Drug Class Description

Generic Name

Drug Description

Presentation

Indications

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 triglycerides (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).

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.

Adult Dosage

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

•Dose recommendations for lipid lowering effect

The recommended starting dose is 40 mg (1 capsule Lescol 40 mg) once daily 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.

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 dose adjustment 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.Dose recommendations for the secondary prevention of coronary events after percutaneous coronary intervention

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

Patients with impaired kidney function

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

Patients with impaired liver function

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

Use in the elderly

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

Children and adolescents with heterozygous familial hypercholesterolemia

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

The recommended starting dose is 40 mg (1 capsule Lescol 40 mg) or 80 mg (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.

Child Dosage

Contra Indications

Known hypersensitivity to any component of Lescol XL.

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

Special Precautions

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

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

Caution should be exercised when LESCOL 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.

Skeletal muscle:

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

Creatine kinase measurement:

There is no current evidence to require routine monitoring of plasma total creatine kinase or other muscle enzyme levels in asymptomatic patients on statins. If creatine kinase has to be measured it should not be done following strenuous exercise or in the presence of any plausible alternative cause of CK-increase as this makes the value interpretation difficult.

Before the treatment:

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

• Renal impairment

• Hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse

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

In such situations, the risk of treatment should be considered in relation to the possible benefit and clinical monitoring is recommended. If CK-levels are significantly elevated at baseline (> 5xULN), levels should be re-measured within 5 to 7 days later to confirm the results. If CK-levels are still significantly elevated (> 5xULN) at baseline, treatment should not be started.

Whilst on treatment:

If muscular symptoms like pain, weakness or cramps occur in patients receiving fluvastatin, their CK-levels should be measured. Treatment should be stopped, if these levels are found to be significantly elevated (> 5xULN).

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

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

The risk of myopathy is known to be increased in patients receiving immunosuppressive drugs (including ciclosporin), fibrates, nicotinic acid or erythromycin together with other HMG-CoA reductase inhibitors. Minimal data exist to support the efficacy or safety of LESCOL 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 colchicine. LESCOL XL should be used with caution in patients receiving such concomitant medication.

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.

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.

Interactions

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.

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 lipidlowering 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 40 mg/day) and ciclosporin resulted in an increase in the bioavailability of fluvastatin by a factor of 1.9. The results from another study wherein Lescol XL (80 mg fluvastatin) was administered to renal transplant patients who were on stable ciclosporin regimen showed that fluvastatin exposure (AUC) and maximum concentration (Cmax) were increased by 2 fold compared to historical data in healthy subjects. The combination of fluvastatin and ciclosporin should be used with caution due to the potential for an increased risk of myopathy and/or rhabdomyolysis.

Fibric acid derivatives (fibrates) and nicotinic acid:

Bezafibrate - An interaction study between 20 mg o.d. fluvastatin and 200 mg t.d.s. bezafibrate showed that mean AUC and C_max values of fluvastatin were increased on average by about 50-60%. No effect was seen on bezafibrate pharmacokinetics. This combination should be used with caution, however, due to the increased risk of developing myopathy and/or rhabdomyolysis when HMG-CoA reductase inhibitors including fluvastatin have been combined with fibrates. Any patient complaining of myalgia should be carefully evaluated.

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

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

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

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

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

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

Antipyrine - Administration of 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 40 mg 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.

Adverse Reactions

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

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

Table 1

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.

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.

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