Novartis Pharmaceuticals UK Ltd

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance: fluvastatin (as fluvastatin sodium)

Lescol XL 80 mg prolonged-release tablets:

One prolonged-release tablet of Lescol XL contains 84.24 mg fluvastatin sodium equivalent to 80 mg fluvastatin free acid.

For a full list of excipients, see Section 6.1.

3.         PHARMACEUTICAL FORM

Prolonged-release tablet.

Lescol XL tablets are yellow, round, slightly biconvex with bevelled edges and are marked "LE” on one side and “NVR” on the other.

Lescol XL 80 mg prolonged-release tablets:

Yellow, round, slightly biconvex film-coated tablets with beveled edges, approx. 10 mm in diameter, debossed with “LE” on one side and “NVR” on the other side.

6.1       List of excipients

Core:

Cellulose microcrystalline

Hypromellose

Hydroxypropyl cellulose

Potassium hydrogen carbonate

Povidone

Magnesium stearate

Coating:

Hypromellose

Macrogol 8000

Iron oxide yellow E172

Titanium dioxide E171

Macrogol 8000

6.5       Nature and contents of container

Alu/Alu blister consisting of an aluminium coating foil and an aluminium covering foil.  Lescol XL tablets come in packs of 28 tablets.

HDPE bottles

Pack size: 28, 30, 50, 98 and 100 (2x50 or 1x100) prolonged-release tablets

Hospital pack size: 300 (15x20) and 600 (30x20) prolonged-release tablets

Alu/Alu-blister (with 7 or 14 prolonged-release tablets):

Pack size: 7, 14, 28 (4x7 or 2x14), 28 (in a perforated unit dose blister), 30, 42, 49 (7x7), 56 (8x7), 70, 84, 90 and 98 (14x7 or 7x14) prolonged-release tablets

Hospital pack size: 28, 56, 98 and 490 (single unit dose) prolonged-release tablets

Not all pack-sizes may be marketed.

6.6       Special precautions for disposal

No special requirements.ne

10.       DATE OF REVISION OF THE TEXT

17 August 2010 10 September 2011

1.         TRADE NAME OF THE MEDICINAL PRODUCT

Lescol^® XL 80 mg prolonged-release tablets.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance: fluvastatin (as fluvastatin sodium)

One prolonged- release tablet of Lescol XL containsing 84.24 mg fluvastatin sodium corresponding equivalent to 80 mg fluvastatin free acid.

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).

Lescol XL is indicated as an adjunct to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B) and triglyceride (TG) levels and for the increase of high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolaemia and mixed dyslipidaemia (Fredrickson Types IIa and IIb).

Lescol XL is also indicated to slow the progression of coronary atherosclerosis in patients with primary hypercholesterolaemia, including mild forms, and coronary heart disease who do not adequately respond to dietary control.

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

4.2       Posology and Method of Administration

Adults

Dyslipidaemia

Prior to initiating treatment with Lescol XL, secondary causes of hypercholesterolaemia should be excluded, and the patients should be placed on a standard cholesterol-lowering diet.  Dietary therapy, which should be continued during treatment.

·          Dose recommendations for lipid lowering effect

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

The recommended starting dose is 40 mg (1 capsule Lescol 40 mg) once daily 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 (1 tablet Lescol XL 80 mg) once 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 once daily.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 may be used as one capsule in the evening. For patients requiring LDL-C reduction to a goal of ≥25%, the recommended starting dose is 40 mg as one capsule in the evening. The dose may be uptitrated to 80 mg daily, administered as a single dose (one Lescol XL tablet) at any time of the day or as one 40 mg capsule given twice daily (one in the morning and one in the evening).

Lescol XL can be administered as a single dose at any time of the day with or without food and must 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 dDose adjustments should be made at intervals of 4 weeks or more.  The therapeutic effect of Lescol XL is maintained with prolonged administration.

Lescol XL is efficacious in monotherapy or in combination with bile acid sequestrants.  When Lescol XL 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 XL in combination with nicotinic acid or fibrates (see Section 4.5 Interactions with other medicaments and other forms of interaction).

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

Secondary prevention in coronary heart disease

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

Lescol is efficacious in monotherapy. When Lescol 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 coadministration 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 hypercholesterolemia

Prior to initiating treatment with Lescol XL  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 one 20 mg Lescol capsule. Dose adjustments should be made at 6-week intervals. Doses should be individualised according to baseline LDL-C levels and the recommended goal of therapy to be accomplished. The maximum daily dose administered is 80 mg either as Lescol capsules 40 mg twice daily or as one Lescol 80 mg tablet once daily.

