Folic Acid 2.5mg / 5ml Oral Solution

1. Name Of The Medicinal Product

Folic Acid 2.5mg/5ml Oral Solution

2. Qualitative And Quantitative Composition

Folic Acid 2.5mg/5ml

Excipients:

Methyl hydroxybenzoate (E218)

Ethyl hydroxybenzoate (E214)

Propyl hydroxybenzoate (E216)

Phenylalanine

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Oral Solution.

A clear, yellow, solution with a strawberry flavour and odour.

4. Clinical Particulars

4.1 Therapeutic Indications

1. Folate deficient megaloblastic anaemia

2. Folate deficient megaloblastic anaemia in infants

3. Treatment of folate deficiency in malabsorption syndromes (parenteral administration of folic acid may need to be considered if oral treatment is not effective)

	3.1 Tropical sprue. Tropical sprue responds to folate supplements in the early stages of the disease but cobalamin status must also be checked, particularly later.
	3.2 Coeliac disease. The necessity of supplementation with folate ceases once a gluten free diet is introduced.
	3.3 Non-tropical sprue. In congenital folate malabsorption, oral treatment may not be effective and parental folate may therefore be required.

4. Megaloblastic anaemia in pregnancy

5. Megaloblastic anaemia associated with alcoholism

6. Megaloblastic anaemia associated with anti-convulsant therapy

7. Folic acid deficiency/megaloblastic anaemia associated with haemolytic anaemia e.g. Sickle Cell Anaemia

4.2 Posology And Method Of Administration

For oral administration only.

Children (persons aged 12 years and younger):

May be given 5 mg to 15 mg daily, in divided doses, according to the severity of the deficiency state.

Adults:

Initial dose of 10 mg to 20 mg daily, in divided doses, for 14 days or until a haemopotoietic response has been obtained.

Maintenance dose is 2.5 mg to 10 mg daily.

Prophylactic dose in pregnancy 0.5 mg (1ml) daily.

Elderly:

As for adults.

4.3 Contraindications

Known hypersensitivity to folic acid.

Known hypersensitivity to hydroxybenzoate esters.

Patients with folate dependent tumours.

Patients with malignant disease, unless megaloblastic anaemia due to folic acid deficiency.

4.4 Special Warnings And Precautions For Use

If folic acid is used indiscriminately, there is a danger that patients with pernicious anaemia and other B₁₂ deficiency states, despite a haematological remission, may develop irreparable neurological lesions. Therefore a full clinical diagnosis should be made before initiating treatment.

Folic acid is removed by haemodialysis.

Contains methyl- ethyl- and propyl- p-hydroxybenzoates; may cause allergic reactions (possibly delayed).

Contains 0.75 mmol (or 17.4mg) sodium per 20 ml dose, and is therefore essentially 'sodium-free'.

Contains phenylalanine. May be harmful for people with phenylketonuria.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Folic acid has been observed to reduce plasma levels of anticonvulsants, particularly phenytoin and primidone and therefore patients should be carefully monitored by the physician and the anticonvulsant drug dose adjusted as necessary.

4.6 Pregnancy And Lactation

There are no known hazards to the use of folic acid, indeed folic acid supplements are often necessary in pregnancy.

Folic acid is excreted in breast milk.

4.7 Effects On Ability To Drive And Use Machines

There are no known effects of this preparation on the ability to drive or use machines.

4.8 Undesirable Effects

Allergic reactions to folic acid have been reported.

Mild gastro-intestinal upsets are rare but may occur.

4.9 Overdose

No cases of acute overdosage appear to have been reported, but even extremely high doses are unlikely to cause harm to patients.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: B03B B

After conversion into co-enzyme forms it is concerned in single carbon unit transfers in the synthesis of purines, pyrimidines and methionine.

5.2 Pharmacokinetic Properties

About 70 – 80 % of a 2 mg oral solution of folic acid is absorbed. Larger doses are probably equally well absorbed. It is distributed into plasma and extracellular fluid. In plasma, folate is bound weakly to albumin (70 %). There is a further high affinity binder for folate but this has a very low capacity and is barely detectable in normal sera. About 70 % of small doses of folate (about 1 mg) are retained and the rest excreted into the urine. With larger doses most is excreted into the urine. With a 5 mg dose of folate, urinary excretion will be complete in about five hours. There is an enterohepatic circulation of folate. The retained folate is taken into cells and reduced by dihydrofolate to tetrahydrofolate. Folic acid is a relatively poor substrate for folate reduction, the normal substrate being dihydrofolate.

Folic acid itself does not occur in natural materials, it is entirely a pharmacological form of the compound. Once reduced, folate has additional glutamic acid residues added, a folate pentaglutamate being the dominant intracellular analogue. These polyglutamates are the active co-enzymes.

5.3 Preclinical Safety Data

Folic Acid is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol (E421)

Glycerol (E422)

Methyl hydroxybenzoate (E218)

Ethyl hydroxybenzoate (E214)

Propyl hydroxybenzoate (E216)

Sodium dihydrogen phosphate dihydrate

Disodium hydrogen phosphate dodecahydrate

Disodium edetate

Strawberry flavour (contains phenylalanine, cherry juice concentrate and maltol)

Purified water

6.2 Incompatibilities

None stated.

6.3 Shelf Life

Unopened: 18 months

After first opening: Three months.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C - 8°C)

Store in the original bottle and outer cardboard carton in order to protect from light.

6.5 Nature And Contents Of Container

150 ml amber soda glass (type III) bottle fitted with a 28 mm white child resistant tamper evident screw cap, with expanded polyethylene (EPE) liner, and outer cardboard carton.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

U.K.

8. Marketing Authorisation Number(S)

PL 29831/0358

PA 1339/22/1

MA154/01302

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 09/04/2010

10. Date Of Revision Of The Text

09/04/2010

Fluvastatin 20mg and 40mg Capsules

1. Name Of The Medicinal Product

Fluvastatin 20 mg and 40mg Capsules

2. Qualitative And Quantitative Composition

Each 20mg capsule contains 21.06 mg fluvastatin sodium corresponding to 20 mg fluvastatin.

Each 40mg capsule contains 42.12 mg fluvastatin sodium corresponding to 40 mg fluvastatin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsule, hard

Brown coloured capsule containing off-white to pale-yellow powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Fluvastatin is indicated as an adjunct to diet for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) when response to diet and other non- pharmacological treatments (e.g. exercise, weight reduction) is inadequate in adults with primary hypercholesterolaemia (heterozygous variant) and mixed dyslipidaemia (Fredrickson Types IIa and IIb).

Fluvastatin is also indicated for the secondary prevention of major adverse cardiac events (cardiac death, non-fatal myocardial infarction and coronary revascularisation) in patients with coronary heart disease after coronary transcatheter therapy.

4.2 Posology And Method Of Administration

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

The recommended starting dose is 20 mg or 40 mg once daily. A dose of 20 mg once daily may be adequate in mild cases. Most patients will require a dose of 20 mg to 40 mg once daily but the dose may be increased to 80 mg daily (1 capsule fluvastatin 40 mg twice daily), individualized according to the baseline LDL-cholesterol (LDL-C) levels and the recommended goal of therapy to be accomplished. The maximum recommended daily dose is 80 mg.

In patients with coronary heart disease after coronary transcatheter therapy the appropriate dose is 80 mg daily.

The capsules should be taken in the evening or at bedtime without regard to meals. The capsules should be swallowed whole with a glass of water.

