Consumer medicine information

Lescol XL

Fluvastatin

BRAND INFORMATION

Brand name

Lescol XL

Active ingredient

Fluvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lescol XL.

What is in this leaflet

This leaflet answers some common questions about Lescol XL.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Lescol XL against the benefits they expect it will provide.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Lescol XL is used for

Lescol XL is used to lower the amount of cholesterol made by the body. Everyone has cholesterol in their blood. It is a type of fat needed by the body for many things, such as building cells, making bile acids (which help to digest food) and making some hormones. However, having too much cholesterol in the blood can contribute to the development of heart disease.

Cholesterol is present in many foods and is also made by your body. If your body does not balance the amount of cholesterol it makes with the amount of cholesterol you eat, then your cholesterol becomes too high. High cholesterol is more likely to occur with certain diseases or if you have a family history of high cholesterol.

Lescol XL does not reduce the cholesterol that comes from fat in food. Therefore, you also need to follow a low fat diet, control your weight and exercise regularly.

Lescol XL can also be used to help prevent further serious cardiac problems in people with heart disease who have already had cardiac catheterisation to open up the blood vessels in their heart.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is only available with a doctor's prescription. It is not addictive.

There is not enough information to recommend this medicine for children.

Before you take Lescol XL

When you must not take it

Do not take Lescol XL if you have ever had an allergic reaction to:

  • fluvastatin, the active ingredient in Lescol XL
  • any of the other ingredients of Lescol XL listed at the end of this leaflet.
  • other brands of fluvastatin
  • other similar "statin" cholesterol lowering medicines (e.g. atorvastatin, pravastatin, simvastatin )

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take Lescol XL if you are pregnant. It may affect your developing baby. If you think there is a possibility that you might become pregnant while you are taking this medicine, your doctor can give you advice about effective contraception.

Do not breast-feed while you are taking Lescol XL. It is not known if the active ingredient passes into the breast milk and could affect your baby.

Do not take Lescol XL after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Before you start to take it

Tell your doctor if you have any of the following health problems / medical conditions:

  • a personal or family history of hereditary muscle disorders
  • a personal or family history of diabetes
  • a past history of inflammation of your muscles when you took a "statin" or "fibrate" medicine to lower your cholesterol. You may have had muscle pain, tenderness or weakness and unusual tiredness or fever.
  • unexplained muscle pain, tenderness or weakness. These might be early signs of potentially severe muscle degradation.
  • liver or kidney problems
  • an underactive thyroid
  • you regularly drink large amounts of alcohol
  • a serious infection
  • very low blood pressure (signs may include dizziness, light-headedness)
  • recently had an injury
  • severe metabolic, endocrine or electrolyte disorders such as decompensated diabetes and low blood potassium
  • uncontrolled epilepsy, or
  • if you are about to have an operation

Your doctor may not want you to take Lescol XL or will monitor you carefully to help prevent side effects during your treatment.

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives. Your doctor will want to know if you are prone to allergies.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and Lescol XL may interfere with each other. These include:

  • other cholesterol lowering medicines, including colestyramine, gemfibrozil and nicotinic acid
  • warfarin, a medicine to prevent blood clots
  • some antibiotics, including erythromycin, fusidic acid and itraconazole
  • cimetidine, ranitidine and omeprazole, medicines used to treat stomach ulcers and reflux
  • ciclosporin
  • phenytoin, a medicine used to treat epilepsy
  • rifampicin, a medicine used to treat tuberculosis

You may need to take different amounts of your medicines or to take different medicines while you are taking Lescol XL. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you start taking this medicine.

How to take Lescol XL

Follow all directions given to you by your doctor and pharmacist carefully. These instructions may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Lescol XL prolonged released tablet is available in 80mg.

To prevent complications in people with heart disease, the usual daily dose is 80 mg.

How to take it

Take the capsules with a full glass of water.

Lescol XL must not be chewed, crushed, cut in half or split.

Lescol XL can be taken anytime of the day.

If you are also taking a medicine called colestyramine to help lower your cholesterol, take your dose of Lescol XL at least 4 hours after taking the dose of colestyramine. These two medicines will interact with one another if they are taken too close together.

Take Lescol XL at about the same time each day. Taking your medicine at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Take this medicine for as long as your doctor recommends.

Lescol XL helps to lower your cholesterol but does not cure your condition. You must continue to take it as directed to keep your cholesterol levels down.

If you forget to take it

If your next dose is not due for more than 4 hours, take the missed dose as soon as you remember. Then take your next dose at the usual time and continue on with your normal schedule.

But, if your next dose is due in less than 4 hours, skip the missed dose. Take your next dose at the usual time and continue on with your normal schedule.

Do not take a double dose to make up for the one that you missed. This may increase the chance of you getting an unwanted side effect.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone number 13 11 26), or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Lescol XL. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy.

While you are taking Lescol XL

Things you must do

If you become pregnant while taking Lescol XL, stop taking it and tell your doctor immediately.

Continue on your cholesterol lowering diet while you are taking Lescol XL.

Have your cholesterol levels checked and any other blood tests done as directed by your doctor. Regular blood tests will help to make sure the treatment is working and prevent unwanted side effects.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Lescol XL.

Tell any other doctor, dentist or pharmacist who treats you that you are taking Lescol XL.

Things you must not do

Do not give this medicine to anyone else, even if their condition seems similar to yours.

Do not take it to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how Lescol XL affects you. There is no information on the possible effects of this medicine on mental alertness. Make sure you know how you react to it before you drive a car, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Lescol XL, even if you do not think it is connected with the medicine.

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you have signs and symptoms of high levels of blood sugar such as an excessive thirst, high urine output, increased appetite with weight loss, tiredness.

