cardiac death, non-fatal myocardial infarction and coronary revascularisation) in patients with coronary heart disease after coronary transcatheter therapy.

Prior to initiating treatment with fluvastatin, the patient should be placed on a standard cholesterol-lowering diet, which should be continued during treatment.

The recommended starting dose is 20 mg or 40 mg once daily. A dose of 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 capsule fluvastatin 40 mg twice daily), individualized according to the baseline LDL-cholesterol (LDL-C) levels and the recommended goal of therapy to be accomplished. The maximum recommended daily dose is 80 mg.

In patients with coronary heart disease after coronary transcatheter therapy the appropriate dose is 80 mg daily.

The capsules should be taken in the evening or at bedtime without regard to meals. The capsules should be swallowed whole with a glass of water.

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 fluvastatin is maintained with prolonged administration.

Fluvastatin is efficient in monotherapy. Data exist to support the efficacy and safety of fluvastatin in combination with nicotinic acid, cholestyramine, or fibrates (see section 4.5).

When fluvastatin is used in combination with colestyramine 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.

Children and adolescent

There is no experience with the use of fluvastatin in individuals less than 18 years of age. The product should not be used in this group of patients.

Elderly

There is no evidence of reduced tolerability or altered dosage requirements in elderly patients thus, no dose adjustment is required in such patients.

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. No dose adjustments are therefore necessary in these patients.

Impaired liver function

Fluvastatin is contraindicated in patients with active liver disease, or unexplained, persistent elevations in serum transaminases (see sections 4.3, 4.4 and 5.2).

Fluvastatin is contraindicated:

• in patients with known hypersensitivity to fluvastatin or to any of the excipients.

• in patients with active liver disease, or unexplained, persistent elevations in serum transaminases (see sections 4.2, 4.4 and 4.8).

• during pregnancy and lactation (see section 4.6).

Liver function

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. Patients whose levels increase the response to the drug should be monitored particularly closely, with immediate repetition of the measurement followed by more frequent measurements. 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 fluvastatin is administered to patients with a history of liver disease or heavy alcohol consumption.

Skeletal muscle

With fluvastatin 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 promptly report 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 predisposing 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 to more than 5 times the upper limit 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.

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 (> 5 x ULN).

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 has been reported to be increased in patients receiving immunosuppressive drugs (including ciclosporin), fibrates, nicotinic acid or erythromycin together with other HMG-CoA reductase inhibitors. However, in clinical trials in patients receiving fluvastatin in combination with nicotinic acid, fibrates, or ciclosporin, myopathy has not been observed. Isolated cases of myopathy have been reported post-marketing for concomitant administration of fluvastatin with ciclosporin and fluvastatin with colchicine. The benefits of the combined use of fluvastatin with fibrates, niacin or colchicin should be carefully weighed against the potential risks of these combinations and fluvastatin should be used with caution in patients receiving such concomitant medication (see section 4.5).

Hyperlipoproteinemia

No data are available for the use of fluvastatin in patients with hyperlipoproteinemia with a major increase in triglycerides.

Homozygous familial hypercholesterolemia

No data are available for the use of fluvastatin in patients with a rare condition known as homozygous familial hypercholesterolemia. The effect is expected to be low due to LDL – receptor deficiency in these patients. Therefore use of fluvastatin is not recommended in these patients.

Food interactions

There are no apparent differences in the lipid-lowering effects of fluvastatin when administered with the evening meal or 4 hours after the evening meal. Based on the lack of interaction of fluvastatin with other CYP3A4 substrates, fluvastatin is not expected to interact with grapefruit juice.

Drug interactions

Fibric acid derivatives (fibrates) and niacin (nicotinic acid)

Concomitant administration of fluvastatin with bezafibrate, gemfibrozil, ciprofibrate or niacin (nicotinic acid) has no clinically relevant effect on the bioavailability of fluvastatin or the other lipid-lowering agent. An increased risk of myopathy and/ or rhabdomyolysis has been observed in patients receiving other HMG-CoA reductase inhibitors together with any of these molecules, probably because they can produce myopathy when given alone. Therefore, the benefit and the risk of concurrent treatment should be carefully weighed and these combinations should only be used with caution (see section 4.4).

Colchicines

Myotoxicity, including muscle pain and weakness and rhabdomyolysis, have been reported in isolated cases with concomitant administration of colchicine. The benefit and the risk of concurrent treatment should be carefully weighed and these combinations should only be used with caution (see section 4.4)

Ciclosporin

Studies in renal transplant patients indicate that the bioavailability of fluvastatin (up to 40 mg/day) is not elevated to a clinically significant extent in patients on stable regimens of ciclosporin. The results from another study wherein 80 mg fluvastatin was administered to renal transplant patients who were on stable ciclosporin regimen showed that fluvastatin exposure (AUC) and maximum concentration (C_max) were increased by 2 fold compared to historical data in healthy subjects. Although these increases in fluvastatin levels were not clinically significant, this combination should be used with caution. Starting and maintaining fluvastatin therapy should be in a dose as low as possible when combined with ciclosporin.