The maximum lipid-lowering effect with a given dose of the drug is achieved within 4 weeks. Doses should be adjusted according to the patient's response and dose adjustment made at intervals of 4 weeks or more. The therapeutic effect of fluvastatin is maintained with prolonged administration.

Fluvastatin is efficient in monotherapy. Data exist to support the efficacy and safety of fluvastatin in combination with nicotinic acid, cholestyramine, or fibrates (see section 4.5).

When fluvastatin is used in combination with colestyramine or other resins, it should be administered at least 4 hours after the resin to avoid a significant interaction due to binding of the drug to the resin.

Children and adolescent

There is no experience with the use of fluvastatin in individuals less than 18 years of age. The product should not be used in this group of patients.

Elderly

There is no evidence of reduced tolerability or altered dosage requirements in elderly patients thus, no dose adjustment is required in such patients.

Impaired kidney function

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

Impaired liver function

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).

4.3 Contraindications

Fluvastatin is contraindicated:

• in patients with known hypersensitivity to fluvastatin or to any of the excipients.

• in patients with active liver disease, or unexplained, persistent elevations in serum transaminases (see sections 4.2, 4.4 and 4.8).

• during pregnancy and lactation (see section 4.6).

4.4 Special Warnings And Precautions For Use

Liver function

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

Caution should be exercised when fluvastatin is administered to patients with a history of liver disease or heavy alcohol consumption.

Skeletal muscle

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

Creatine kinase measurement

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

Before the treatment

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

• Renal impairment

• Hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse

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

In such situations, the risk of treatment should be considered in relation to the possible benefit and clinical monitoring is recommended. If CK-levels are significantly elevated at baseline to more than 5 times the upper limit of normal (ULN), levels should be re-measured within 5 to 7 days later to confirm the results. If CK-levels are still significantly elevated (> 5 x ULN) 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 (> 5 x ULN).

If muscular symptoms are severe and cause daily discomfort, even if CK-levels are elevated to

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 drugs (including ciclosporin), fibrates, nicotinic acid or erythromycin together with other HMG-CoA reductase inhibitors. However, in clinical trials in patients receiving fluvastatin in combination with nicotinic acid, fibrates, or ciclosporin, myopathy has not been observed. Isolated cases of myopathy have been reported post-marketing for concomitant administration of fluvastatin with ciclosporin and fluvastatin with colchicine. The benefits of the combined use of fluvastatin with fibrates, niacin or colchicin should be carefully weighed against the potential risks of these combinations and fluvastatin should be used with caution in patients receiving such concomitant medication (see section 4.5).

Hyperlipoproteinemia

No data are available for the use of fluvastatin in patients with hyperlipoproteinemia with a major increase in triglycerides.

Homozygous familial hypercholesterolemia

No data are available for the use of fluvastatin in patients with a rare condition known as homozygous familial hypercholesterolemia. The effect is expected to be low due to LDL – receptor deficiency in these patients. Therefore use of fluvastatin is not recommended in these patients.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Food interactions

There are no apparent differences in the lipid-lowering effects of fluvastatin when administered with the evening meal or 4 hours after the evening meal. Based on the lack of interaction of fluvastatin with other CYP3A4 substrates, fluvastatin is not expected to interact with grapefruit juice.

Drug interactions

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

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. An increased risk of myopathy and/ or rhabdomyolysis has been observed in patients receiving other HMG-CoA reductase inhibitors together with any of these molecules, probably because they can produce myopathy when given alone. Therefore, 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, have been reported in isolated cases with concomitant administration of colchicine. 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 wherein 80 mg fluvastatin was administered to renal transplant patients who were on stable ciclosporin regimen showed that fluvastatin exposure (AUC) and maximum concentration (C_max) were increased 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. Starting and maintaining fluvastatin therapy should be in a dose as low as possible when combined with ciclosporin.

Fluvastatin (40 mg and 80 mg) had no effect on ciclosporin bioavailability when co-administered

Warfarin and other coumarin derivatives

In healthy volunteers, the use of fluvastatin and warfarin (single dose) did not adversely influence warfarin plasma levels and prothrombin times compared to warfarin alone. However, isolated incidences of bleeding episodes and/or increased prothrombin times have been reported very rarely in patients on fluvastatin receiving concomitant warfarin or other coumarin derivatives. It is recommended that prothrombin times are monitored when fluvastatin treatment is initiated, discontinued, or the dosage changed in patients receiving warfarin or other coumarin derivatives.

Rifampicin (rifampin)

Administration of fluvastatin to healthy volunteers pre-treated with rifampicin (rifampin) resulted in a reduction of the bioavailability of fluvastatin by about 50%. Although at present there is no clinical evidence that fluvastatin efficacy in lowering lipid levels is altered, for patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis), appropriate adjustment of fluvastatin dosage may be warranted to ensure a satisfactory reduction in lipid levels.

Oral antidiabetic agents

For patients receiving oral sulfonylureas (glibenclamide [glyburide], tolbutamide) for the treatment of non-insulin-dependent (type 2) diabetes mellutis (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycemic control.

In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean C_max, AUC, and t_1/2 of glibenclamide approximately 50%, 69% and 121%, respectively. Glibenclamide (5 to 20 mg daily) increased the mean C_max and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in glucose, insulin and C-peptide levels. However, patients on concomitant therapy with glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 80 mg per day.

Bile acid sequestrants

Fluvastatin should be administered at least 4 hours after the resin (e.g. cholestyramine) to avoid a significant interaction due to drug binding of the resin.

Fluconazole

Administration of fluvastatin to healthy volunteers pre-treated with fluconazole (CYP 2C9 inhibitor) resulted in an increase in the exposure and peak concentration of fluvastatin by about 84% and 44%.

Although there was no clinical evidence that the safety profile of fluvastatin was altered in patents pre-treated with fluconazole for 4 days, caution should be exercised when fluvastatin is administered concomitantly with fluconazole.

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.

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 are relatively small and not clinically significant. Thus, routine monitoring of phenytoin plasma levels is sufficient during co-administration with fluvastatin. The minimal effect of phenytoin on fluvastatin pharmacokinetics indicates that dosage adjustment of fluvastatin is not warranted when co-administered with phenytoin.

Cardiovascular agents

No clinically significant pharmacokinetic interactions occur when fluvastatin is concomitantly administered with propranolol, digoxin, losartan, amlodipine or ACE- inhibitors. Based on the pharmacokinetic data, no monitoring or dosage adjustments are required when fluvastatin is concomitantly administered with these agents.

4.6 Pregnancy And Lactation

Pregnancy

Fluvastatin is contraindicated during pregnancy (see section 4.3).

There are 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. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid- lowering medicinal products durinig pregnancy should have little impact on the long- term risk associated with primary hypercholesterolaemia. For these reasons, fluvastatin must not be used in women who are pregnant or suspect they are pregnant and in women of childbearing potential not taking adequate contraceptive precautions. Treatment with fluvastatin should be suspended for the duration of pregnancy or until has been determined that the woman is not pregnant (see section 4.3).

Lactation

It is not known whether fluvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking fluvastatin should not breast-feed their infants (see section 4.3).