Tell your doctor if you notice any of the following and they worry you:

  • upset stomach or heartburn
  • nausea (feeling sick)
  • diarrhoea
  • headache
  • difficulty sleeping
  • numbness or tingling in the hands or feet
  • prickling or burning sensation or decreased sensitivity of the skin
  • impotence
  • unexplained muscle pain, tenderness or weakness

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • unexpected pain, tenderness or weakness in your muscles, which may be accompanied by unusual tiredness or fever. These may be early signs of an inflammation of your muscles that can lead to destruction of muscle tissue. This can be avoided if your doctor stops your treatment as quickly as possible.
  • signs of allergy such as swelling of the face, eyelids, lips, tongue or other parts of the body; rash, itching or hives on the skin; shortness of breath, wheezing or difficulty breathing; unusual bleeding or bruising under the skin.
  • signs of a possible liver problem, including yellowing of the skin and/or eyes and dark coloured urine, nausea, vomiting, loss of appetite, impaired brain function, easy bruising or bleeding.
  • signs of a possible lung problem, including shortness of breath, non-productive cough, fatigue, weight loss and fever.

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet.

After using Lescol XL

Storage

  • Keep your medicine in the original container until it is time to take it.
  • Store it in a cool dry place.
  • Do not store Lescol XL or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on window sills.

Keep the medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Lescol XL or the expiry date has passed, ask your pharmacist what to do with any medicine you have left over.

Product description

What it looks like

Lescol XL 80 mg tablet: yellow, round, slightly biconvex film-coated tablet, marked "LE" on one side and "NVR" on the other; packs of 28.

Ingredients

Lescol XL tablets contain 80 mg of the active ingredient, fluvastatin (as the sodium salt).

They also contain:

  • magnesium stearate
  • potassium bicarbonate
  • hypromellose
  • microcrystalline cellulose
  • hyprolose
  • povidone
  • yellow film coating (containing macrogol, titanium oxide, iron oxide yellow)

Lescol XL does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Lescol XL is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone: 1 800 671 203

®= Registered Trademark

This leaflet was prepared in
January 2021

Australian Registration Number.
Lescol XL 80mg AUSTR 82743

(les290121c.doc) based on PI (les290121i.doc)

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Lescol XL

Active ingredient

Fluvastatin

Schedule

S4

 

1 Name of Medicine

Fluvastatin sodium.

2 Qualitative and Quantitative Composition

Fluvastatin sodium is a white to pale yellow powder, odourless or weak odour only. Fluvastatin sodium is a racemic mixture of the two enantiomers of which the 3R,5S form possesses more than 30 times the activity of the 3S,5R form.
Each prolonged release tablet contains 84.24 mg fluvastatin sodium equivalent to 80 mg fluvastatin free acid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Prolonged release tablets.
Yellow, round, slightly biconvex, film-coated tablet, marked "LE" on one side and "NVR" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypercholesterolaemia.

Prior to initiating therapy with fluvastatin for treating hypercholesterolaemia, secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, alcoholism) should be identified and treated.

Adults.

As an adjunct to diet in the treatment of hypercholesterolaemia.

Heterozygous familial hypercholesterolaemia in paediatric patients.

As an adjunct to diet in adolescent boys and in adolescent girls who are at least one year postmenstruation, 10-16 years of age, with heterozygous familial hypercholesterolaemia whose response to dietary restriction has not been adequate and in whom the following findings are present:
1. LDL-C remains ≥ 4.9 mmol/L (190 mg/dL); or
2. LDL-C remains ≥ 4.1 mmol/L (160 mg/dL) and there is a positive family history of premature cardiovascular disease or two or more other cardiovascular disease risk factors are present.

Secondary prevention of cardiac events.

For the prevention of major adverse cardiac events in adult patients with coronary heart disease who have undergone successful coronary transcatheter therapy.

4.2 Dose and Method of Administration

Prior to initiating fluvastatin, the patient should be placed on a standard cholesterol lowering diet for a minimum of 3 months. Dietary therapy should be continued during treatment.

Dosage regimen for adults.

Lescol 20 mg and 40 mg capsules are no longer marketed in Australia.
Lescol XL 80 mg must be swallowed whole with a glass of water and must not be chewed, crushed nor split or cut in half.
The recommended fluvastatin starting dose is 40 mg once or twice daily, or 80 mg once daily (1 tablet Lescol XL). A 20 mg dose of fluvastatin may be adequate in mild cases. Starting doses should be individualised according to baseline LDL-C levels and the recommended goal of therapy to be accomplished.
In patients with coronary heart disease after successful coronary transcatheter therapy, the appropriate daily dose is 80 mg.
Lescol XL tablet can be administered as single dose at any time of the day with or without food. Lescol XL tablets must be swallowed whole with a glass of water. Lescol XL tablets must not be chewed, crushed, nor split or cut in half. Since the maximal reductions in LDL-C at a given dose are seen within 4 weeks, periodic lipid determinations should be performed and dosage adjusted according to the patient's response to therapy and established treatment guidelines at intervals of 4 weeks or more. The therapeutic effect of Lescol XL tablets are maintained with prolonged administration.
Lescol XL tablets are efficacious in monotherapy or in combination with bile acid sequestrants. When Lescol XL tablets are used in combination with colestyramine or other resins, it should be administered at bedtime at least four hours after the resin to avoid a significant interaction due to binding of the drug to the resin. Limited clinical data are available to support the use of Lescol XL tablets in combination with nicotinic acid or gemfibrozil. However, these combinations should be used with caution (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle).
No dosage adjustments are required for elderly patients or patients with impaired renal function (see Section 4.4 Special Warnings and Precautions for Use, Precautions in special patient groups). For use in patients with impaired hepatic function, see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Precautions in special patient groups.

Heterozygous familial hypercholesterolaemia in paediatric patients, aged 10-16 years.