Fluvastatin (40 mg and 80 mg) had no effect on ciclosporin bioavailability when co-administered

Warfarin and other coumarin derivatives

In healthy volunteers, the use of fluvastatin and warfarin (single dose) did not adversely influence warfarin 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.

Rifampicin (rifampin)

Administration of fluvastatin to healthy volunteers pre-treated with rifampicin (rifampin) resulted in a reduction of the bioavailability of fluvastatin 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.

Oral antidiabetic agents

For patients receiving oral sulfonylureas (glibenclamide [glyburide], tolbutamide) for the treatment of non-insulin-dependent (type 2) diabetes mellutis (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycemic control.

In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean C_max, AUC, and t_1/2 of glibenclamide approximately 50%, 69% and 121%, respectively. Glibenclamide (5 to 20 mg daily) increased the mean C_max 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 glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 80 mg per day.

Bile acid sequestrants

Fluvastatin should be administered at least 4 hours after the resin (e.g. cholestyramine) to avoid a significant interaction due to drug binding of the resin.

Fluconazole

Administration of fluvastatin to healthy volunteers pre-treated with fluconazole (CYP 2C9 inhibitor) resulted in an increase in the exposure and peak concentration of fluvastatin by about 84% and 44%.

Although there was no clinical evidence that the safety profile of fluvastatin was altered in patents pre-treated with fluconazole for 4 days, caution should be exercised when fluvastatin is administered concomitantly with fluconazole.

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, ciclosporin) are unlikely to affect the bioavailability of fluvastatin.

Histamine H₂-receptor antagonists and proton pump inhibitors

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

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.

Cardiovascular agents

No clinically significant pharmacokinetic interactions occur when fluvastatin is concomitantly administered with propranolol, digoxin, losartan, amlodipine or ACE- inhibitors. Based on the pharmacokinetic data, no monitoring or dosage adjustments are required when fluvastatin is concomitantly administered with these agents.

Pregnancy

Fluvastatin is contraindicated during pregnancy (see section 4.3).

There are insufficient data on the use of fluvastatin during pregnancy. Since HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly of other biologically active substances derived from cholesterol, they may cause foetal harm when administered to pregnant women. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid- lowering medicinal products durinig pregnancy should have little impact on the long- term risk associated with primary hypercholesterolaemia. For these reasons, fluvastatin must not be used in women who are pregnant or suspect they are pregnant and in women of childbearing potential not taking adequate contraceptive precautions. Treatment with fluvastatin should be suspended for the duration of pregnancy or until has been determined that the woman is not pregnant (see section 4.3).

Lactation

It is not known whether fluvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking fluvastatin should not breast-feed their infants (see section 4.3).

No studies on the effects on the ability to drive and use machines have been performed. However, based on its pharmacodynamic properties, fluvastatin is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 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.

Blood and lymphatic system disorders

Very rare: Thrombocytopenia

Psychiatric disorders

Common: Insomnia

Nervous system disorders

Common: Headache, fatigue, dizziness

Very rare: Paraesthesia, dysaesthesia, hypoaesthesia and peripheral neuropathy also known to be associated with the underlying hyperlipidemic disorders

Vascular disorders

Very rare: Vasculitis

Gastrointestinal disorders

Common: Dyspepsia, abdominal pain, nausea, constipation, flatulence, diarrhoea

Very rare: Pancreatitis

Hepatobiliary disorders

Very rare: Hepatitis

Skin and subcutaneous tissue disorders

Rare: Hypersensitivity reactions such as rash, urticaria

Very rare: Other skin reactions (e.g. eczema, dermatitis, bullous exanthema), face oedema, angioedema

Musculoskeletal and connective tissue disorders

Common: Arthralgia

Rare: Myalgia, muscle tenderness, muscle weakness, myopathy

Very rare: Rhabdomyolysis, myositis, lupus erythematosus-like reactions

Investigations

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 1 to 2% of patients.

Marked elevations of CK levels to more than 5 x ULN developed in 0.3 to 1.0% of patients.

Should an accidental overdosage occur, administration of activated charcoal is recommended and the liver function should be monitored. In the case of a very recent oral intake gastric lavage may be considered. Treatment should be symptomatic.

Pharmacotherapeutic group: HMG-CoA reductase inhibitors

ATC Code: C10A A04

Fluvastatin, 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. Fluvastatin exerts its main effect in the liver and is mainly a racemate of the two erythro enantiomers of which one 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 in the plasma cholesterol concentration.

