4.1. Therapeutic indications

Dyslipidaemia

Treatment of adults with primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Secondary prevention in coronary heart disease

Secondary prevention of major adverse cardiac events in adults with coronary heart disease after percutaneous coronary interventions (see section 5.1).

4.2. Posology and method of administration

Posology

Adults

Dyslipidaemia

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

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

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

Secondary prevention in coronary heart disease

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

Fluvastatin is efficacious in monotherapy. When Fluvastatin is used in combination with cholestyramine or other resins, it should be administered at least 4 hours after the resin to avoid significant interaction due to binding of the active substance 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 hypercholesterolamia

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

The recommended starting dose is 20 mg fluvastatin. Dose adjustments should be made at 6-week intervals. Doses should be individualized 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 fluvastatin 40 mg twice daily or as one Fluvastatin 80 mg prolonged-release tablet once daily.

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

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

Renal Impairment

Fluvastatin is cleared by the liver, with less than 6% of the administered dose excreted into the urine.

The pharmacokinetics of fluvastatin remain unchanged in patients with mild to severe renal insufficiency.

No dose adjustments are therefore necessary in these patients however, due to limited experience with doses >40mg/day in case of severe renal impairment (CrCL <0,5 mL/sec or 30 mL/min), these doses should be initiated with caution.

Hepatic Impairment

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

Elderly population

No dose adjustments are necessary in this population.

Method of administration

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

4.3. Contraindications

Fluvastatin is contraindicated:

• in patients with hypersensitivity to the active substance or to any of the excipients listed in sections 6.1.

• 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 breast-feeding(see section 4.6).

4.4. Special warnings and precautions for use

Liver function

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

As with other lipid-lowering agents, it is recommended that liver function tests be performed before the initiation of treatment and at 12 weeks following initiation of treatment or elevation in dose and periodically thereafter in all patients. Should an increase in aspartate aminotransferase 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 Fluvastatin is administered to patients with a history of liver disease or heavy alcohol ingestion.

Skeletal muscle

Myopathy has rarely been reported with fluvastatin. Myositis and rhabdomyolysis have been reported very rarely. In patients with unexplained diffuse myalgias, muscle tenderness or muscle weakness, and/or marked elevation of creatine kinase (CK) values, myopathy, myositis or rhabdomyolysis have to be considered.

Patients should therefore be advised to promptly report unexplained muscle pain, muscle tenderness or muscle weakness, particularly if accompanied by malaise or fever.

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

Interaction with Fusidic acid

Fluvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

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

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

Creatine kinase measurement

There is no current evidence to require routine monitoring of plasma total 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

• Sepsis

• Hypotension

• Excessive exercise of muscle

• Major surgery

• Severe metabolic, endocrine or electrolyte disorders

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

In such situations, the risk of treatment should be considered in relation to the possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline > 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. Fluvastatin should be used with caution in patients receiving such concomitant medicinal product (see section 4.5).

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Fluvastatin should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

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 fluvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. (see section 5.1).

Fluvastatin has only been investigated in children of 9 years and older with heterozygous familial hypercholesterolaemia (for details see section 5.1). In the case of pre-pubertal children, as experience is very limited in this group, the potential risks and benefits should be carefully evaluated before the initiation of treatment.

Homozygous familial hypercholesterolaemia

No data are available for the use of fluvastatin in patients with the very rare condition of homozygous familial hypercholesterolaemia.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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 HMGCoA 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 80 mg fluvastatin prolonged-release tabletswere administered to renal transplant patients who were on stable ciclosporin regimen showed that fluvastatin exposure (AUC) and maximum concentration (Cmax) 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.

80 mg Fluvastatin prolonged-release tablets had no effect on the bioavailability of ciclosporin when co-administered.

Warfarin and other coumarin derivatives

In healthy volunteers, the use of fluvastatin and warfarin (single dose) did not adversely influence warfarin plasma levels and prothrombin times compared to warfarin alone.