Lescol 20 mg and 40 mg capsules are no longer marketed in Australia. Lescol XL 80 mg should not be used as a starting dose in children and should only be used for maintenance dosing in existing patients.
Lescol XL tablets must not be chewed, crushed, cut in half or split (see Section 4.4 Special Warnings and Precautions for Use).
Prior to initiating treatment with fluvastatin, the patient should be placed on a standard cholesterol lowering diet for 6 months. Dietary therapy should be continued during treatment.
Paediatric patients should not be initiated on fluvastatin therapy with Lescol XL. The recommended starting dose is 20 mg fluvastatin once daily. Dosage adjustments, up to a maximum daily dose administered either as fluvastatin 40 mg twice daily or one Lescol XL 80 mg tablet once daily, should be made at intervals of at least 6 weeks after careful clinical and laboratory review. In line with the uncontrolled data available on such parameters as growth and sexual maturation, these latter parameters should be regularly reviewed while the child is on treatment and if treatment is ceased. Doses should be individualised according to the goal of therapy. Lescol XL tablets must not be chewed, crushed, cut in half or split.
The use of fluvastatin in combination with nicotinic acid, colestyramine, or fibrates in children and adolescents has not been investigated.

4.3 Contraindications

In patients with known hypersensitivity to fluvastatin or any of the excipients of Lescol XL tablets.
In patients with active liver disease or unexplained, persistent elevations in serum transaminases (see Section 4.4 Special Warnings and Precautions for Use, Liver enzymes).
During pregnancy, in breastfeeding mothers and in women of childbearing potential, unless they are taking adequate contraceptive precautions (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).

4.4 Special Warnings and Precautions for Use

General.

Before instituting therapy with fluvastatin, an attempt should be made to control hypercholesterolaemia with appropriate diet, exercise and weight reduction in obese patients, and to treat other underlying medical problems (see Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration).

Use in patients with homozygous familial hypercholesterolaemia.

HMG-CoA reductase inhibitors are reported to be less effective in patients with rare homozygous familial hypercholesterolaemia, possibly because these patients have few functional LDL receptors.
No data are available for the use of fluvastatin in patients with a rare condition known as homozygous familial hypercholesterolaemia.

Liver enzymes.

Postmarketing cases of fatal and nonfatal 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.
Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid lowering agents. Confirmed elevations of transaminase levels to more than three times the upper limit of normal developed in a small number of patients (1-2%). The majority of these abnormal biochemical findings were asymptomatic and resolved or improved towards pretreatment values after discontinuation of treatment.
It is recommended that liver function tests be performed before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or an elevation in dose, and periodically thereafter in all patients (e.g. six monthly). Liver enzyme changes generally occur in the first three months of treatment with fluvastatin. Should an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) exceed three 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.
The incidence of abnormal liver enzymes was higher in those patients receiving 80 mg per day than in those receiving 40 mg per day.

Use in hepatic impairment.

As fluvastatin is subject to saturable first-pass metabolism/ sequestration by the liver and is primarily eliminated via the biliary route, the potential exists for drug accumulation in patients with hepatic insufficiency. Caution should therefore be exercised when fluvastatin is administered to patients with a history of liver disease or heavy alcohol ingestion (see Section 4.4 Special Warnings and Precautions for Use, Liver enzymes). Fluvastatin is contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases (see Section 4.3 Contraindications).

Skeletal muscle.

Myopathy has rarely been reported; myositis and rhabdomyolysis have very rarely been reported in patients receiving fluvastatin. Patients should be advised to promptly report unexplained muscle pain, muscle tenderness or muscle weakness, particularly if accompanied by malaise or fever. In patients with unexplained diffuse myalgias, muscle tenderness or muscle weakness and/or marked elevation of creatine phosphokinase (CPK) values (greater than 5 times the upper limit of normal (> 5 x ULN)), myopathy, myositis or rhabdomyolysis must be considered and fluvastatin therapy should be discontinued immediately.
Statins must not be coadministered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination (see Section 4.8 Adverse Effects (Undesirable Effects)). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. 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 reintroduced 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 coadministration of statin and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Immune mediated necrotizing myopathy.

There have been rare reports of immune mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation. Treatment involves discontinuation of fluvastatin and using immunosuppressive agents.

Creatine kinase measurement.

Measurement of CPK before commencing treatment.

Physicians should prescribe fluvastatin with caution in patients with predisposing factors for rhabdomyolysis and its complications. A CPK 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; trauma; major surgery; severe metabolic, endocrine or electrolyte disorders; uncontrolled epilepsy; in elderly patients (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 the CPK level is significantly elevated (> 5 x ULN) before starting treatment with fluvastatin, the CPK level should be remeasured within 5 to 7 days to confirm the results. If the CPK level is still significantly elevated (> 5 x ULN), treatment should not be started.

Note.

Measurement of CPK should not be done following strenuous exercise or in the presence of any plausible alternative cause of an increase in CPK level as this makes interpretation of the CPK value difficult.

Measurement of CPK during treatment.

If muscular symptoms such as muscle pain, tenderness, weakness or cramps occur in patients receiving fluvastatin, their CPK level should be measured. Treatment should be stopped if the CPK level is found to be significantly elevated (> 5 x ULN). If muscular symptoms are severe and cause daily discomfort, even if CPK levels are elevated to ≤ 5 x ULN, treatment discontinuation should be considered.
Should the symptoms resolve and the CPK level return to normal, reintroduction of fluvastatin or another statin should only be considered at the lowest dose and under close monitoring.
Fluvastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing them to the development of renal failure secondary to rhabdomyolysis e.g. sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine or electrolyte disorders or uncontrolled epilepsy.
The risk of myopathy and/or rhabdomyolysis during treatment with HMG-CoA reductase inhibitors has been reported to be increased if therapy with ciclosporin, fibrates (e.g. gemfibrozil), erythromycin or nicotinic acid is administered concurrently. However, in clinical trials involving small numbers of patients receiving fluvastatin in combination with nicotinic acid, fibrates or ciclosporin, myopathy has not been observed. Isolated cases of myopathy have been reported postmarketing for concomitant administration of fluvastatin with ciclosporin and fluvastatin with colchicine. Fluvastatin should nevertheless be used with caution in patients receiving such concomitant medication (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Uncomplicated myalgia has been observed infrequently in patients treated with fluvastatin, at rates indistinguishable from placebo.
The incidence of elevations in CPK levels is increased with the higher doses of fluvastatin.

Use of statins and effects on glucose metabolism.