The use of fluvastatin in combination with nicotinic acid, cholestyramine, or fibrates in children and adolescents has not been investigated.

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

Renal Impairment Patients with impaired kidney function

Fluvastatin Lescol XL 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 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 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 and 5.2).

Use in the elderly

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

Elderly population

No dose adjustments are necessary in this population.

Method of administration

Lescol XL tablets can be taken with or without meals and should be swallowed whole with a glass of water.

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 (1 prolonged release tablet Lescol 80 mg once 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.

4.3       Contraindications

Lescol XL is contraindicated:

·                  in patients with known hypersensitivity to fluvastatin or 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).

Known hypersensitivity  to any component of Lescol XL.

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

4.4       Special Warnings and Special Precautions for Use

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

Liver function

As with other lipid-lowering drugs 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 LESCOLescol XL 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 XL, mMyopathy has rarely been reported with fluvastatin., whereas mMyositis 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 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 CK or other muscle enzyme levels in asymptomatic patients on statins.  If CK 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 has been reported to be increased in patients receiving immunosuppressive drugs agents (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 XL 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 ciclosporin and fluvastatin with colchicines.  LESCOLescol XL should be used with caution in patients receiving such concomitant medication 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.

Paediatric population

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 XL therapy in childhood to reduce morbidity and mortality in adulthood has not been established. (see sSection 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 the very  rare condition of homozygous familial hypercholesterolaemia.

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, has been reported in isolated cases with concomitant administration of colchicines. 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 Lescol XL tablets (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 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 maintenance dose of fluvastatin should be as low as possible when combined with ciclosporin.

Both Lescol capsules(40 mg fluvastatin) and Lescol XL tablets (80 mg fluvastatin) 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 changes 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 C_max, AUC, and t_½ of glibenclamide by 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 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 co-administration with fluvastatin is relatively small and not clinically significant.  Thus routine monitoring of phenytoin plasma levels is sufficient during co-administration with fluvastatin.

Cardiovasular agents

No clinically significant pharmacokinetic interactions occur when fluvastatin is concomitantly administered with propranaolol, digoxin, losartan 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.

Grapefruit juice

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

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

Mean AUC and C_max were increased by 49% and 45% respectively and t_max prolonged when fluvastatin (LESCOL XL) was taken with food, compared to fasting state.  However, no clinically obvious differences in the lipid‑lowering effects and safety are anticipated when LESCOL XL is taken with or without food.

Drug interactions

Effects of other drugs on fluvastatin:

Ciclosporin - In an interaction study concomitant administration of fluvastatin (up to 40mg/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 20mg o.d. fluvastatin and 200mg 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 fluvastatin 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 fluvastatin with propranolol has no effect on the bioavailability of fluvastatin.

Bile-acid sequestering agents - Administration of fluvastatin 4 hours after cholestyramine results in a clinically significant additive effect compared with that achieved with either drug alone.  LESCOL XL 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 fluvastatin 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 fluvastatin with cimetidine, ranitidine or omeprazole results in an increase in the bioavailability of fluvastatin, which, however, is of no clinical relevance.

            Rifampicin - Administration of fluvastatin to subjects pre-treated with rifampicin 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.

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 colchicine.

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 40mg b.i.d. and glibenclamide was done in diabetic patients stabilised on 5-20mg 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 fluvastatin 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.

4.6       Pregnancy and Lactation

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, Lescol XL is contraindicated during pregnancy (see section 4.3).

Women of childbearing potential have to use effective contraception.

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

Lactation

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.

Lescol XL is contraindicated in breastfeeding women.

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 foetal 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 XL is contraindicated in nursing mothers.

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 performedNo data exist on the effects of Lescol XL on the ability to drive and use machines.

4.8       Undesirable Effects

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

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), including isolated reportsnot 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             Adverse reactions

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)

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 to17 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.

Laboratory Findings

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 2%).  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. 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 aminotranferase levels to more than 3 times the upper limit of normal occurred in 0.2% on Lescol capsules 20 mg/day, 1.5% to 1.8% on Lescol capsules 40 mg/day, 1.9% on Lescol XL tablets 80 mg/day and in 2.7% to 4.9% on twice daily Lescol capsules 40 mg. The majority of patients with these abnormal biochemical findings were asymptomatic. Marked elevations of CK levels to more than 5x ULN developed in a very small number of patients (0.3 to 1.0%).

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.