However, isolated incidences of bleeding episodes and/or increased prothrombin times have been reported very rarely in patients on fluvastatin receiving concomitant warfarin or other coumarin derivatives. It is recommended that prothrombin times are monitored when fluvastatin treatment is initiated, discontinued, or the dose 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 dose 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 noninsulin-dependent (type 2) diabetes mellitus (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycaemic control. In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean Cmax, AUC, and t½ of glibenclamide by approximately 50%, 69%, and 121%, respectively. Glibenclamide (5 to 20 mg daily) increased the mean Cmax and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in glucose, insulin, and C-peptide levels. However, patients on concomitant therapy with glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 80 mg per day.

Bile acid sequestrants

Fluvastatin should be administered at least 4 hours after the resin (e.g. cholestyramine) to avoid a significant interaction due to active substance 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 pretreated 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, clopidogrel or amlodipine. Based on the pharmacokinetic data, no monitoring or dose adjustments are required when fluvastatin is concomitantly administered with these agents.

Itraconazole and erythromycin

Concomitant administration of fluvastatin with the potent cytochrome P450 (CYP) 3A4 inhibitors itraconazole and erythromycin has minimal effects on the bioavailability of fluvastatin. Given the minimal involvement of this enzyme in the metabolism of fluvastatin, it is expected that other CYP3A4 inhibitors (e.g. ketoconazole, ciclosporin) are unlikely to affect the bioavailability of fluvastatin.

Fusidic acid

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

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

Grapefruit juice

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

4.6. Fertility, pregnancy and lactation

Pregnancy

There is insufficient data on the use of fluvastatin during pregnancy.

Since HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly of other biologically active substances derived from cholesterol, they may cause foetal harm when administered to pregnant women. Therefore, fluvastatin is contraindicated during pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception. If a patient becomes pregnant while taking fluvastatin, therapy should be discontinued.

Breastfeeding

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

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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

Adverse drug reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency categoryusing the following convention (CIOMS III), is also provided for each adverse drug reaction: very common (≥1/10); common (≥1/100 to < 1/10); uncommon (≥1/1,000to < 1/100); rare (≥1/10,000 to < 1/1,000) very rare (< 1/10,000), not known (cannot be estimated from the available data). s.

Table 1 Adverse drug reactions

System organ class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Very rare

Thrombocytopenia

Immune system disorders

Rare

Hypersensitivity reactions (rash, urticaria)

Very rare

Anaphylactic reaction

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Common

Headache

Very rare

Paresthesia, dysesthesia, hypoesthesia also known to be associated with the underlying hyperlipidaemic disorders

Not known

Myasthenia gravis

Vascular disorders

Very rare

Vasculitis

Respiratory, thoracic and mediastinal disorders

Not known*

Interstitial lung disease

Gastrointestinal disorders

Common

Nausea, abdominal pain, dyspepsia

Very rare

Pancreatitis

Not known

Diarrhoea

Hepatobiliary disorders

Very rare

Hepatitis

Skin and subcutaneous tissue disorders

Very rare

Angioedema, face oedema and other skin reactions (e.g. eczema, dermatitis, bullous exanthema)

Musculoskeletal and connective tissue disorders

Rare

Myalgia, muscular weakness, myopathy

Very rare

Rhabdomyolysis, lupus like syndrome, myositis

Not known

Immune-mediated necrotizing myopathy (see section 4.4)

Reproductive system and breast disorders

Not known*

Erectile dysfunction

Investigations

Common

Blood creatine phosphokinase increased, blood transaminases increased

Eye disorders

Not known

Ocular myasthenia

* Based on post-marketing experience with fluvastatin via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares,

• Memory loss

• Sexual dysfunction

• Depression

• Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).

• Tendinopathy, sometimes complicated by tendon rupture

Paediatric population

Children and adolescents with heterozygous familial 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-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 fluvastatin capsules 20 mg/day, 1.5% to 1.8% on fluvastatin capsules 40 mg/day, 1.9% on Fluvastatin prolonged-release tablets 80 mg/day and in 2.7% to 4.9% on twice daily fluvastatin 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%).

Reporting of suspected adverse reactions

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

4.9. Overdose

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