Increased glycosylated haemoglobin (HbA1c) and/or fasting plasma glucose levels were observed in patients treated with HMG-CoA reductase inhibitors (statins). New onset of diabetes mellitus was also reported in patients with risk factors for diabetes mellitus.

Endocrine function.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production.
Fluvastatin exhibited no effect upon nonstimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by TSH. Small declines in total testosterone have been noted in treatment groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of fluvastatin upon female sex hormones may be made.
Patients treated with fluvastatin sodium who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone or cimetidine) that may decrease the levels of endogenous steroid hormones.

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, nonproductive 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.

Precautions in special patient groups.

Paediatric use.

Lescol 20 mg and 40 mg capsules are no longer marketed in Australia. Lescol XL 80 mg should not be used as a starting dose in children and should only be used for maintenance dosing in existing patients.
Lescol XL tablets must not be chewed, crushed, cut in half or split (see Section 4.2 Dose and Method of Administration).
In patients aged < 18 years, efficacy and safety have not been studied for treatment periods longer than two years.
Fluvastatin has only been investigated in children aged 9-16 years of age with heterozygous familial hypercholesterolaemia in two open label, uncontrolled clinical trials.
The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. The specific effects of fluvastatin on the safety and growth and sexual maturation parameters could not be directly compared between patients receiving fluvastatin and untreated controls, as these were uncontrolled studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Heterozygous familial hypercholesterolaemia in paediatric patients; Section 4.8 Adverse Effects (Undesirable Effects), Children and adolescents; Section 4.2 Dose and Method of Administration, Heterozygous familial hypercholesterolaemia in paediatric patients, aged 10-16 years). Adolescent, pubertal and postpubertal females who are sexually active should be counselled on appropriate contraceptive methods while on fluvastatin therapy (see Section 4.6 Fertility, Pregnancy and Lactation).

Use in the elderly.

There is no evidence of reduced tolerability or altered dosage requirements in elderly patients. Elderly patients (> 65 years of age) demonstrated a greater treatment response in respect of LDL-C, total-C and LDL/HDL ratio than patients < 65 years of age.

Use in patients with impaired renal function.

The pharmacokinetics of fluvastatin remain unchanged in patients with mild to severe renal insufficiency. Therefore, no dose adjustments are necessary in these patients.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Liver enzymes; Section 4.8 Adverse Effects (Undesirable Effects), Laboratory findings.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Food.

There were no apparent differences in the lipid lowering effects of fluvastatin when administered with the evening meal or four hours after the evening meal. Based on the lack of interaction of fluvastatin with other CYP3A4 substrates, fluvastatin should not interact with grapefruit juice.

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 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. Although these increases in fluvastatin levels were not clinically significant, this combination should be used with caution. No effect of fluvastatin (40 and 80 mg/day) on blood ciclosporin levels has been observed during coadministration. In an interaction study with small numbers of patients, concomitant administration of fluvastatin and ciclosporin resulted in an increase in the bioavailability of fluvastatin. Although this was not associated with an increase in the incidence of adverse events, the combination should be used with caution due to a theoretical potential for an increased risk of myopathy and/or rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle).

Colchicines.

No information is available on the pharmacokinetic interaction between fluvastatin and colchicines. However, myotoxicity, including muscle pain and weakness and rhabdomyolysis, have been reported with concomitant administration of colchicine.

Fibric acid derivatives (fibrates) and niacin (nicotinic acid).

Concomitant administration of fluvastatin with bezafibrate, gemfibrozil, ciprofibrate or nicotinic acid has no clinically relevant effect on the bioavailability of fluvastatin or other lipid lowering agent. However, since an increased risk of myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors together with any of these molecules, these combinations should be used with caution (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle).

Itraconazole and erythromycin.

Concomitant administration of fluvastatin with the potent cytochrome P450 (CYP) 3A4 inhibitors itraconazole or 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) are unlikely to affect the bioavailability of fluvastatin (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle).

Fluconazole.

Administration of fluvastatin to healthy volunteers pretreated with fluconazole (CYP2C9 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.

Propranolol.

Concomitant administration of fluvastatin with propranolol has no effect on the bioavailability of fluvastatin. Based on the pharmacokinetic data, no monitoring or dosage adjustments are required.

Colestyramine.

Administration of fluvastatin sodium concomitantly with or up to 4 hours after colestyramine results in fluvastatin decreases of more than 50% for AUC and 50-80% for Cmax. However, administration of fluvastatin sodium 4 hours after colestyramine resulted in a clinically significant additive effect in reducing total-C and LDL-C compared with that achieved with either component drug alone (see Section 4.2 Dose and Method of Administration).

Phenytoin.

Coadministration of fluvastatin with phenytoin increased the AUC of phenytoin by approximately 20%. Routine monitoring of phenytoin plasma levels is sufficient during coadministration with fluvastatin. Phenytoin increased fluvastatin AUC by approximately 40% and fluvastatin Cmax by 27% but dosage adjustment of fluvastatin is not warranted when coadministered with phenytoin.

Losartan.

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

Digoxin.

In a crossover study involving 18 patients chronically receiving digoxin, concomitant administration of a single 40 mg dose of fluvastatin had no effect on digoxin AUC and small but clinically insignificant increases in the digoxin Cmax and urinary clearance were noted. Based on the pharmacokinetic data, no monitoring or dosage adjustments are required.

Amlodipine.

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

Histamine H2-receptor antagonists/ proton pump inhibitors.

Concomitant administration of fluvastatin with cimetidine, ranitidine or omeprazole results in an increase in the bioavailability of fluvastatin. The clinical relevance of this interaction has not been established. While additional interaction studies have not been performed, it is expected that other H2-receptor antagonists/ proton pump inhibitors are unlikely to affect the bioavailability of fluvastatin.

Rifampicin.

Administration of fluvastatin to healthy volunteers pretreated with rifampicin resulted in a reduction of the bioavailability of fluvastatin by about 50%. The clinical significance of this interaction has not been established. 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.

Warfarin/ salicylic acid.