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. However, based on its pharmacodynamic properties, fluvastatin is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

4.8 Undesirable Effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

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

Blood and lymphatic system disorders

Very rare: Thrombocytopenia

Psychiatric disorders

Common: Insomnia

Nervous system disorders

Common: Headache, fatigue, dizziness

Very rare: Paraesthesia, dysaesthesia, hypoaesthesia and peripheral neuropathy also known to be associated with the underlying hyperlipidemic disorders

Vascular disorders

Very rare: Vasculitis

Gastrointestinal disorders

Common: Dyspepsia, abdominal pain, nausea, constipation, flatulence, diarrhoea

Very rare: Pancreatitis

Hepatobiliary disorders

Very rare: Hepatitis

Skin and subcutaneous tissue disorders

Rare: Hypersensitivity reactions such as rash, urticaria

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

Musculoskeletal and connective tissue disorders

Common: Arthralgia

Rare: Myalgia, muscle tenderness, muscle weakness, myopathy

Very rare: Rhabdomyolysis, myositis, lupus erythematosus-like reactions

Investigations

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 3 times the upper limit of normal (ULN) developed in 1 to 2% of patients.

Marked elevations of CK levels to more than 5 x ULN developed in 0.3 to 1.0% of patients.

4.9 Overdose

Should an accidental overdosage occur, administration of activated charcoal is recommended and the liver function should be monitored. In the case of a very recent oral intake gastric lavage may be considered. Treatment should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors

ATC Code: C10A A04

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

The overall cholesterol profile is improved with the principal effects being the reduction of total-C and LDL-C. Fluvastatin also produces a moderate reduction in triglycerides (TG) and a moderate increase in HDL-C.

In a pooled analysis of all placebo-controlled studies, patients with primary mixed dyslipidaemia (Type IIb) defined as baseline TG levels

In the Lescol Intervention Prevention Study (LIPS), the effect of fluvastatin on major adverse cardiac events (MACE) was assessed in patients with coronary heart disease who had first successful transcathether therapy (TCT). The study included male and female patients (18-80 years old) and with baseline total cholesterol levels ranging from 3.5-7.0 mmol/l.

In this randomised, double-blind, placebo-controlled trial fluvastatin (N = 844), given as 80 mg daily over 4 years, significantly reduced the risk of the first MACE by 22% (p = 0.013) as compared to placebo (N = 833). These beneficial effects were particularly noteworthy, in diabetics and in patients with multivessel disease. Therapy with fluvastatin reduced the risk of cardiac death and/or myocardial infarction by 31% (p = 0.065).

5.2 Pharmacokinetic Properties

Absorption

Fluvastatin is absorbed rapidly and completely (98%) after oral administration to fasted volunteers. In a fed state, the drug is absorbed at a reduced rate. No significant difference in AUC was observed when fluvastatin was administered with the evening meal or 4 hours after the evening meal.

Distribution

Absolute bioavailability is variable and it increases with increasing doses. The absolute bioavailability of fluvastatin following a 10 mg dose was 24% (range: 9% - 50%). At doses above 20 mg, fluvastatin exhibits nonlinear kinetics, at least in the fasting state, resulting in dose normalized AUC values 20% - 40% higher than expected for the 40 mg dose. The apparent volume distribution for the drug is 330 l. More than 98% of the circulating drug is bound to plasma proteins, and this binding is not affected either by the concentration of fluvastatin, or by warfarin, salicylic acid, and glyburide.

Metabolism

Fluvastatin is mainly metabolized in the liver. The major components circulating in the blood are fluvastatin and the pharmacologically inactive N-desisopropyl-propionic acid metabolite. The hydroxylated metabolites have pharmacological activity but do not circulate systemically. 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.

Several detailed in vitro studies have addressed the inhibitory potential of fluvastatin on common CYP isoenzymes. Fluvastatin inhibited only the metabolism of compounds that are metabolized by CYP2C9. Despite the potential that therefore exists for competitive interaction between fluvastatin and compounds that are CYP2C9 substrates, such as diclofenac, phenytoin, tolbutamide, and warfarin, clinical data indicate that this interaction is unlikely.

Elimination

Following administration of ³H-fluvastatin to healthy volunteers, excretion of radioactivity is about 6% in the urine and 93% in the faeces, and fluvastatin accounts for less than 2% of the total radioactivity excreted. The plasma clearance 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 40 mg daily. Following oral administration of 40 mg fluvastatin, the terminal disposition half-life for fluvastatin is 2.3 ± 0.9 hours.

Characteristics in patients

Plasma concentrations of fluvastatin do not vary as a function of either age or gender in the general population. However, enhanced treatment response was observed in women and in elderly people.

Since fluvastatin is eliminated primarily via the biliary route and is subject to significant pre-systemic metabolism, the potential exists for drug accumulation in patients with hepatic insufficiency (see sections 4.3 and 4.4).

5.3 Preclinical Safety Data

Repeat toxicity studies with fluvastatin identified a variety of changes that are common to HMG-CoA reductase inhibitors, viz. hyperplasia and hyperkeratosis of the rodent non-glandular stomach, cataracts in dogs, myopathy in rodents, mild liver changes in most laboratory animals, with gall bladder changes in the dog, monkey and hamster, thyroid weight increases in the rat and testicular degeneration in the hamster. Fluvastatin is devoid of the CNS vascular and degenerative changes recorded in dogs with other members of this class of compounds.

Carcinogenicity studies in rats and mice revealed a low incidence of forestomach squamous papillomas in mice and rats and one carcinoma in rats at the highest dose (18 mg/kg per day escalated to 24 mg/kg per day after 1 year). The forestomach neoplasms reflect chronic hyperplasia caused by direct contact exposure to fluvastatin rather than a genotoxic effect of the drug. In addition, an increase incidence of thyroid follicular cell neoplasms in male rats given the highest dose of fluvastatin was recorded. This is consistent with species-specific findings with other HMGCoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no treatment-related increases in the incidence of hepatic adenomas or carcinomas were observed.

In vitro and in vivo mutagenicity studies revealed no evidence of mutagenicity.

Reproductive toxicity studies indicated that fluvastatin had no adverse effects on fertility or reproductive performance in males or females, nor was it embryotoxic or teratogenic. Late gestational effects at high doses resulted in maternal mortality and fetal and neonatal lethality attributable to exaggerated pharmacological effects of fluvastatin during pregnancy.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule contents:

Calcium carbonate

Cellulose microcrystalline

Pregelatinised maize starch

Talc

Sodium hydrogen carbonate

Magnesium stearate

Hard gelatin capsule:

Gelatin

Titanium dioxide (E171)

Iron oxide red (E172)

Sodium lauryl sulphate

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

OPA/ Al/ PVC/ Al blister: 3 years

HDPE bottle: 3 years

After first opening the HDPE bottle: 4 months

6.4 Special Precautions For Storage

OPA/ Al/ PVC/ Al blister: Do not store above 25°C

HDPE bottle: Do not store above 25°C

Store in the original package in order to protect from light .

6.5 Nature And Contents Of Container

OPA/ Al/ PVC/ Al blister: 14, 20, 28, 30, 50, 56, 84, 90, 98, 100, 490 hard capsules

HDPE bottle with PP cap: 98 hard capsules

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sandoz Limited

37 Woolmer Way

Bordon

Hampshire

GU35 9QE

8. Marketing Authorisation Number(S)

PL 04416/0748

PL 04416/0749

9. Date Of First Authorisation/Renewal Of The Authorisation

30/11/2007

10. Date Of Revision Of The Text

05/2009

Fluoxetine 20mg Capsules (Actavis UK Ltd)

1. Name Of The Medicinal Product

Fluoxetine 20mg Capsules

2. Qualitative And Quantitative Composition

Fluoxetine 20mg as Fluoxetine Hydrochloride.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsule, hard. Size 3 hard gelatine capsule, light green cap and yellow body. Markings are C on one half and FX on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults:

• Major depressive episodes.