The overall cholesterol profile is improved with the principal effects being the reduction of total-C and LDL-C. Fluvastatin also produces a moderate reduction in triglycerides (TG) 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 fluvastatin 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 apolipoprotein-B, TG, and an 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 fluvastatin (N = 844), given as 80 mg daily over 4 years, significantly reduced the risk of the first MACE by 22% (p = 0.013) as compared to placebo (N = 833). These beneficial effects were particularly noteworthy, in diabetics and in patients with multivessel disease. Therapy with fluvastatin reduced the risk of cardiac death and/or myocardial infarction by 31% (p = 0.065).

Absorption

Fluvastatin is absorbed rapidly and completely (98%) after oral administration to fasted volunteers. In a fed state, the drug is absorbed at a reduced rate. No significant difference in AUC was observed when fluvastatin was administered with the evening meal or 4 hours after the evening meal.

Distribution

Absolute bioavailability is variable and it increases with increasing doses. The absolute bioavailability of fluvastatin following a 10 mg dose was 24% (range: 9% - 50%). At doses above 20 mg, fluvastatin exhibits nonlinear kinetics, at least in the fasting state, resulting in dose normalized AUC values 20% - 40% higher than expected for the 40 mg dose. The apparent volume distribution for the drug is 330 l. More than 98% of the circulating drug is bound to plasma proteins, and this binding is not affected either by the concentration of fluvastatin, or by warfarin, salicylic acid, and glyburide.

Metabolism

Fluvastatin is mainly metabolized in the liver. The major components circulating in the blood are fluvastatin and the pharmacologically inactive N-desisopropyl-propionic acid metabolite. The hydroxylated metabolites have pharmacological activity but do not circulate systemically. The hepatic pathways of fluvastatin metabolism in humans have been completely elucidated. There are multiple, alternative cytochrome P450 (CYP450) pathways for fluvastatin biotransformation and thus fluvastatin metabolism is relatively insensitive to CYP450 inhibition, a major cause of adverse drug-drug interactions.

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. Despite the potential that therefore exists for competitive interaction between fluvastatin and compounds that are CYP2C9 substrates, such as diclofenac, phenytoin, tolbutamide, and warfarin, clinical data indicate that this interaction is unlikely.

Elimination

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 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 fluvastatin, the terminal disposition half-life for fluvastatin is 2.3 ± 0.9 hours.

Characteristics in patients

Plasma concentrations of fluvastatin do not vary as a function of either age or gender in the general population. However, enhanced treatment response was observed in women and in elderly people.

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 (see sections 4.3 and 4.4).

Repeat toxicity studies with fluvastatin identified a variety of changes 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 the 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 compounds.

Carcinogenicity studies in rats and mice revealed a low incidence of forestomach squamous papillomas in mice and rats and one carcinoma in rats at the highest dose (18 mg/kg per day escalated to 24 mg/kg per day after 1 year). The forestomach neoplasms reflect chronic hyperplasia caused by direct contact exposure to fluvastatin rather than a genotoxic effect of the drug. In addition, an increase incidence of thyroid follicular cell neoplasms in male rats given the highest dose of fluvastatin was recorded. This is consistent with species-specific findings with other HMGCoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no treatment-related increases in the incidence of hepatic adenomas or carcinomas were observed.

In vitro and in vivo mutagenicity studies revealed no evidence of mutagenicity.

Reproductive toxicity studies indicated that fluvastatin had no adverse effects on fertility or reproductive performance in males or females, nor was it embryotoxic or teratogenic. Late gestational effects at high doses resulted in maternal mortality and fetal and neonatal lethality attributable to exaggerated pharmacological effects of fluvastatin during pregnancy.

Capsule contents:

Calcium carbonate

Cellulose microcrystalline

Pregelatinised maize starch

Talc

Sodium hydrogen carbonate

Magnesium stearate

Hard gelatin capsule:

Gelatin

Titanium dioxide (E171)

Iron oxide red (E172)

Sodium lauryl sulphate

Not applicable.

OPA/ Al/ PVC/ Al blister: 3 years

HDPE bottle: 3 years

After first opening the HDPE bottle: 4 months

OPA/ Al/ PVC/ Al blister: Do not store above 25°C

HDPE bottle: Do not store above 25°C

Store in the original package in order to protect from light .

OPA/ Al/ PVC/ Al blister: 14, 20, 28, 30, 50, 56, 84, 90, 98, 100, 490 hard capsules

HDPE bottle with PP cap: 98 hard capsules

Not all pack sizes may be marketed.

No special requirements.

Sandoz Limited

37 Woolmer Way

Bordon

Hampshire

GU35 9QE

PL 04416/0748

PL 04416/0749

30/11/2007

05/2009