In vitro protein binding studies demonstrated no interaction at therapeutic concentrations. In healthy volunteers, the concomitant use of fluvastatin and warfarin did not influence warfarin plasma levels after one single dose compared with warfarin alone. AUC and Cmax of fluvastatin were increased by 31% and 67% respectively after a single 30 mg dose of racemic warfarin given to patients taking 40 mg fluvastatin daily. The possibility of an interaction after chronic concomitant use of both drugs has not been investigated. In very rare cases, a possible increase of the anticoagulant effect (bleeding episodes and/or increased prothrombin times) have been reported in patients concomitantly treated with fluvastatin and warfarin or other coumarin derivatives. Patients receiving warfarin type anticoagulants should have their prothrombin times closely monitored when fluvastatin therapy is initiated, discontinued or the dosage of fluvastatin adjusted.

Glibenclamide and tolbutamide.

For patients receiving oral sulfonylureas (glibenclamide, tolbutamide) for the treatment of non-insulin dependent (type 2) diabetes mellitus (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycaemic control.
In glibenclamide treated NIDDM patients (n = 32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean Cmax, AUC, and t½ of glibenclamide 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.

Fusidic acid.

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic statins with fusidic acid. Coadministration of this combination may cause increased plasma concentrations of both agents. 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 fusidic acid is necessary, statin treatment should be discontinued throughout the duration of the fusidic acid treatment (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A study in rats given oral fluvastatin at dose levels up to 6 mg/kg/day (up to 0.6 times the human daily dose based on body surface BSA for females) and up to 20 mg/kg/day (up to 2 times the human daily dose based on BSA) for males showed no adverse effects on fertility or reproductive performance in either sex.
Seminal vesicles and testes were reduced in size in hamsters treated for 3 months at 20 mg/kg/day (about 1.4 times the human daily dose based on BSA). There was tubular degeneration and aspermatogenesis in the testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and oedema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (1.8 times the human daily dose based on BSA).
In a study of 26 male volunteers treated for 16 weeks with fluvastatin 40 mg per day or placebo, no differences were observed between groups in sperm count, sperm motility or sex hormone levels. The effects of higher doses or longer treatment have not been studied.
(Category D)
Definition of Category D: Drugs which have caused, are suspected to have caused or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
HMG-CoA reductase inhibitors are contraindicated during pregnancy. The risk of fetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
In two series of 178 and 143 cases where pregnant women took a HMG-CoA reductase inhibitor (statin) during the first trimester of pregnancy, serious fetal abnormalities occurred in several cases. These included limb and neurological defects, spontaneous abortions and fetal deaths. The exact risk of injury to the fetus occurring after a pregnant woman has been exposed to a HMG-CoA reductase inhibitor has not been determined. The current data do not indicate that the risk of fetal injury in women exposed to HMG-CoA reductase inhibitors is high. If a pregnant woman is exposed to a HMG-CoA reductase inhibitor she should be informed of the possibility of fetal injury and discuss the implications with her pregnancy specialist.
Since HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women.
HMG-CoA reductase inhibitors are also contraindicated 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. All women of childbearing potential should be warned of the potential hazard to the fetus should they become pregnant.
Animal studies with fluvastatin showed no evidence of teratogenic effects at oral doses up to 36 mg/kg/day in rats (up to 3.7 times the human dose based on BSA) and 10 mg/kg/day in rabbits (up to 1.9 times the human dose based on BSA), although an increased incidence of skeletal malformations has been reported in rats exposed to other HMG-CoA reductase inhibitors. Oral administration of fluvastatin (12 to 24 mg/kg/day or 1.2 to 2.4 times the human dose based on BSA) to rats towards the end of the gestation period caused mortality associated with an increase in sensitivity to the cardiotoxic effects of the drug.
It is not known whether fluvastatin is excreted into human milk, but a study in rats showed that unchanged drug is excreted in milk to a limited extent, although higher amounts of fluvastatin metabolites are present. Peri/ postnatal studies in rats showed that oral administration of fluvastatin (12-24 mg/kg/day or 1.2-2.4 times the human dose based on BSA) caused mortality associated with an increase in sensitivity to the cardiotoxic effects of the drug. Therefore, fluvastatin is contraindicated in breastfeeding mothers.

4.7 Effects on Ability to Drive and Use Machines

No data exist on the effects of fluvastatin on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

In all controlled clinical studies of fluvastatin and their open extensions, fluvastatin was discontinued in 5.9% of 2960 patients receiving fluvastatin monotherapy due to adverse experiences (mean exposure approximately 58 weeks). This results in an exposure adjusted discontinuation rate of 5.2% per year in fluvastatin patients compared with an adjusted rate of 6.4% per year in placebo patients. Adverse reactions have usually been mild and their incidences have been similar to those observed in the placebo group. A dose of 80 mg/day was associated with an increased incidence of abdominal pain and dyspepsia compared to a dose of 40 mg/day.
Adverse experiences occurring at an incidence of greater than 2% in controlled studies of fluvastatin at doses > 20 mg/day, regardless of causality, include the following (see Table 1).

Adverse reactions from clinical trials and postmarketing experience.

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

Blood and lymphatic system disorders.

Very rare: thrombocytopenia.

Immune system disorders.

Rare: hypersensitivity reactions such as rash, urticaria.
Very rare: anaphylactic reaction.

Gastrointestinal disorders.

Common: dyspepsia, abdominal pain, nausea.
Very rare: pancreatitis.

Psychiatric disorders.

Common: insomnia.

Nervous system disorders.

Common: headache.
Very rare: paraesthesia, dysaesthesia and hypoaesthesia, also known to be associated with the underlying hyperlipidaemic disorders.

Vascular disorders.

Very rare: vasculitis.

Skin and subcutaneous tissue disorders.

Very rare: other skin reactions (e.g. eczema, dermatitis, bullous exanthema), face oedema, angioedema.

Musculoskeletal system and connective tissue disorders.

(See Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle.)
Rare: myalgia, muscle weakness, myopathy.
Very rare: myositis, rhabdomyolysis, lupus erythematosus-like reactions.

