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Drug Details

Lescol XL 80 mg Prolonged Release Tablets

• Drug Class Description
  HMG-CoA reductase inhibitors - ATC code: C10A A04
• Generic Name
  fluvastatin sodium
• Presentation
  Prolonged-release tablet. 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.
• Description
  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.
• 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.

• Adult Dosage
  

  Adults

  Dyslipidaemia

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

  Starting and maintenance doses should be individualized 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 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).

  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.

  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).

  Renal Impairment

  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. 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

  Lescol XL is contraindicated in patients with active liver disease, or unexplained, persistent elevations in serum transaminases.

  Method of administration

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

• Child Dosage
  

  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.

• Elderly Dosage
  

  No dose adjustments are necessary in this population.

• Contra Indications
  

  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.

  • during pregnancy and lactation.

• Special Precautions
  

  Liver function

  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 or alanine aminotransferase exceed 3 times the upper limit of normal and persist, therapy should be discontinued. In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.

  Caution should be exercised when Lescol XL 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.

  Creatine kinase measurement

  There is no current evidence to require routine monitoring of plasma total CK or other muscle enzyme levels in asymptomatic patients on statins. If CK 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 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 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. Lescol XL should be used with caution in patients receiving such concomitant medicine.

  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.

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

• Interactions
  

  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.

  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.

  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.

• Adverse Drug Reactions
  

  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 reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

  Table 1 Adverse reactions

  Blood and lymphatic system disorders
  Very rare:	Thrombocytopenia
  Immune system disorders
  Very rare	Anaphylactic reaction
  Psychiatric disorders
  Common:	Insomnia.
  Nervous system disorders
  Common:	Headache.
  Very rare:	Paraesthesia, dysaesthesia, hypoaesthesia also known to be associated with the underlying hyperlipidemic disorders.
  Vascular disorders
  Very rare:	Vasculitis.
  Gastrointestinal disorders
  Common:	Dyspepsia, abdominal pain, nausea.
  Very rare	Pancreatitis
  Hepatobiliary disorders
  Very rare:	Hepatitis.
  Skin and subcutaneous tissue disorders
  Rare:	Hypersensitivity reactions such as rash, urticaria.
  Very rare:	Other skin reactions (e.g. eczema, dermatitis, bullous exanthema), face oedema, angioedema
  Musculoskeletal and connective tissue disorders
  Rare:	Myalgia, muscle weakness, myopathy.
  Very rare:	Rhabdomyolysis, myositis, lupus erythematosus-like 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

  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

  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%).