Surgam 300mg

1. Name Of The Medicinal Product

Surgam Tablets 300 mg.

2. Qualitative And Quantitative Composition

Each tablet contains 300 mg Tiaprofenic Acid.

3. Pharmaceutical Form

Tablets

4. Clinical Particulars

4.1 Therapeutic Indications

Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, low back pain, musculo-skeletal disorders such as fibrositis, capsulitis, epicondylitis and other soft-tissue inflammatory conditions, sprains and strains, post-operative inflammation and pain and other soft tissue injuries.

4.2 Posology And Method Of Administration

For oral administration.

To be swallowed whole.

To be taken preferably with or after food.

Adults:

600 mg daily in divided doses

300mg twice a day

Alternatively 200mg three times a day

Elderly:

As for adults (see Section 4.4, Special Warnings and Precautions). NSAIDs should be used with particular caution in older patients who are at increased risk of the serious consequences of adverse reactions.

In cases of renal, cardiac or hepatic impairment, the dosage should be kept as low as possible. It is suggested that in such cases, the dosage be reduced to 200 mg twice daily.

If an NSAID is considered necessary, elderly patients should receive the lowest effective dose for the shortest possible duration and be monitored regularly for gastrointestinal bleeding for following initiation of NSAID therapy

Children:

There are insufficient data to recommend use of Surgam in children.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

4.3 Contraindications

- Active or history of recurrent peptic ulcer/hemorrage (two or more distinct episodes of proven ulceration or bleeding).

- History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

- Active bladder or prostatic disease or symptoms.

- History of recurrent urinary tract disorders.

- Hypersensitivity to tiaprofenic acid or to any of the excipients.

- NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.

- During the last trimester of pregnancy (see Section 4.6)

- Severe heart failure, hepatic failure and renal failure (see section 4.4).

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below). Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.

The use of Surgam with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Tiaprofenic acid should be used with caution in:

- patients with chronic renal insufficiency (particularly careful monitoring of renal function is required)

- patients with arterial hypertension and/or heart failure

- elderly subjects as they have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal (see section 4.2)

- patients with a history of hepatic insufficiency

Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Tiaprofenic acid may cause sodium and water retention with oedema. At the start of therapy, urine volume and renal function should be carefully monitored in patients with a history of hypertension, cardiac insufficiency, liver cirrhosis, or nephrotic syndrome, and in patients on diuretics.

Urinary symptoms and cystitis have been reported with tiaprofenic acid and other NSAIDs. Tiaprofenic acid appears to have a greater propensity than other NSAIDs to generate reports of cystitis.Tiaprofenic acid can cause cystitis which may become severe if the treatment is continued after the onset of urinary symptoms. Non-recognition has led to extensive investigations and even surgical intervention, in some patients. If urinary symptoms such as frequency, urgency, dysuria, nocturia or haematuria occur, tiaprofenic acid should be stopped immediately and urinalysis and urine culture performed and complete recovery is the rule. Before starting treatment with tiaprofenic acid, the patient should be asked to inform his/her physician of any urinary symptom, even if the physician is familiar with these symptoms from the patient's medical history (see Adverse Reactions).Patients should be warned about the onset of urinary symptoms which may suggest cystitis and are advised to stop taking the drug and seek medical advice if these occur.

Gastrointestinal bleeding, ulceration and perforation:

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving Surgam, the treatment should be withdrawn.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see section 4.8).

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDSs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Surgam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Impaired female fertility:

The use of Surgam may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Surgam should be considered.

There is a risk of cross-sensitivity among aspirin and NSAIDs, including the group to which tiaprofenic acid belongs. These pseudo-allergic reactions may include rash, urticaria and angioedema or more potentially severe manifestations (e.g. laryngeal oedema, bronchoconstriction and shock). The risk of pseudo-allergic reactions is greater in patients with recurrent rhino-sinusitis, nasal polyposis or chronic urticaria. Asthmatic patients are particularly at risk of dangerous reactions. Therefore tiaprofenic acid must not be administered to patients with a history of asthma.

As NSAIDs can interfere with platelet function, they should be used with caution in patients with intracranial haemorrhage and bleeding diathesis.

Cardiovascular, Renal and Hepatic Impairment:

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3).