Hepatobiliary disorders.

(See Section 4.4 Special Warnings and Precautions for Use, Liver enzymes.) Very rare: hepatitis.

Investigations.

Common: blood creatine phosphokinase increased, blood transaminases increased.

Other adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been derived from postmarketing 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 categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Reproductive system and breast disorders.

Erectile dysfunction.

Musculoskeletal and connective tissue disorders.

Immune mediated necrotizing myopathy (see Section 4.4 Special Warnings and Precautions for Use, Immune mediated necrotizing myopathy).

Musculoskeletal system.

Rhabdomyolysis (examples of signs and symptoms are muscle weakness, muscle swelling, muscle pain, dark urine, myoglobinuria, elevated serum creatine kinase, acute renal failure, cardiac arrhythmia). (See Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle; Section 4.8 Adverse Effects (Undesirable Effects)). Rhabdomyolysis may be fatal.

Children and adolescents.

The safety profile of fluvastatin in children and adolescents with heterozygous familial hypercholesterolaemia assessed in two open label, uncontrolled studies was similar to the one observed in adults. The most common adverse events observed were influenza and infections. In these limited, uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or menstrual cycle length in girls. (See Section 4.4 Special Warnings and Precautions for Use, Precautions in special patient groups, Paediatric use.) The specific effects of fluvastatin on the safety and growth and sexual maturation parameters could not be directly compared between patients receiving fluvastatin and untreated controls, as these were uncontrolled studies.

Laboratory findings.

Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid lowering agents. Marked elevations of CPK levels to more than 10 x ULN developed in a very small number of patients.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

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. No specific treatment of overdosage can be recommended. Should an accidental overdosage occur, treat symptomatically and institute supportive measures as required. Liver function tests and serum CPK levels should be monitored.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

A variety of clinical studies has demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (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. Epidemiological 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 nonpharmacologic interventions that simultaneously lowered LDL-C and increased HDL-C reduced the rate of cardiovascular events (both fatal and nonfatal myocardial infarctions) in high risk males or in males and females with established coronary artery disease.
In patients with hypercholesterolaemia, treatment with both fluvastatin and Lescol XL tablets reduced total-C, LDL-C and apolipoprotein B. Both fluvastatin and Lescol XL tablets also moderately reduced triglycerides while producing an increase in HDL-C. The agent had no consistent effect on Lp(a) or fibrinogen. Therapeutic response was well established within 2 weeks and maximum response was achieved within 4 weeks from treatment initiation and maintained during chronic therapy. It has not been established what effect fluvastatin induced changes in lipoprotein levels, including reduction of serum cholesterol, has on cardiovascular morbidity or mortality, as well as on total mortality.

5.1 Pharmacodynamic Properties

Mechanism of action.

Fluvastatin, a fully synthetic cholesterol lowering agent, is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Fluvastatin exerts its main effect in the liver and is mainly a racemate of the two erythro enantiomers of which the 3R,5S enantiomer exerts the pharmacological activity. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of low density lipoprotein (LDL) receptors and thereby increases the uptake of LDL particles. The ultimate result of these mechanisms is a reduction of the plasma cholesterol concentration.

Clinical trials.

The lipoprotein and coronary atherosclerosis study (LCAS).

In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of fluvastatin therapy on coronary atherosclerosis in patients with mild to moderately elevated LDL cholesterol levels (3.0-4.9 mmol/L (115-190 mg/dL)) and documented coronary artery disease was assessed by quantitative coronary angiography. In this double blind, placebo controlled trial in which 429 patients were randomised, angiograms were evaluated in 340 patients at baseline and at 2.5 years, or after at least one year of double blind treatment. Colestyramine, up to 12 g/day, was administered from week 12 after the beginning of the double blind treatment to patients with a baseline LDL-C level ≥ 4.1 mmol/L (160 mg/dL). 42 and 37 patients in the fluvastatin and placebo groups, respectively, received colestyramine. The primary endpoint was the change in the minimum lumen diameter (MLD) of qualified lesions of left ventricular epicardial vessels. Restricted maximum likelihood was used to account for correlation amongst lesions in subjects having more than one lesion.
Fluvastatin treatment significantly (p = 0.005) slowed the progression of atherosclerosis as judged from change in MLD. There was a smaller increase in percent stenosis of qualified lesions (p = 0.014) and the number of patients with new lesions was lower (p = 0.032) in the fluvastatin treated group compared to the placebo group. (See Table 2 for results.) When interpreting angiographic results, it is important to be aware that angiography may underestimate the extent and severity of atherosclerosis and cannot predict the site of future coronary occlusions. Acute ischaemic events tend to occur not at the sites of severe stenosis but at lesser stenotic lesions, which are lipid rich, soft and more prone to rupture. The incidence of any cardiac morbid or any fatal event in the 429 randomised patients was 14.5% in the fluvastatin group and 19.1% in the placebo group (p = 0.20). Cardiac morbid events were probable myocardial infarction, acute myocardial infarction requiring hospitalisation, unstable angina pectoris requiring hospitalisation, coronary artery bypass graft and percutaneous transluminal coronary angioplasty.

The Lescol intervention prevention study (LIPS).

The Lescol Intervention Prevention Study (LIPS) was an international, multicentre, randomised, double blind, parallel group trial of fluvastatin 80 mg daily or placebo, administered to male and female patients aged 18-80 years with coronary heart disease. All 844 fluvastatin treated and 833 placebo treated patients in the trial had undergone successful transcutaneous catheter therapy (TCT) for one or more lesions. These patients had cholesterol levels between 3.5 and 7 mmol/L (135 and 270 mg/dL). In this trial, the effect of fluvastatin treatment for approximately 4 years on the risk of developing one of several major cardiac adverse events (MACE) was assessed. The primary endpoint of the trial was the time to a patient suffering their first MACE, defined as either cardiac death, nonfatal acute myocardial infarction (AMI) or new revascularisation procedure (TCT, coronary artery bypass grafting (CABG)).
Fluvastatin significantly reduced the risk of developing one of the cardiac events included as a MACE (p = 0.013) over four years. (See Figure 1.) In the fluvastatin group, 181 patients developed a MACE during treatment compared to 222 patients in the placebo group. There was no significant reduction in any specific cardiac adverse event, including cardiac death (p = 0.06) and nonfatal AMI (p = 0.27).
LIPS indicated that, after a median of 3.9 years of treatment, there was a statistically significant reduction in the proportion of patients who had suffered a first MACE. In the fluvastatin group, 78.3% of patients survived 4 years without suffering a MACE compared to 72.6% in the placebo group. There was no statistically significant separation of the effect between fluvastatin and placebo until 3 years. Prescribers should note that the benefit of fluvastatin treatment for periods of less than 4.5 years was not examined in the LIPS trial.