• Obsessive-compulsive disorder.

• Bulimia nervosa: Fluoxetine is indicated as a complement of psychotherapy for the reduction of binge-eating and purging activity.

4.2 Posology And Method Of Administration

For oral administration to adults only.

• Major depressive episodes

Adults and the elderly: 20mg/day to 60mg/day. A dose of 20mg/day is recommended as the initial dose. Although there may be an increased potential for undesirable effects at higher doses, a dose increase may be considered after three to four weeks if there is no response. Dosage adjustment should be made gradually and carefully on an individual patient basis to maintain the patients at the lowest effective dose, and should not exceed 60mg daily.

In agreement with the consensus statement of the WHO, antidepressant medication should be continued for at least 6 months to ensure that patients are free from symptoms.

• Obsessive-compulsive disorder

Adults and the elderly: 20mg/day to 60mg/day. A dose of 20mg/day is recommended as the initial dose. Although there may be an increased potential for side-effects at higher doses, a gradual dose increase may be considered after two weeks if there is no response. If no improvement is observed within 10 weeks, treatment with fluoxetine should be reconsidered. If a good therapeutic response has been obtained, treatment can be continued at a dosage adjusted on an individual basis. Whilst there are no systematic studies to answer the question of how long to continue fluoxetine treatment, OCD is a chronic condition and it is reasonable to consider continuation beyond 10 weeks in responding patients. Dosage adjustments should be made carefully on an individual patient basis, to maintain the patient at the lowest effective dose. The need for treatment should be reassessed periodically. Some clinicians advocate concomitant behavioural psychotherapy for patients who have done well on pharmacotherapy.

Long-term efficacy (more than 24 weeks) has not been demonstrated in OCD.

• Bulimia nervosa

Adults and the elderly: A dose of 60mg/day is recommended.

Long-term efficacy (more than 3 months) has not been demonstrated in bulimia nervosa.

• Adults - All indications

The recommended dose may be increased or decreased. Doses above 80mg/day have not been systematically evaluated.

Fluoxetine may be administered as a single or divided dose, during or between meals.

When dosing is stopped, active drug substance will persist in the body for weeks. This should be borne in mind when starting or stopping treatment. Dosage tapering is unnecessary in most patients.

Children and adolescents (<18 years)

Fluoxetine should not be used in the treatment of children and adolescents under the age of 18 years (see section 4.4).

.

Elderly: Caution is recommended when increasing the dose and the daily dose should generally not exceed 40mg. Maximum recommended dose is 60mg/day.

A lower or less frequent dose (e.g. 20mg every second day) should be considered in patients with hepatic impairment (see 5.2 Pharmacokinetic properties), or in patients where concomitant medication has the potential for interaction with fluoxetine (see 4.5 Interactions).

Withdrawal symptoms seen on discontinuation of Fluoxetine: Abrupt discontinuation should be avoided. When stopping treatment with fluoxetine the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 and section 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

4.3 Contraindications

Hypersensitivity to fluoxetine or to any of its excipients.

Monoamine Oxidase Inhibitors: Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued an SSRI and have started on a MAOI. Treatment of fluoxetine should only be started 2 weeks after discontinuation of an irreversible MAOI and the following day after discontinuation of a reversible MAOI-A.

Some cases presented with features resembling serotonin syndrome (which may resemble and be diagnosed as neuroleptic malignant syndrome). Cyproheptadine or dantrolene may benefit patients experiencing such reactions. Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

Therefore, fluoxetine is contra-indicated in combination with a non-selective MAOI. Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment before starting a MAOI. If fluoxetine has been prescribed chronically and/or at a high dose, a longer interval should be considered.

The combination of fluoxetine with a reversible MAOI is not recommended. Treatment with fluoxetine can be initiated the following day after discontinuation of a reversible MAOI (e.g. moclobemide).

4.4 Special Warnings And Precautions For Use

Warnings

Rash and allergic reactions: Rash, anaphylactoid events and progressive systemic events, sometimes serious (involving skin, kidney, liver or lung) have been reported. Upon the appearance of rash or of other allergic phenomena for which an alternative aetiology cannot be identified, fluoxetine should be discontinued.

Precautions

Seizures: Seizures are a potential risk with antidepressant drugs. Therefore, as with other antidepressants, fluoxetine should be introduced cautiously in patients who have a history of seizures. Treatment should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency. Fluoxetine should be avoided in patients with unstable seizure disorders/epilepsy and patients with controlled epilepsy should be carefully monitored.

Mania: Antidepressants should be used with caution in patients with a history of mania/hypomania. As with all antidepressants, fluoxetine should be discontinued in any patient entering a manic phase.

Hepatic/Renal Function: Fluoxetine is extensively metabolised by the liver and excreted by the kidneys. A lower dose, e.g., alternate day dosing, is recommended in patients with significant hepatic dysfunction. When given fluoxetine 20mg/day for 2 months, patients with severe renal failure (GFR < 10 ml/min) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function.

Cardiac Disease: No conduction abnormalities that resulted in heart block were observed in the ECG of 312 patients who received fluoxetine in double

Weight Loss: Weight loss may occur in patients taking Fluoxetine but it is usually proportional to baseline body weight.

Diabetes: In patients with diabetes, treatment with an SSRI may alter glycaemic control. Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has developed following discontinuation. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide

Other psychiatric conditions for which Fluoxetine is prescribed can also be associated with an increased risk of suicide

Patients with a history of suicide

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Akathisia/psychomotor restlessness: The use of fluoxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Withdrawal symptoms seen on discontinuation of SSRI treatment: Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation occurred in approximately 60% of patients in both the fluoxetine and placebo groups. Of these adverse events, 17% in the fluoxetine group and 12% in the placebo group were severe in nature.

The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor, and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that fluoxetine should be gradually tapered when discontinuing treatment over a period of at least one to two weeks, according to the patient's needs (see 'Withdrawal symptoms seen on discontinuation of Fluoxetine', section 4.2).

Haemorrhage: There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with SSRIs. Ecchymosis has been reported as an infrequent event during treatment with fluoxetine. Other hemorrhagic manifestations (e.g., gynaecological haemorrhages, gastro intestinal bleedings and other cutaneous or mucous bleedings) have been reported rarely. Caution is advised in patients taking SSRIs, particularly in concomitant use with oral anticoagulants, drugs known to affect platelet function (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCAs, aspirin, NSAIDs) or other drugs that may increase risk of bleeding as well as in patients with a history of bleeding disorders.

Electroconvulsive Therapy (ECT): There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment, therefore caution is advisable.

St John's Wort: An increase in serotonergic effects, such as serotonin syndrome, may occur when selective serotonin reuptake inhibitors and herbal preparations containing St John's Wort (Hypericum perforatum) are used together.

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome

Use in children and adolescents under 18 years of age

Fluoxetine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo.

If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive behavioural development are lacking.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Half

Monoamine oxidase inhibitors: (see 'Contraindications'). Not recommended combinations: MAOI

Combinations requiring precautions for use: MAOI

Phenytoin: Changes in blood levels have been observed when combined with fluoxetine. In some cases manifestations of toxicity have occurred. Consideration should be given to using conservative titration schedules of the concomitant drug and to monitoring clinical status.