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for tiaprofenic acid.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with tiaprofenic acid after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Heparin, Hypoglycaemic agents and Diuretics: Since Surgam is highly protein-bound, it is not recommended for co-administration with other highly protein-bound drugs such as heparin. Modification of the dosage may be necessary with hypoglycaemic agents, phenytoin and diuretics. With oral hypoglycaemic agents, an inhibition of metabolism of sulphonylurea drugs, prolonged half-life and increased risk of hypoglycaemia has been reported.

Anticoagulants and antiplatelet agents: It is considered unsafe to take NSAIDs in combination with anticoagulants (i.e. heparin, warfarin) and platelet aggregation inhibitors (i.e. ticlopidine, clopidogrel) due to increased risk of bleeding. If coadministration is unavoidable, patient should be closely monitored.

Other analgesics including cyclooxygenase-2 selective inhibitors: Concomitant use of Surgam with other NSAIDs (including cyclooxygenase-2 selective inhibitors) and high-dose salicylates should be avoided due to an increased risk of adverse effects, particulary upper gastrointestinal disorders.

Corticosteroids:Caution must be exercised when Surgam is administered with corticosteroids due to increased risk of gastrointestinal ulceration or bleeding.

Cardiac glycosides and sulphonamides: Caution should be exercised when Surgam is administered with cardiac glycosides and sulphonamides. With cardiac glycosides, NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels.

Methotrexate: Concomitant use of Surgam with methotrexate causes a decreased elimination of methotrexate. Concomitant use with high dose methotrexate should be avoided. Use with caution with low dose methotrexate.

Lithium: Decreased elimination of lithium

NSAIDs have been reported to increase steady state plasma levels of lithium and it is, therefore, recommended that these levels are monitored in patients receiving Surgam therapy.

Mifepristone: Aspirin and other NSAIDs should not be used for at least 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Diuretics: Caution must be exercised when Surgam is administered with diuretics: it reduces both the diuretic and antihypertensive effect of diuretics and increase risk of renal impairment and/or hyperkalemia.

Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Caution must be exercised when Surgam is administered with ACE inhibitors and Angiotensin II Receptor Antagonists: Further deterioration of renal function, including possible acute renal failure, in patients with compromised renal function (e.g. dehydrated patients or elderly patients).

The possibility of interaction must be taken into account with:

- Thrombolytics: Increased risk of haemorrhage.

- anti-hypertensives agents (diuretics, beta-blockers, ACE-inhibitors, Angiotensin II Receptor Antagonists): Reduced activity of these drugs. This should be borne in mind in patients with incipient or actual congestive heart failure and/or hypertension.

Selective serotonin reuptake inhibitors (SSRIs): The possibility of interaction must be taken into account with selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

Ciclosporin: The risk of nephrotoxicity may be increased if NSAIDs are given with ciclosporins.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Aminoglycosides or probenecid: Care should also be taken if Surgam is concomitantly administered with aminoglycosides or probenecid. Aminoglycosides may interact with NSAIDs to cause a reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations. A reduction in metabolism and elimination of NSAID and metabolites has been observed with probenecid.

4.6 Pregnancy And Lactation

Pregnancy:

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. Tiaprofenic acid crosses the placental barrier. Although animal studies have not revealed evidence of teratogenicity, safety in human pregnancy and lactation cannot be assumed and, in common with other NSAIDs, Surgam should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

In view of the known effects of NSAIDs on the foetal cardiovascular system (a closure of ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3).

Lactation: The level of Surgam in mother's milk has been studied and the total daily exposure is very small; approximately 0.2% of the administered dose and is unlikely to be of pharmacological significance. Breast feeding or treatment of the mother should be stopped as necessary.

See section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable Effects

Gastrointestinal disorders:

Reported reactions include dyspepsia, nausea, vomiting, abdominal / upper abdominal pain, melaena, haematemesis, anorexia, indigestion, heartburn, disorders of intestinal transit (flatulence, diarrhoea, constipation), gastritis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (See section 4.4). Pancreatitis has been reported very rarely.

Peptic ulcers, occult or active gastrointestinal haemorrhage and perforation have occasionally been reported, particularly in the elderly, and in exceptional case may have been associated with fatalities.