Clinical trials with Lescol XL.

In three multicentre, double blind, active controlled studies in nearly 1700 patients with primary hypercholesterolaemia or mixed dyslipidaemia, Lescol XL 80 mg administered at bedtime was compared to fluvastatin 40 mg given at bedtime and to fluvastatin 40 mg given twice daily at breakfast and at bedtime over 24 weeks of therapy. Patients with diabetes and familial hypercholesterolaemia were excluded from these studies. Responder rates at the time when maximum therapeutic response is achieved are illustrated in Figure 2 for the fluvastatin 40 mg (mean LDL-C reduction of 26%) and Lescol XL 80 mg doses (mean LDL-C reduction of 36%).
In these studies, both fluvastatin 40 mg twice a day and Lescol XL 80 mg once daily reduced total-C, LDL-C, apolipoprotein-B (Apo-B) and triglycerides (TG), and increased HDL-C after 24 weeks of therapy (see Table 3).
Of the 857 patients randomised to Lescol XL 80 mg, 271 with primary mixed dyslipidaemia (Fredrickson type IIb) as defined by baseline plasma triglyceride levels ≥ 2.25 mmol/L (200 mg/dL), had a median reduction in triglycerides of 25%. In these patients, Lescol XL 80 mg produced meaningful increases in HDL-C of 13%. This effect was even more pronounced in those patients with very low HDL-C levels at baseline (i.e. ≤ 0.9 mmol/L (35 mg/dL)), who had mean increases in HDL-C of 16%. Significant decreases in total-C, LDL-C and Apo-B were also achieved. In these studies, patients with triglycerides > 4.5 mmol/L (400 mg/dL) were excluded.

Heterozygous familial hypercholesterolaemia in paediatric patients.

Fluvastatin sodium was studied in two open label, uncontrolled, dose titration studies (ZA01 and B2301) which enrolled paediatric patients with heterozygous familial hypercholesterolaemia. The studies included patients aged 9 years and above with an established diagnosis of heterozygous familial hypercholesterolaemia.
The first study (ZA01) enrolled 29 prepubertal boys, 9-12 years of age, who had an LDL-C level > 90th percentile for age and one parent with primary hypercholesterolaemia and either a family history of premature ischaemic heart disease or tendon xanthomas. All patients were started on fluvastatin 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 2.5 to 3.2 mmol/L (96.7 to 123.7 mg/dL). The mean baseline LDL-C was 5.8 mmol/L (226 mg/dL) (range: 3.6 to 9.2. mmol/L). Endpoint analyses were performed at year 2. Fluvastatin 20 mg to 80 mg daily doses decreased plasma levels of total-C and LDL-C by 21% and 27%, respectively (see Table 4). The mean achieved LDL-C (primary endpoint) was 4.2 mmol/L (161 mg/dL) (range: 1.9 to 8.7 mmol/L).
The second study (B2301) enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C ≥ 4.9 mmol/L (190 mg/dL) or LDL-C ≥ 4.1 mmol/L (160 mg/dL) and one or more risk factors for coronary heart disease, or LDL-C > 4.1 mmol/L (160 mg/dL) and a proven LDL-receptor defect. The main exclusion criteria were patients with homozygous familial hypercholesterolaemia; secondary forms of dyslipoproteinaemia; serum triglyceride levels > 6.8 mmol/L (600 mg/dL); ALAT, ASAT or creatinine levels > 1.5 x ULN; serum CK or serum TSH > 2 x ULN; BMI > 30 kg/m2. All patients were started on fluvastatin 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (Lescol 80 mg XL tablet) to achieve an LDL-C goal of ≤ 3.4 mmol/L (130 mg/dL). 70 patients were pubertal or postpubertal (n = 69 evaluated for efficacy; see Table 4). The mean baseline LDL-C was 5.8 mmol/L (225 mg/dL) (range 3.8 to 8.9 mmol/L).
Endpoint analyses were performed at week 114. Fluvastatin 20 mg to 80 mg daily doses decreased plasma levels of total-C and LDL-C by 22% and 28%, respectively (see Table 4). The mean achieved LDL-C was 4.1 mmol/L (159 mg/dL) (range: 2.3 to 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. The long-term efficacy of fluvastatin or Lescol XL tablets therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

5.2 Pharmacokinetic Properties

Absorption.

The following pharmacokinetic information is based on an immediate release formulation of fluvasatin.
Fluvastatin is absorbed rapidly and completely following oral administration of the immediate release formulation, with peak concentrations reached in less than 1 hour. Following administration of a 10 mg dose, the absolute bioavailability is 24% (range 9-50%). Administration with food reduces the rate but not the extent of absorption. At steady state, administration of fluvastatin with the evening meal results in a twofold decrease in Cmax and more than twofold increase in tmax as compared to administration four hours after the evening meal. No significant difference in extent of absorption or in lipid lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in higher than expected plasma fluvastatin concentrations. The inactive enantiomer accounts for about 60% of the increase.

Lescol XL prolonged release tablets.

After oral administration of Lescol XL 80 mg, and in comparison with the immediate release formulation, the absorption rate of fluvastatin is almost 60% slower, while the mean residence time of fluvastatin is increased by approximately four hours.

Distribution.