4.9       Overdose

To date there has been limited experience with overdose of fluvastatin. Specific treatment is not available for Lescol XL 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.

In a placebo-controlled study including 40 hypercholesterolaemic patients, doses up to 320 mg/day (n=7 per dose group) administered as Lescol XL 80 mg tablets over two weeks were well tolerated.

The experience with overdoses of Lescol XL 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.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

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.  Lescol XL 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 of the plasma cholesterol concentration.

A variety of clinical studies have 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 XL also produces a moderate reduction in triglycerides and a moderate increase in HDL-C.  Therapeutic response is well established within 2 weeks, and maximum response is achieved within 4 weeks from treatment initiation and maintained during chronic therapy.

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).

Lescol XL reduces total-C, LDL-C, Apo B, and triglycerides, and increases HDL-C in patients with hypercholesterolaemia and mixed dyslipidaemia.

In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoproteinaemia, Lescol 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).

Lescol XL was administered to over 800 patients in three pivotal trials of 24 weeks active treatment duration and compared to Lescol 40 mg once or twice daily. Given as a single daily dose of 80 mg, Lescol XL 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 (Lescol) and active-controlled trials (Lescol XL)

¹ Data for Lescol from 12 placebo-controlled trials

² Data for Lescol XL 80 mg tablet from three 24-week controlled trials

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 hypercholesterolemia

The safety and efficacy of Lescol and Lescol XL 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/day to 40 mg twice daily)20 mg - 40 mg bid or Lescol XL 80 mg extended prolonged-release tablets once daily 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 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 Lescol capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (Lescol 80 mg XLprolonged release tablet) 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), 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(in pubertal or postpubertal girls and boys), 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).

5.2       Pharmacokinetic Properties

Lescol XL is a racemate of the two erythro enantiomers of which one exerts the pharmacological activity.  Fluvastatin is absorbed rapidly and completely (98%) following oral administration to fasted volunteers.  After oral administration of Lescol XL 80 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.  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 metabolised 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 80 mg daily.  Following oral administration of 40 mg of Lescol, the terminal disposition half-life for fluvastatin is 2.3 ± 0.9 hours.

Food - Mean AUC and C_max were increased by 49% and 45% respectively and t_max prolonged when fluvastatin (Lescol XL) was taken with food, compared to fasting state.  However, no clinically obvious differences in the lipid‑lowering effects and safety are anticipated when Lescol XL is taken with or without food.

Plasma concentrations of fluvastatin do not vary as a function of age.  Mean AUC and C_max were increased by 36% and 44% respectively in females compared to males.  However, no clinically obvious differences in the lipid‑lowering effects of fluvastatin are anticipated between males and females.

Absorption

Fluvastatin is absorbed rapidly and completely (98%) after oral administration of a solution to fasted volunteers. After oral administration of Lescol XL, 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 substance 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 litres. 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 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 Lescol, 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 hypercholesterolemia

No pharmacokinetic data in children are available.

5.3       Preclinical safety data

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 foetal and neonatal lethality.  No effects on the pregnant females or foetuses 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.

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.

6.6       Special precautions for disposalInstructions for use/handling

1.         TRADE NAME OF THE MEDICINAL PRODUCT

Lescol® XL 80 mg Prolonged Release Tablets.

Nandovar® XL 80 mg Prolonged Release Tablets.

The following information has been added to section 4.4:

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy. 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.

The following information has been added to section 4.8:

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.

Section 4.2:

Changed from:

USE IN CHILDREN

As there is no experience with the use of Lescol XL in individuals less than 18 years of age, its use is contraindicated in this group.

To:

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 (1 prolonged release tablet Lescol 80 mg once 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.

Section 4.3

The following contraindication has been deleted:

Individuals under 18 years of age.

Section 4.4

The following information has been added:

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.

Section 4.8

The following information has been added:

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.

Section 5.1

The following information has been added:

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).

Section 5.2

The following information has been added:

Children and adolescents with heterozygous familial hypercholesterolemia

No pharmacokinetic data in children are available.

The shelf life of Lescol XL 80mg Prolonged release Tablets has been extended from 24 to 36 months. The storage recommendations have also been changed from

Do not store above 25 ^o C.  Store in the original package.

to

“Do not store above 30 ^o C. Store in the original package.

• Further information added with regards to liver monitoring after initiation of treatment and when increasing the dose

• Additional informationadded with regards to co-administration of Lescol XL with ciclosporin, fluconazole, phenytoin and amlodipine
• Spelling of ciclosporin changed