Skin and subcutaneous tissue disorders:

Rash, urticaria, pruritus, purpura, alopecia and erythema multiforme and dermatitis bullous (Stevens-Johnson Syndrome or toxic epidermal necrolysis), photosensitivity reactions have been reported.

Immune system disorders:

Hypersensitivity reactions have been reported following treatment with NSAIDs.

Non-specific allergic reactions,asthma, especially in subjects allergic to aspirin and other NSAIDs, bronchospasm, dyspnoea, angio-oedema, anaphylactic shock has also been reported.

Blood and lymphatic system disorders:

Thrombocytopenia , prolonged bleeding time anemia due to bleeding may occur.

Ear and labyrinth disorders:

Vertigo, dizziness, tinnitus and drowsiness.

Nervous system disorders:

Headaches

Renal and urinary disorders:

- bladder pain, dysuria, and pollakiuria

- hematuria or cystitis may occur

- after continuous, prolonged treatment with tiaprofenic acid in presence of urinary symptoms, inflammatory changes to the urinary tract, sometimes severe, have been observed.

- sodium and water retention (see Section 4.4, Special Warnings and Precautions).

- NSAIDs have been reported to cause nephrotoxicity in various forms. As with other NSAIDs, isolated cases of interstitial nephritis, nephrotic syndrome and renal failure have also been reported with tiaprofenic acid.

Hepatobiliary disorders:

Hepatitis, jaundice.

Investigations:

Abnormal liver function test

Other side-effects that have been reported with NSAIDS but not specifically with Surgam are:

- Nervous system disorders: –, optic neuritis

- Eye disorders: visual disturbances

- Musculoskeletal and connective tissue disorders: paraesthesia

- Psychiatric disorders: depression, confusion, hallucinations

- General disorders and administration site conditions: fatigue, malaise

- Blood and lymphatic system disorders – Neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.

- Nervous disorders: reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting,fever or disorientation (See section 4.4)

Vascular and cardiac disorders:

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

4.9 Overdose

In the event of overdosage with Surgam, supportive and symptomatic therapy is indicated.

a) Symptoms

- Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

b) Therapeutic measure

- Patients should be treated symptomatically as required.

- Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

- Good urine output should be ensured.

- Renal and liver function should be closely monitored.

- Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

- Frequent or prolonged convulsions should be treated with intravenous diazepam.

- Other measures may be indicated by the patient's clinical condition.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Non-steroidal anti-inflammatory drug.

Further Information:

The effects of tiaprofenic acid on articular cartilage have been investigated in in-vitro experiments and in ex-vivo studies using different animal models of arthritis. Ex-vivo experiments on human chondrocyte cultures have also been conducted. In these experiments, tiaprofenic acid, in concentrations equivalent to the therapeutic dose, did not depress the biosynthesis of proteoglycans and did not alter the differentiation of proteoglycans secreted. The degradation of proteoglycan aggregates was inhibited. These results suggest a neutral or possibly beneficial effect of tiaprofenic acid on joint cartilage under experimental conditions. The clinical significance of these findings has been studied in a long term double-blind controlled study, in which tiaprofenic acid did not significantly increase the rate of radiological deterioration of joint space in patients with osteoarthritis of the knee.

5.2 Pharmacokinetic Properties

Single dose studies: Following oral administration (max. at 90mins). Plasma level zero at 24 hours. t½ = 1.5 to 2 hours.

Repeated dose studies: Surgam is rapidly eliminated and there is no accumulation after repeated doses of 600mg/day in divided doses. Steady state after first day. No impairment of absorption in patients with RA undergoing long term therapy. There is no evidence of different pharmacokinetics in the elderly.

Protein Binding = 97 - 98%

Plasma clearance = 6 litres/hour

Elimination = 60% of urine remainder in bile

Metabolites = there two main metabolites which account for about 10% of urinary excretion and have low pharmacological activity. The parent compound is excreted mostly in the form of acylglucuronide.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch, pluronic F68, magnesium stearate and talc.

6.2 Incompatibilities

None known

6.3 Shelf Life

60 months

6.4 Special Precautions For Storage

Store below 25°C. Protect from light.