Serotonergic drugs: Co

Lithium and tryptophan: There have been reports of serotonin syndrome when SSRIs have been given with lithium or tryptophan and, therefore, the concomitant use of fluoxetine with these drugs should be undertaken with caution. When fluoxetine is used in combination with lithium, closer and more frequent clinical monitoring is required.

CYP2D6 isoenzyme: Because fluoxetine's metabolism (like tricyclic antidepressants and other selective serotonin antidepressants) involves the hepatic cytochrome CYP2D6 isoenzyme system, concomitant therapy with drugs also metabolised by this enzyme system may lead to drug interactions. Concomitant therapy with drugs predominantly metabolised by this isoenzyme, and which have a narrow therapeutic index (such as flecainide, encainide, carbamazepine and tricyclic antidepressants), should be initiated at or adjusted to the low end of their dose range. This will also apply if fluoxetine has been taken in the previous 5 weeks.

Oral anticoagulants: Altered anti

Electroconvulsive Therapy (ECT): There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment, therefore caution is advisable.

Alcohol: In formal testing, fluoxetine did not raise blood alcohol levels or enhance the effects of alcohol. However, the combination of SSRI treatment and alcohol is not advisable.

St. John's Wort: In common with other SSRIs, pharmacodynamic interactions between fluoxetine and the herbal remedy St. John's Wort (Hypericum perforatum) may occur, which may result in an increase of undesirable effects.

4.6 Pregnancy And Lactation

Pregnancy: Data on a large number of exposed pregnancies do not indicate a teratogenic effect of fluoxetine. Fluoxetine can be used during pregnancy, but caution should be exercised, especially during late pregnancy or just prior to the onset of labour since the following effects have been reported in neonates: irritability, tremor, hypotonia, persistent crying, difficulty in sucking or in sleeping. These symptoms may indicate either serotonergic effects or a withdrawal syndrome. The time to occur and the duration of these symptoms may be related to the long half

Epidemiological data have suggested that the use of SSRIs in pregnancy, particular in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

Some epidemiological studies suggest an increased risk of cardiovascular defects associated with the use of fluoxetine during the first trimester. The mechanism is unknown. Overall the data suggest that the risk of having an infant with a cardiovascular defect following maternal fluoxetine exposure is in the region of 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population.

Lactation: Fluoxetine and its metabolite norfluoxetine, are known to be excreted in human breast milk. Adverse events have been reported in breastfeeding infants. If treatment with fluoxetine is considered necessary, discontinuation of breastfeeding should be considered; however, if breastfeeding is continued, the lowest effective dose of fluoxetine should be prescribed.

4.7 Effects On Ability To Drive And Use Machines

Although fluoxetine has been shown not to affect psychomotor performance in healthy volunteers, any psychoactive drug may impair judgement or skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected.

4.8 Undesirable Effects

Undesirable effects may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.

In common with other SSRIs, the following undesirable effects have been seen:

Body as a whole: Hypersensitivity (e.g. pruritus, rash, urticaria, anaphylactoid reaction, vasculitis, serum sickness

Digestive system: Gastrointestinal disorders (e.g. diarrhoea, nausea, vomiting, dyspepsia, dysphagia, taste perversion), dry mouth. Abnormal liver function tests have been reported rarely. Very rare cases of idiosyncratic hepatitis.

Nervous system: Headache, sleep abnormalities (e.g. abnormal dreams, insomnia), dizziness, anorexia, fatigue (e.g. somnolence, drowsiness), euphoria, transient abnormal movement (e.g., twitching, ataxia, tremor, myoclonus), seizures and rarely psychomotor restlessness/akathisia (see section 4.4) and very rarely serotonin syndrome.

Psychiatric disorders: Hallucinations, manic reaction, confusion, agitation, anxiety and associated symptoms (e.g. nervousness), impaired concentration and thought process (e.g. depersonalisation), panic attacks (these symptoms may be due to the underlying disease)

Cases of suicidal ideation and suicidal behaviours have been reported during Fluoxetine therapy or early after treatment discontinuation (see section 4.4).

Urogenital system: Urinary retention, urinary frequency

Reproductive disorders: Sexual dysfunction (delayed or absent ejaculation, anorgasmia), priapism, galactorrhoea.

Miscellaneous: Alopecia, yawn, abnormal vision (e.g., blurred vision, mydriasis), sweating, vasodilatation. arthralgia, myalgia, postural hypotension, ecchymosis. Other haemorrhagic manifestations (e.g., gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings) have been reported rarely (see 'Precautions', Haemorrhage).

Hyponatraemia: Hyponatraemia (including serum sodium below 110 mmol/1) has been rarely reported and appeared to be reversible when fluoxetine was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients, and patients taking diuretics or otherwise volume depleted.

Respiratory system: Pharyngitis, dyspnoea. Pulmonary events (including inflammatory processes of varying histopathology and/or fibrosis) have been reported rarely. Dyspnoea may be the only preceding symptom.

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

Withdrawal symptoms seen on discontinuation of fluoxetine treatments: Discontinuation of fluoxetine commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally, these events are mild to moderate and are self-limiting; however, in some patients they may be severe and/or prolonged (see section 4.4). It is therefore advised that when Fluoxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 and section 4.4).

4.9 Overdose

Cases of overdose of fluoxetine alone usually have a mild course. Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias to cardiac arrest, pulmonary dysfunction, and signs of altered CNS status ranging from excitation to coma. Fatality attributed to overdose of fluoxetine alone has been extremely rare. Cardiac and vital signs monitoring are recommended, along with general symptomatic and supportive measures. No specific antidote is known.

Forced diuresis, dialysis, haemoperfusion, and exchange transfusion are unlikely to be of benefit. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage. In managing overdosage, consider the possibility of multiple drug involvement. An extended time for close medical observation may be needed in patients who have taken excessive quantities of a tricyclic antidepressant if they are also taking, or have recently taken, fluoxetine.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Selective serotonin reuptake inhibitors.

ATC code: N06A B03.

Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism of action. Fluoxetine has practically no affinity to other receptors such as alpha l

Major depressive episodes: Clinical trials in patients with major depressive episodes have been conducted versus placebo and active controls. Fluoxetine has been shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM

Dose response: In the fixed dose studies of patients with major depression there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, it is clinical experience that uptitrating might be beneficial for some patients.

Obsessive

Bulimia nervosa: In short term trials (under 16 weeks), in out

Two placebo

5.2 Pharmacokinetic Properties

Absorption

Fluoxetine is well absorbed from the gastrointestinal tract after oral administration. The bioavailability is not affected by food intake.

Distribution

Fluoxetine is extensively bound to plasma proteins (about 95%) and it is widely distributed (Volume of Distribution: 20

Metabolism

Fluoxetine has a non

Elimination

The elimination half

At

• Elderly: Kinetic parameters are not altered in healthy elderly when compared to younger subjects

• Hepatic insufficiency: In case of hepatic insufficiency (alcoholic cirrhosis), fluoxetine and norfluoxetine half

• Renal insufficiency: After single

5.3 Preclinical Safety Data

There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies.

In a juvenile toxicology study in CD rats, administration of 30mg/kg/day of fluoxetine hydrochloride on postnatal days 21 to 90 resulted in irreversible testicular degeneration and necrosis, epididymal epithelial vacuolation, immaturity and inactivity of the female reproductive tract and decreased fertility. Delays in sexual maturation occurred in males (10 and 30mg/kg/day) and females (30mg/kg/day). The significance of these findings in humans is unknown. Rats administered 30mg/kg also had decreased femur lengths compared with controls and skeletal muscle degeneration, necrosis and regeneration. At 10mg/kg/day, plasma levels achieved in animals were approximately 0.8 to 8.8-fold (fluoxetine) and 3.6 to 23.2-fold (norfluoxetine) those usually observed in paediatric patients. At 3mg/kg/day, plasma levels achieved in animals were approximately 0.04 to 0.5-fold (fluoxetine) and 0.3 to 2.1-fold (norfluoxetine) those usually achieved in paediatric patients.

A study in juvenile mice has indicated that inhibition of the serotonin transporter prevents the accrual of bone formation. This finding would appear to be supported by clinical findings. The reversibility of this effect has not been established.

Another study in juvenile mice (treated on postnatal days 4 to 21) has demonstrated that inhibition of the serotonin transporter had long-lasting effects on the behaviour of the mice. There is no information on whether the effect was reversible. The clinical relevance of this finding has not been established.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The capsule also contains: pregelatinised maize starch, anhydrous colloidal silica, magnesium stearate and talc.

The capsule shell contains: E104, E127, E132, E171 and gelatin.

The printing ink contains: shellac glaze and iron oxide black (E172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25ºC.

6.5 Nature And Contents Of Container

Al/transparent glassclear or white opaque PVC blisters: 14, 20, 28, 30, 50, 60, 90 or 100 capsules/pack

HDPE bottle with snap on cap: 28, 30, 50, 100, 250 or 500 capsules/pack

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0444

9. Date Of First Authorisation/Renewal Of The Authorisation

06 August 1999

Renewed – 10^th January 2010

10. Date Of Revision Of The Text

30/09/2010

Flucloxacillin 500mg Capsules

1. Name Of The Medicinal Product

Flucloxacillin 500mg Capsules BP

2. Qualitative And Quantitative Composition

Flucloxacillin Sodium equivalent to 500mg Flucloxacillin per Capsule.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsules.

Hard gelatin size '0' capsules with Caramel body and Black cap printed with 'FLU500 MIL' and filled with white to almost white granular powder.

4. Clinical Particulars

Flucloxacillin is an isoxazolyl penicillin of the β-lactam group of antibiotics which exerts a bactericidal effect upon many Gram-positive organisms including β-lactamase-producing staphylococci and streptococci

4.1 Therapeutic Indications

Flucloxacillin Sodium is indicated for the treatment of infections due to sensitive Gram-positive organisms including β-lactamase producing staphylococci and streptococci. Typical indications include:

Skin and soft tissue infections:

Boils, cellulitis, infected burns, abscesses, infected skin conditions (e.g. ulcer, eczema, and acne). protection for skin grafts,carbuncles , furunculosis ,infected wounds and impetigo

Respiratory tract infections:

Pneumonia, lung abscess, empyema, sinusitis, pharyngitis, otitis media and externa, tonsillitis and quinsy.

Other infections caused by Flucloxacillin-sensitive organisms:

Osteomyelitis ,urinary tract infection, enteritis ,meningitis,endocarditis and septicaemia

Flucloxacillin sodium is also indicated for use as a prophylactic agent during major surgical procedures when appropriate; for example cardiothoracic and orthopaedic surgery.

Parenteral usage is indicated where oral dosage is inappropriate.

4.2 Posology And Method Of Administration

Depends on the age, weight and renal function of the patient, as well as on the severity of the infection.

Usual adult dosage (including elderly patients)

Oral –250 mg four times a day.

Osteomyelitis, endocarditis - Up to 8 g daily in divided doses six to eight hourly.

Surgical prophylaxis - 1 to 2 g IV at induction of anaesthesia followed by 500 mg six hourly IV, IM or orally for up to 72 hours.

Usual children's dosage:

2-10 years: half adult dose

Under 2 years: quarter adult dose.

Abnormal renal function; In common with other penicillins, flucloxacillin usage in patients with renal impairment does not usually require dosage reduction. However, in the presence of severe renal failure (creatinine clearance <10ml/min) a reduction in dose or an extension of dose interval should be considered. Flucloxacillin is not significantly removed by dialysis and hence no supplementary dosages need to be administered either during, or at the end of the dialysis period.

Administration:

Oral: Oral doses should be administered half to one hour before meals.

4.3 Contraindications

Flucloxacillin should not be given to patients with a history of hypersensitivity to β-lactam antibiotics (e.g. penicillins, cephalosporins) or excipients.

Flucloxacillin is contra-indicated in patients with a previous history of flucloxacillin associated jaundice/hepatic dysfunction.

4.4 Special Warnings And Precautions For Use

Before initiating therapy with flucloxacillin, careful enquiry should be made concerning previous hypersensitivity reactions to β-lactams.

Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving β-lactam antibiotics. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral therapy. These reactions are more likely to occur in individuals with a history of β-lactam hypersensitivity.

Flucloxacillin should be used with caution in patients with evidence of hepatic dysfunction, patients

During prolonged treatments (e.g., osteomyelitis, endocarditis), regular monitoring of hepatic and renal functions is recommended.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

Flucloxacillin capsules contain approximately 51 mg sodium per g. This should be included in the daily allowance of patients on sodium restricted diets.

If anaphylaxis occurs flucloxacillin should be discontinued and the appropriate therapy instituted. Serious anaphylactic reactions may require immediate emergency treatment with adrenaline (epinephrine). Ensure adequate airway and ventilation and give 100% oxygen. IV crystalloids, hydrocortisone, antihistamine and nebulised bronchodilators may also be required.

The use of flucloxacillin (like other penicillins) in patients with renal impairment does not usually require dosage reduction. In the presence of severe renal failure (creatinine clearance less than 10ml/min), however, a reduction in dose or an extension of dose interval should be considered because of the risk of neurotoxicity (see section 4.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Probenecid decreases the renal tubular secretion of flucloxacillin. Concurrent administration of probenecid delays the renal excretion of flucloxacillin.

In common with other antibiotics, flucloxacillin may affect the gut flora, leading to lower oestrogen, reabsorption and reduced efficacy of combined oral contraceptives

4.6 Pregnancy And Lactation

Pregnancy: Animal studies with flucloxacillin have shown no teratogenic effects. The product has been in clinical use since 1970 and the limited number of reported cases of use in human pregnancy have shown no evidence of untoward effects. The decision to administer any drug during pregnancy should be taken with the utmost care. Therefore flucloxacillin should only be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.

Lactation: trace quantities of flucloxacillin can be detected in breast milk. The possibility of hypersensitivity reactions must be considered in breast-feeding infants. Therefore flucloxacillin should only be administered to a breast-feeding mother when the potential benefits outweigh the potential risks associated with the treatment.

4.7 Effects On Ability To Drive And Use Machines

Adverse effects on the ability to drive or operate machinery have not been observed.

4.8 Undesirable Effects

The following convention has been utilised for the classification of undesirable effects:- Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1,000), very rare ( <1/10,000).

Unless otherwise stated, the frequency of the adverse events has been derived from more than 30 years of post-marketing reports.

Blood and lymphatic system disorders

Very rare: Neutropenia (including agranulocytosis) and thrombocytopenia. These are reversible when treatment is discontinued. Haemolytic anaemia.

Immune system disorders

Very rare: Anaphylactic shock (exceptional with oral administration) (see Section 4.4 Special warnings and special precautions for use), angioneurotic oedema.

If any hypersensitivity reaction occurs, the treatment should be discontinued. (See also Skin and subcutaneous tissue disorders).

Gastrointestinal disorders

*Common: Minor gastrointestinal disturbances.

Very rare: Pseudomembranous colitis.

If pseudomembranous colitis develops, flucloxacillin treatment should be discontinued and appropriate therapy, e.g. oral vancomycin should be initiated.

Hepato-biliary disorders

Very rare: Hepatitis and cholestatic jaundice. (See Section 4.4 Special Warnings and Special Precautions for Use). Changes in liver function laboratory test results (reversible when treatment is discontinued).

These reactions are related neither to the dose nor to the route of administration. The onset of these effects may be delayed for up to two months post-treatment; in several cases the course of the reactions has been protracted and lasted for some months. Hepatic events may be severe and in very rare circumstances a fatal outcome has been reported. Most reports of deaths have been in patients

Skin and subcutaneous tissue disorders

*Uncommon: Rash, urticaria and purpura.

Very rare: Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necroylsis.

(See also Immune system disorders).

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia and myalgia sometimes develop more than 48 hours after the start of the treatment.

Renal and urinary disorders

Very rare: Interstitial nephritis.

This is reversible when treatment is discontinued.

General disorders and administration site conditions

Very rare: Fever sometimes develops more than 48 hours after the start of the treatment.

*The incidence of these AEs was derived from clinical studies involving a total of approximately 929 adult and paediatric patients taking flucloxacillin.

4.9 Overdose

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically.

Flucloxacillin is not removed from the circulation by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Beta-Lactamase Resistant Penicillins-ATC code: J01CF05

Properties: Flucloxacillin is a narrow-spectrum antibiotic of the group of isoxazolyl penicillins; it is not inactivated by staphylococcal β-lactamases.

Activity: Flucloxacillin, by its action on the synthesis of the bacterial wall, exerts a bactericidal effect on streptococci except those of group D (Enterococcus faecalis) staphylococci. It is not active against methicillin-resistant staphylococci.

5.2 Pharmacokinetic Properties

Absorption:

.

Flucloxacillin is stable in acid media and can therefore be administered either by the oral or parenteral route. The peak serum levels of flucloxacillin reached after one hour are as follows.

- After 250 mg by the oral route (in fasting subjects): Approximately 8.8 mg/l.

- After 500 mg by the oral route (in fasting subjects): Approximately 14.5 mg/l.

- After 500 mg by the IM route: Approximately 16.5 mg/l.

The total quantity absorbed by the oral route represents approximately 79% of the quantity administered.

Distribution:

Flucloxacillin diffuses well into most tissue. Specifically, active concentrations of flucloxacillin have been recovered in bones: 11.6mg/l (compact bone) and 15.6mg/l (spongy bone), with a mean serum level of 8.9 mg/l.

Crossing the meningeal barrier: Flucloxacillin diffuses in only small proportion into the cerebrospinal fluid of subjects whose meninges are not inflamed. Crossing into mothers' milk: flucloxacillin is excreted in small quantities in mothers' milk.

Metabolism;

In normal subjects approximately 10% of the flucloxacillin administered is metabolised to penicilloic acid. The elimination half-life of flucloxacillin is in the order of 53 minutes.

Excretion:

Excretion occurs mainly through the kidney. Between 65.5%( oral route) and 76.1% (parenteral route) of the dose administered is recovered in unaltered active form in the urine within 8 hours. A small portion of the dose administered is excreted in the bile. The excretion of flucloxacillin is slowed in cases of renal failure.

Protein binding: The serum protein-binding rate is 95%.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Magnesium Stearate (E572)

Colloidal Anhydrous Silica

Capsule Shell Components:

Body:

Red Iron Oxide (E172)

Yellow Iron Oxide (E172)

Titanium Dioxide (E171)

Gelatin

Cap:

Black Iron Oxide (E172)

Titanium Dioxide (E171)

Gelatin

Ink components:

Titanium Dioxide (E171)

Shellac (E904)

Industrial Methylated Spirits

Soya Lecithin

Dimethyl siloxane

Mono and di glycerides of fatty acids (E471)

Methyl cellulose

Polyethylene glycol stearate

Xanthan gum

Benzoic acid

Polyethylene glycol

Sorbic acid

6.2 Incompatibilities

None stated

6.3 Shelf Life

3 years: polypropylene containers

2 years: blister strips

6.4 Special Precautions For Storage

Container: Do not store above 25°C. Store in the original container. Keep tightly closed.

Blister: Do not store above 25°C. Store in the original pack.

6.5 Nature And Contents Of Container

White polypropylene container with polyethylene lid: 14, 28, 100, 250, 500 and 1000 capsules.

Blister Strips: 14, 28 and 100 capsules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Nothing stated

7. Marketing Authorisation Holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0042

9. Date Of First Authorisation/Renewal Of The Authorisation

14 May 2002

10. Date Of Revision Of The Text

24/05/2011

Flotros 20mg film-coated tablets

1. Name Of The Medicinal Product

Flotros 20mg film-coated tablets

2. Qualitative And Quantitative Composition

The active ingredient is trospium chloride. Each film-coated tablet contains:

20 mg of trospium chloride.

Excipients: Each tablet contains 93 mg lactose-monohydrate.

For a full list of excipients see section 6.1

3. Pharmaceutical Form

Film-coated tablet

Round, white film-coated tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder (e.g. idiopathic or neurologic detrusor overactivity).

4.2 Posology And Method Of Administration

1 film-coated tablet twice a day (corresponding to 40 mg of trospium chloride daily).

The film-coated tablet should be taken whole on an empty stomach with a glass of water before meals.

In patients with severe kidney dysfunction (creatinine clearance between 10 and 30 mL/min/1.73 m²) the recommended dose is 1 film-coated tablet once a day or every second day (corresponding to 20 mg of trospium chloride every day or every second day).

The necessity of continuing the treatment should be reassessed at regular intervals of 3 - 6 months.

As no corresponding data is available, the use of this product in children under the age of 12 is not recommended.

4.3 Contraindications

- Flotros 20mg is contraindicated in patients with urinary retention, severe gastrointestinal dysfunctions (including toxic megacolon and severe colitis ulcerosa), myasthenia gravis, narrow-angle glaucoma and tachyarrhythmias.

- Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Flotros 20mg should only be used with caution in patients:

- with obstructions to the gastrointestinal tract, such as pyloric stenosis

- with urinary obstructions, with the risk of formation of residual urine

- with autonomous neuropathy

- with hiatus hernia

- with reflux oesophagitis

- in whom an accelerated pulse rate is undesirable, e.g. patients with hyperthyroidism, coronary diseases and congestive heart failure,

- slight to moderate liver insufficiency,

- with renal insufficiency (trospium chloride is mainly excreted via the kidney. A considerable rise in plasma levels has been observed in patients with severe impairment to kidney function. See section 4.2)

As no results of clinical trials are available with respect to patients with severe liver dysfunction, the treatment of these patients with trospium chloride is discouraged.

Before the beginning of treatment, organic causes of frequency, urgency and urge incontinence, such as heart or kidney diseases, polydipsia or infections and tumours of the urinary organs, should be excluded.

Flotros 20mg contains lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Flotros 20mg.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Pharmacodynamic Interactions:

The following pharmacodynamic interactions may occur:

- Increase in the effect of substances with anticholinergic properties (amantadine, tricyclic antidepressants, quinidine, antihistamines, disopyramide),

- Reinforcement of the tachycardic effect of ß sympathomimetics and

- Weakening of the effect of prokinetics (e.g. metoclopramide, cisapride).

As trospium chloride may influence gastrointestinal motility and secretion, the possibility of changes to the absorption of other medications administered simultaneously cannot be ruled out.

Pharmacokinetic Interactions:

Inhibition of the absorption of trospium chloride by medications containing guar, cholestyramine and colestipol cannot be ruled out. For this reason the simultaneous administration of these medications with trospium chloride is not recommended.

Metabolic interactions of trospium chloride have been investigated in vitro on cytochrome P450 enzymes involved in active substance metabolism (P450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). No effect on their metabolic activity was found. As trospium chloride is only slightly metabolised and ester hydrolysis is the only relevant metabolic route, metabolic interactions are not to be expected.

4.6 Pregnancy And Lactation

For trospium chloride no clinical data on exposed pregnancies are available.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see 5.3).

Caution should be exercised when prescribing to pregnant women.

It is unknown whether trospium chloride is excreted in human breast milk. Animal studies have shown excretion of trospium chloride in breast milk of rats. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Flotros 20mg should be made taking into account the benefit of breast-feeding to the child and the benefit of Flotros 20mg to the woman.

4.7 Effects On Ability To Drive And Use Machines

Disturbance of visual accommodation is the main reason for the impaired ability to operate a motor vehicle or machinery.

However, investigations into other parameters for measuring the ability to drive a motor vehicle (visual orientation, general ability to react, reaction under stress, concentration and motor coordination) have not revealed any negative effects of trospium chloride.

4.8 Undesirable Effects

During treatment with trospium chloride, anticholinergic side effects may occur such as dryness of the mouth, dyspepsia and constipation.

	Very common (	Common (	Uncommon (	Rare (	Very rare (<1/10,000), not known (cannot be estimated from the available data)
Cardiac disorders				tachycardia	tachyarrhythmia
Nervous system disorders					headache, dizziness
Eye disorders				disorders of accommodation (this applies in particular to patients who are hypermetropic and whose vision has not been adequately corrected)
Respiratory, thoracic and mediastinal disorders				dyspnoea
Gastrointestinal disorders	dry mouth	dyspepsia, constipation, abdominal pain, nausea	flatulence, diarrhoea
Renal and urinary disorders				micturition disorders (e.g. formation of residual urine), urinary retention
Skin and subcutaneous tissue disorders				rash	angio-oedema
Musculoskeletal and connective tissue disorders					myalgia, arthralgia
General disorders				asthenia, chest pain	anaphylaxis
Hepatobiliary disorders					mild to moderate increase in serum transaminase levels

4.9 Overdose

After the administration of a maximum individual dose of 360 mg of trospium chloride, excessive dryness of the mouth, tachycardia and micturition problems have been observed in healthy probands. There have been no known cases of severe overdose or intoxication with trospium chloride. The expected symptoms of intoxication with trospium chloride are exacerbated anticholinergic symptoms.

In the case of intoxication, the following measures should be taken:

- Gastrolavage and resorption reduction (e.g. active charcoal)

- Local administration of pilocarpine in glaucoma patients

- Catheterisation in patients with urine retention

- Administration of a parasympathomimetic (e.g. neostigmine) in the case of severe symptoms

- Administration of beta-blockers in cases of insufficient response, pronounced tachycardia and/or circulatory instability (e.g. initially 1 mg of propranolol intravenously with ECG and blood pressure monitoring).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: urological spasmolytic agent, ATC Code G04BD09

Trospium chloride is a quaternary derivative of nortropane and therefore belongs to the class of parasympatholytics or anticholinergics. The substance competes in a concentration-dependent manner with acetylcholine, the body's own transmitter on postsynaptic parasympathic binding sites.

Trospium chloride displays a high level of affinity to muscarinic receptors of the so-called M₁, M₂ and M₃ subtype and binds only to a negligible degree to nicotine receptors.

Consequently, the anticholinergic effect of trospium chloride exerts a relaxing action on smooth muscle tissue and organ functions mediated by muscarinic receptors. Both in preclinical as well as in clinical experiments, trospium chloride diminishes the contractile tone of smooth muscle in the gastrointestinal and genito-urinary tract.

Furthermore, it can inhibit bronchial secretion, the secretion of saliva and sweat, as well as the accommodation ability of the eyes. No central effects have so far been observed.

A long-term study with 20 mg of trospium chloride twice a day showed an increase of QT >60msec in 3/197 (1.5%) of the patients involved in the study. The clinical relevance of this is unclear. The routine determination of cardiac safety in two further placebo-controlled clinical studies lasting three months do not provide any indications of such an effect of trospium chloride: in the first study an increase of QTcF >=60 msec in 4/258 (1.6%) of the patients treated with trospium chloride was observed, in comparison to 9/256 (3.5%)in the placebo group. Comparable figures were also found in the second study with 8/326 (2.5%) in the patients treated with trospium chloride in comparison to 8/325 (2.5%) in the placebo group.

5.2 Pharmacokinetic Properties

After the oral application of trospium chloride the maximum blood level values are reached after 4 - 6 hours.

Following a single dose of 20 mg the maximum plasma level is about 4 ng/mL. Within the tested interval, 20 to 60 mg as a single dose, the plasma levels are proportional to the administered dose. The absolute bioavailability of a single oral dose of 20 mg of trospium chloride is 9.6 ± 4.5% (mean value ± standard deviation). At steady state the intraindividual variability is 16%, the interindividual variability is 36%.

The bioavailability of trospium chloride is reduced by the simultaneous intake of food, particularly food with a high fat content. After a meal that is rich in fat the mean C_max and AUC value falls to 15 - 20 % of the values in a fasting state.

Trospium chloride exhibits diurnal variability in exposure with a decrease of both C_max and AUC for evening relative to morning doses.

Most of the systemically available trospium chloride is excreted unchanged by the kidneys, though a small portion (10 % of the renal excretion) appears in the urine as the spiroalcohol, a metabolite formed by ester hydrolysis. The terminal elimination half-life is in the range of 10-20 hours.

No accumulation occurs. Plasma protein binding is 50 - 80 %.

Pharmacokinetic data do not indicate any significant differences in elderly patients or any differences between the sexes.

In a study conducted on patients with severe impairment to kidney function (creatinine clearance 8 -32 ml/min) the average AUC was increased fourfold and the C_max twofold. In comparison to healthy individuals the half life was extended twofold. There are no known studies that have been conducted on patients with a lesser degree of kidney function impairment.

Pharmacokinetic results of a study with mildly and moderately hepatically impaired patients do not suggest a need for dose adjustment in patients with hepatic impairment, and are consistent with the limited role of hepatic metabolism in the elimination of trospium chloride.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Trospium chloride passes into the placenta and mother's milk in the rat.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core: Silica, colloidal anhydrous Cellulose, microcrystalline Lactose monohydrate Povidone K 25 Sodium starch glycolate (type A) Magnesium stearate   Tablet film: Talc Hypromellose Macrogol 6000 Titanium dioxide (E 171) Saccharin sodium

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

PVC/PVDC/Aluminium blisters

Original packs of 10, 20, 30, 50, 60 and 100 film-coated tablets

Hospital packs of 500 (10 x 50) film-coated tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Galen Limited

Seagoe Industrial Estate

Craigavon

BT63 5UA

UK

8. Marketing Authorisation Number(S)

PL 27827/0025

9. Date Of First Authorisation/Renewal Of The Authorisation

25 November 2008

10. Date Of Revision Of The Text

21 September 2009