Fluvastatin is 98% bound to plasma proteins. The apparent volume of distribution is estimated at 330 L. The parent drug is targeted to the liver and no active metabolites are present systemically.

Metabolism.

Fluvastatin is metabolised in the liver, primarily via hydroxylation of the indole ring at the 5 and 6 positions. N-dealkylation and beta-oxidation of the side chains also occurs. The major components circulating in the blood are fluvastatin and the pharmacologically inactive N-desisopropyl-propionic acid metabolite. The hydroxy metabolites have some pharmacological activity, but do not circulate in the blood. Both enantiomers of fluvastatin are metabolised in a similar manner.
In vitro data indicate that fluvastatin metabolism involves multiple cytochrome P450 (CYP) isoenzymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (≈ 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e. ≈ 5% and ≈ 20% respectively. If one pathway is inhibited in the elimination process of fluvastatin, other pathways may compensate. The hepatic pathways of fluvastatin metabolism in humans have been completely elucidated. There are multiple, alternative cytochrome P450 (CYP450) pathways for fluvastatin biotransformation and thus fluvastatin metabolism is relatively insensitive to CYP450 inhibition, a major cause of adverse drug/ drug interactions.
In an in vitro study with human liver microsomes, fluvastatin inhibited the metabolism of CYP2C9 substrates, diclofenac and tolbutamide with Ki about 0.2 microM (about 86 nanogram/mL). Therefore, there is potential for competitive interaction between fluvastatin and compounds that are CYP2C9 substrates such as diclofenac, phenytoin, tolbutamide and warfarin and, although unlikely, such interactions need to be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

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 fluvastatin, the terminal disposition half-life for fluvastatin is 2.3 ± 0.9 hours.

Pharmacokinetics in special patient groups.

Patients with impaired renal function.

The pharmacokinetics of fluvastatin remain unchanged in patients with mild to severe renal insufficiency. Therefore, no dose adjustments are necessary in these patients.

Patients with impaired hepatic function.

As fluvastatin is subject to saturable first-pass metabolism/ sequestration by the liver and is primarily eliminated via the biliary route, the potential exists for drug accumulation in patients with hepatic insufficiency (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Age and gender.

Due to their generally smaller bodyweight, female patients show higher fluvastatin plasma concentrations after administration of 20-40 mg of fluvastatin compared to males.

Paediatric use.

Pharmacokinetic data in the paediatric population are not available.

5.3 Preclinical Safety Data

Carcinogenicity.

Animal carcinogenicity studies showed an increased incidence of benign and malignant thyroid follicular tumours in male rats receiving fluvastatin orally at 18 to 24 mg/kg/day (1.8 to 2.4 times the human daily dose based on body surface area (BSA) comparisons) and a low incidence of squamous papillomas in the forestomach of female mice dosed orally at 0.3 to 30 mg/kg/day (0.01 to 1.5 times the maximum human dose based on BSA comparisons), as well as in rats dosed at 18 to 24 mg/kg/day. The thyroid tumours in rats may be secondary to alterations in thyroid hormone levels. The forestomach tumours in mice and rats appear to be related to the pharmacological activity of the drug, but are not considered relevant to its clinical use. Although there was no evidence of an increase in the incidence of hepatic tumours with fluvastatin, it should be noted that high doses of other HMG-CoA reductase inhibitors have been reported to cause hepatocellular adenomas and carcinomas in mice and rats.
Animal studies have shown that fluvastatin causes the development of cataracts in dogs at oral doses greater than 8 mg/kg/day for 8 weeks or longer, and the development of gallstones in hamsters receiving dietary doses of 5 to 40 mg/kg/day. Mean plasma levels at the no effect dose for cataract formation in dogs were about 40 times greater than that achieved in humans at the maximum therapeutic dose of 40 mg per day. Clinical trials of fluvastatin have shown no evidence for drug related development of cataracts or gallstones in humans. Testicular degeneration and aspermatogenesis occurred in hamsters following dietary administration of fluvastatin at 40 mg/kg per day for six months; a no effect dose level for this toxicity was not established. No evidence of testicular toxicity was seen in chronic toxicity studies in mice, rats, dogs or monkeys at oral doses up to 30, 24, 36 and 40 mg/kg respectively.

Genotoxicity.

Fluvastatin demonstrated no evidence of genotoxic activity in a standard battery of assays.

CNS toxicity.

Preclinical safety data.

CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex and ptosis, were seen in the following animal studies: the 18 month mouse carcinogenicity study at 50 mg/kg/day (2.5 times the human daily dose based on BSA), the 6 month dog study at 36 mg/kg/day (12 times the human dose based on BSA), the 6 month hamster study at 40 mg/kg/day (2.7 times the human dose based on BSA), and in acute, high dose studies in rats and hamsters (50 mg/kg or 5 (rats) and 3.4 (hamster) times the human dose based on BSA), rabbits (300 mg/kg; 56 times the human dose based on BSA) and mice (1500 mg/kg). CNS toxicity in the acute high dose studies was characterised (in mice) by conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rat) by oedema with separation of myelinated fibres of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterised by periaxonal vacuolisation, was observed in the medulla of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterised by perivascular haemorrhages, oedema and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. No CNS lesions have been observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day; 17.8 times the maximum human dose based on BSA), rat (up to 24 mg/kg/day; 2.4 times the maximum human dose based on BSA) or dog (up to 16 mg/kg/day; 5.4 times the maximum human dose based on BSA).

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, hypromellose, hyprolose, potassium bicarbonate, povidone, magnesium stearate, and Opadry complete film coating system 00F22737 yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Lescol XL tablets should be kept out of the reach of children.

6.5 Nature and Contents of Container

Lescol XL prolonged release tablets:
Alu/Alu-blister packs. Blister packs contain 7 or 28 prolonged-release tablets.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Empirical formula: C24H25FNO4.Na.
Chemical name: [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)- 1-(1-methylethyl)-1H-indol-2-yl]- 3,5-dihydroxy-6-heptenoic acid monosodium salt.
Molecular weight: 433.46.

CAS number.

93957-55-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes