PINMACTIL 80 MG PROLONGED-RELEASE FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Pinmactil 80 mg prolonged-release film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 80 mg fluvastatin (as fluvastatin sodium).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

4.   CLINICAL PARTICULARS

4.1 Therapeutic indications

Dyslipidaemia

Treatment of adults with primary hypercholeste­rolaemia or mixed dyslipidaemia, as an adjunct to diet, when

response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Secondary prevention in coronary heart disease

Secondary prevention of major adverse cardiac events in adults with coronary heart disease after

percutaneous coronary interventions (see section 5.1).

4.2 Posology and method of administration

Posology

Not all approved dosage recommendations can be followed with this product.

Adults

Dyslipidaemia

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

Starting and maintenance doses should be individualised according to the baseline LDL-C levels and the treatment goal to be accomplished.

The recommended dosing range is 20 to 80 mg/day. For patients requiring LDL-C reduction to a goal of < 25% a starting dose of 20 mg fluvastatin may be used in the evening. For patients requiring LDL-C reduction to a goal of > 25%, the recommended starting dose is 40 mg in the evening. The dose may be uptitrated to 80 mg daily, administered as a single dose (one Pinmactil 80 mg prolonged-release tablet) at any time of the day or as one 40 mg dose of fluvastatin given twice daily (one dose in the morning and one dose in the evening).

Pinmactil is only available as 80 mg prolonged-release tablets. For doses of 20 mg and 40 mg, other fluvastatin medicinal products must be used.

The maximum lipid-lowering effect with a given dose is achieved within 4 weeks. Dose adjustments should be made at intervals of 4 weeks or more.

Secondary prevention in coronary heart disease

In patients with coronary heart disease after percutaneous coronary interventions the appropriate daily dose is 80 mg.

Fluvastatin is efficacious in monotherapy. When fluvastatin is used in combination with cholestyramine or other resins, it should be administered at least 4 hours after the resin to avoid significant interaction due to binding of the drug to the resin. In cases where co administration with a fibrate or niacin is necessary, the benefit and the risk of concurrent treatment should be carefully considered (for use with fibrates or niacin see section 4.5).

Paediatric population

Children and adolescents with heterozygous familial hypercholeste­rolaemia

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

The recommended starting dose is 20 mg fluvastatin. Dose adjustments should be made at 6-week intervals. Doses should be individualised according to baseline LDLC levels and the recommended goal of therapy to be accomplished. The maximum daily dose administered is 80 mg either as fluvastatin 40 mg twice daily or as one 80 mg prolonged-release tablet once daily.

The use of fluvastatin in combination with nicotinic acid, cholestyramine, or fibrates in children and

adolescents has not been investigated.

Fluvastatin has only been investigated in children of 9 years and older with heterozygous familial hypercholeste­rolaemia.

Renal Impairment

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 however, due to limited experience with doses

>40mg/day in case of severe renal impairment (CrCL <0,5 mL/sec or 30 mL/min), these doses should be initiated with caution.

Hepatic Impairment

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).

Elderly population

No dose adjustments are necessary in this population.

Method of administration

Oral use.

Pinmactil 80 mg prolonged-release tablet can be taken with or without meals and should be swallowed as whole with a glass of water.

The tablet should not be divided, chewed or crushed.

4.3 Contraindications

Fluvastatin is contraindicated in patients:

with hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

during pregnancy and breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Liver function

Post marketing cases of fatal and non-fatal hepatic failures have been reported with some statins including fluvastatin. Although a causal relationship with fluvastatin treatment has not been determined, patients should be advised to report any potential symptoms or signs of hepatic failure (e.g. nausea, vomiting, loss of appetite, jaundice, impaired brain function, easy bruising or bleeding), and treatment discontinuation should be considered.

As with other lipid-lowering agents, 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 fluvastatin is administered to patients with a history of liver disease or heavy alcohol ingestion.

Skeletal muscle

Myopathy has rarely been reported with fluvastatin. 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.

There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

Interaction with Fusidic acid

Fluvastatin must not be co-administered with systemic formulations of fusidic acid or within seven days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of fluvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.

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

Sepsis

Hypotension

Excessive exercise of muscle

Major surgery

Severe metabolic, endocrine or electrolyte disorders

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 >5× upper limit of normal, levels should be re-measured within 5 to 7 days later to confirm the results. If CK-levels are still significantly elevated >5× upper limit of normal 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×ULN).

If muscular symptoms are severe and cause daily discomfort, even if CK-levels are elevated to less than 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 agents (including ciclosporin), fibrates, nicotinic acid or erythromycin together with other HMG-CoA reductase inhibitors. Isolated cases of myopathy have been reported post-marketing for concomitant administration of fluvastatin with ciclosporin and fluvastatin with colchicines. fluvastatin should be used with caution in patients receiving such concomitant medicine (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.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. The risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L,

BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Paediatric population

Children and adolescents with heterozygous familial hypercholeste­rolaemia

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 fluvastatin 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.

Homozygous familial hypercholeste­rolaemia

No data are available for the use of fluvastatin in patients with a rare condition known as homozygous familial hypercholeste­rolemia.

4.5 Interaction with other medicinal products and other forms of interaction

Fibrates and niacin

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. Since an increased risk of myopathy and/ or rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors together with any of these molecules, 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 in which fluvastatin 80 mg prolonged-release tablets were 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. Although these increases in fluvastatin levels were not clinically significant, this combination should be used with caution (see section 4.4). Starting and maintenance dose of fluvastatin should be as low as possible when combined with ciclosporin.

Fluvastatin 80 mg prolonged-release tablets had no effect on the bioavailability of ciclosporin 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

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 mellitus (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycaemic control.

In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean Cmax, AUC, and t1/2 of glibenclamide by approximately 50%, 69% and 121%, respectively. Glibenclamide (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 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 patients pre-treated with fluconazole for 4 days, caution should be exercised when fluvastatin is administered concomitantly with fluconazole.

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 coadministration with fluvastatin is relatively small and not clinically significant. Thus routine monitoring of phenytoin plasma levels is sufficient during co-administration with fluvastatin.

Cardiovascular agents

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

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.

Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, fluvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.

Grapefruit juice

Based on the lack of interaction of fluvastatin with other CYP3A4 substrates, fluvastatin is not expected to interact with grapefruit juice.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential have to use effective contraception.

If a patient becomes pregnant while taking fluvastatin, therapy should be discontinued.

Pregnancy

There is 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. Therefore, fluvastatin is contraindicated during pregnancy (see section 4.3).

Breast-feeding

Based on preclinical data, it is expected that fluvastatin is excreted into human milk. There is insufficient information on the effects of fluvastatin in newborns / infants.

Fluvastatin is contraindicated in breastfeeding women (see section 4.3).

Fertility

In animal studies no effects on male and female fertility were observed.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

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

Adverse drug reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category, using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common ( 1/10); common (ž 1/100 to <1/10);

uncommon (fe 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).

Table 1 Adverse drug reactions

* Based on post-marketing experience with fluvastatin via spontaneous case

reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.

The following adverse events have been reported with some statins:

Sleep disturbances, including insomnia and nightmares

Memory loss

Sexual dysfunction

Depression

Diabetes Mellitus: Frequency will depend on the presence or absence of risk

factors (fasting blood glucose > 5.6 mmol/L, BMI > 30kg/m2, raised triglycerides, history of hypertension).

Tendinopathy, sometimes complicated by tendon rupture.

Paediatric population

Children and adolescents with heterozygous familial hypercholeste­rolaemia

The safety profile of fluvastatin in children and adolescents with heterozygous familial hypercholeste­rolaemia assessed in 114 patients aged 9–17 years treated in two open-label 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.

Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid-lowering agents. Based on pooled analyses of controlled clinical trials confirmed elevations of alanine aminotransferase or aspartate aminotransferase levels to more than 3 times the upper limit of normal occurred in 0.2% on fluvastatin capsules 20 mg/day, 1.5% to 1.8% on fluvastatin capsules 40 mg/day, 1.9% on fluvastatin prolonged-release tablets 80 mg/day and in 2.7% to 4.9% on twice daily fluvastatin 40 mg capsules. The majority of patients with these abnormal biochemical findings were asymptomatic. Marked elevations of CK levels to more than 5× ULN developed in a very small number of patients (0.3 to 1.0%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

To date there has been limited experience with overdose of fluvastatin. Specific treatment is not available for fluvastatin overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests and serum CK levels should be monitored.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors ATC code: C10A A04

Mechanism of action

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 erythroenantiomers 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 of the plasma cholesterol concentration.

Fluvastatin prolonged-release tablets reduces total-C, LDL-C, Apo B, and triglycerides, and increases HDL-C in patients with hypercholeste­rolaemia and mixed dyslipidaemia.

Clinical efficacy and safety

In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoprote­inaemia, fluvastatin capsules alone was administered to 1,621 patients in daily dose regimens of 20 mg, 40 mg and 80 mg (40 mg twice daily) for at least 6 weeks duration. In a 24-week analysis, daily doses of 20 mg, 40 mg and 80 mg produced dose-related reductions in total-C, LDL-C, Apo B and in triglycerides and increases in HDL-C (see Table 2).

Fluvastatin prolonged-release tablets was administered to over 800 patients in three pivotal trials of 24 weeks active treatment duration and compared to fluvastatin 40 mg once or twice daily. Given as a single daily dose of 80 mg, fluvastatin prolonged-release tablets significantly reduced total-C, LDL-C, triglycerides (TG) and Apo B (see Table 2).

Therapeutic response is well established within two weeks, and a maximum response is achieved within four

weeks. After four weeks of therapy, the median decrease in LDL-C was 38% and at week 24 (endpoint) the

median LDL-C decrease was 35%. Significant increases in HDL-C were also observed.

Table 2 Median percent change in lipid parameters from baseline to week 24 Placebo-controlled studies (fluvastatin capsules) and active-controlled trials (fluvastatin prolonged-release tablets)

1 Data for fluvastatin capsules from 12 placebo-controlled trails

2

2 Data for fluvastatin prolonged-release tablets 80mg from three 24-week controlled trails

In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of fluvastatin on coronary

atherosclerosis was assessed by quantitative coronary angiography in male and female patients (35 to

75 years old) with coronary artery disease and baseline LDL-C levels of 3.0 to 4.9 mmol/l (115 to

190 mg/dl). In this randomised, double-blind, controlled clinical study, 429 patients were treated with either

fluvastatin 40 mg/day or placebo. Quantitative coronary angiograms were evaluated at baseline and after

2.5 years of treatment and were evaluable in 340 out of 429 patients. Fluvastatin treatment slowed the

progression of coronary atherosclerosis lesions by 0.072 mm (95% confidence intervals for treatment

difference from –0.1222 to –0.022 mm) over 2.5 years as measured by change in minimum lumen diameter

(fluvastatin –0.028 mm vs. placebo –0.100 mm). No direct correlation between the angiographic findings

and the risk of cardiovascular events has been demonstrated.

In the Lescol Intervention Prevention Study (LIPS), the effect of fluvastatin on major adverse cardiac events

(MACE; i.e. cardiac death, non-fatal myocardial infarction and coronary revascularisation) was assessed in

patients with coronary heart disease who had first successful percutaneous coronary intervention. The study

included male and female patients (18 to 80 years old) and with baseline total-C levels ranging from 3.5 to

7.0 mmol/l (135 to 270 mg/dl).

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).

The primary endpoint of MACE occurred in 21.4% of patients treated with fluvastatin vs 26.7% of patients

treated with placebo (absolute risk difference: 5.2%; 95% CI: 1.1 to 9.3). These beneficial effects were

particularly noteworthy in patients with diabetes mellitus and in patients with multivessel disease.

Paediatric Population

Children and adolescents with heterozygous familial hypercholeste­rolaemia

The safety and efficacy of fluvastatin capsules and fluvastatin prolonged-release tablets 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 fluvastatin capsules 20 mg/day to 40 mg twice daily or fluvastatin 80 mg prolonged release tablets once daily using a dose-titration regimen based upon LDL-C response.

The first study enrolled 29 prepubertal 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 fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg twice daily) 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 Fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (fluvastatin prolonged-release tablets) to achieve an LDL-C goal of < 130 mg/dL (3,4 mmol/L). 70 patients were pubertal or postpubertal (n=69 evaluated for efficacy).

In the first study (in prepubertal boys), fluvastatin 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 (in pubertal or postpubertal girls and boys), Fluvastatin 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).

5.2 Pharmacokinetic properties

Absorption

Fluvastatin is absorbed rapidly and completely (98%) following oral administration of a solution to fasted volunteers. After oral administration of fluvastatin prolonged-release tablets, and in comparison with the capsules, the absorption rate of fluvastatin is almost 60% slower while the mean residence time of fluvastatin is increased by approximately 4 hours. In a fed state, the drug is absorbed at a reduced rate.

Distribution

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 (Vz/f) 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 concentration of fluvastatin , or by warfarin, salicylic acid or glyburide.

Biotransformation

Fluvastatin is mainly metabolised 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. There are multiple, alternative cytochrome

P450 (CYP450) pathways for fluvastatin biotransformation and thus fluvastatin metabolism is relatively insensitive to CYP450 inhibition.

Fluvastatin inhibited only the metabolism of compounds that are metabolised 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 (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 80 mg daily.

Following oral administration of 40 mg fluvastatin capsules, 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 presystemic metabolism,

the potential exists for drug accumulation in patients with hepatic insufficiency (see sections 4.3 and 4.4).

Children and adolescents with heterozygous familial hypercholeste­rolaemia No pharmacokinetic data in children are available

5.3 Preclinical safety data

The conventional studies, including safety pharmacology, genotoxicity, repeated dose toxicity, carcinogenicity and toxicity on reproduction studies did not indicate other risks for the patient than those expected due to the pharmacological mechanism of action. A variety of changes were identified in toxicity studies that are common to HMG-CoA reductase inhibitors. Based on clinical observations, liver function tests are already recommended (see section 4.4). Further toxicity seen in animals was either not relevant for human use or occurred at exposure levels sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Despite the theoretical considerations concerning the role of cholesterol in embryo development, animal studies did not suggest an embryotoxic and teratogenic potential of fluvastatin.

6.1 List of excipients

Tablet core:

Povidone

Microcrystalline cellulose

Hydroxyethyl cellulose

Mannitol

Magnesium stearate

Film-coating:

Hypromellose 50

Macrogol 6000

Iron oxide yellow (E172)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years for Blister (OPA/Alu/PVC-Alu)

2 years for HDPE bottle with desiccant and Glass bottle

6.4 Special precautions for storage

Do not store above 30°C.

Blisters: Keep the blisters in the outer carton in order to protect from light.

Glass bottle and HDPE bottle: Keep the container tightly closed in order to protect from moisture and light.

6.5 Nature and contents of container

Blister (OPA/Alu/PVC-Alu). Pack sizes of 10, 14, 20, 28, 30, 50, 56, 60, 90, 98, 100 or 490 prolonged-release tablets

HDPE bottle with desiccant and snap-on cap (LDPE) with a tamper evident ring. Desiccants are HDPE plastic canisters filled with activated silica gel. Pack sizes of 250 prolonged release tablets.

Round, brown glass container closed with rubbed plastic cap (HDPE) with thread including seal. Desiccants are HDPE plastic canisters filled with activated silica gel.

Pack sizes of 28, 98, 100, 250 or 500 prolonged release tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04659/0829

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 November 2008

Date of latest renewal: 22 March 2013