6.5 Nature And Contents Of Container

Blister packs sealed with aluminium foil in a cardboard carton in packs of 56.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey,

GU1 4YS,

UK

8. Marketing Authorisation Number(S)

04425/0318

9. Date Of First Authorisation/Renewal Of The Authorisation

27 February 2009

10. Date Of Revision Of The Text

16 July 2009

Legal category: POM

Stefluvin XL 80mg Prolonged Release Tablets

1. Name Of The Medicinal Product

Stefluvin XL 80mg Prolonged Release Tablets

2. Qualitative And Quantitative Composition

84.2mg fluvastatin sodium corresponding to 80mg fluvastatin.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Prolonged release tablet.

Stefluvin XL tablets are dark yellow, round, biconvex tablets. 10.1 ± 0.1 mm in diameter and 4.0mm ± 0.2 mm in thickness

4. Clinical Particulars

4.1 Therapeutic Indications

Dyslipidaemia

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

Secondary prevention in coronary heart disease

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

4.2 Posology And Method Of Administration

Adults

Dyslipidaemia

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

Starting and maintenance doses should be individualized according to the baseline LDL-C levels and the treatment goal to be accomplished.

The recommended dosing range is 20 to 80 mg/day. For patients requiring LDL-C reduction to a goal of < 25% a starting dose of 20 mg may be used as one capsule in the evening. For patients requiring LDL-C reduction to a goal of

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

Secondary prevention in coronary heart disease

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

Stefluvin XL is efficacious in monotherapy. When Stefluvin XL is used in combination with cholestyramine or other resins, it should be administered at least 4 hours after the resin to avoid significant interaction due to binding of the drug to the resin. In cases where coadministration with a fibrate or niacin is necessary, the benefit and the risk of concurrent treatment should be carefully considered (for use with fibrates or niacin see section 4.5).

Paediatric population

Children and adolescents with heterozygous familial hypercholesterolaemia

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

The recommended starting dose is one 20 mg (1 capsule fluvastatin 20 mg) . Dose adjustments should be made at 6-week intervals. Doses should be individualised according to baseline LDL-C levels and the recommended goal of therapy to be accomplished. The maximum daily dose administered is 80 mg either as capsules 40 mg twice daily or as one Stefluvin XL 80 mg tablet once daily.

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

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

Renal Impairment

Fluvastatin is cleared by the liver, with less than 6% of the administered dose excreted into the urine. The pharmacokinetics of fluvastatin remains unchanged in patients with mild to severe renal insufficiency. No dose adjustments are therefore necessary in these patients however, due to limited experience with doses>40mg/day in case of severe renal impairment (CrCL <0.5 mL/sec or 30 mL/min), these doses should be initiated with caution.

Hepatic impairment

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

Elderly population

No dose adjustments are necessary in this population.

Method of administration

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

4.3 Contraindications

Stefluvin XL is contraindicated:

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

• in patients with active liver disease, or unexplained, persistent elevations in serum transaminases (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 agents, it is recommended that liver function tests be performed before the initiation of treatment and at 12 weeks following initiation of treatment or elevation in dose and periodically thereafter in all patients. Should an increase in aspartate aminotransferase or alanine aminotransferase exceed 3 times the upper limit of normal and persist, therapy should be discontinued. In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.

Caution should be exercised when Stefluvin XL is administered to patients with a history of liver disease or heavy alcohol ingestion.

Skeletal muscle

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

Creatine kinase measurement

There is no current evidence to require routine monitoring of plasma total 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 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 (> 5xULN), levels should be re-measured within 5 to 7 days later to confirm the results. If CK levels are still significantly elevated (> 5xULN) at baseline, treatment should not be started.

Whilst on treatment

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

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

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

The risk of myopathy has been reported to be increased in patients receiving immunosuppressive agents (including ciclosporin), fibrates, nicotinic acid or erythromycin together with other HMG-CoA reductase inhibitors. Isolated cases of myopathy have been reported post-marketing for concomitant administration of fluvastatin with ciclosporin and fluvastatin with colchicines. Stefluvin XL should be used with caution in patients receiving such concomitant medicine (see section 4.5).

Interstitial lung disease

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

Paediatric population

Children and adolescents with heterozygous familial hypercholesterolaemia

In patients aged <18 years, efficacy and safety have not been studied for treatment periods longer than two years. No data are available about the physical, intellectual and sexual maturation for prolonged treatment period. The long-term efficacy of fluvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. (see section 5.1).

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

Homozygous familial hypercholesterolaemia

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Fibrates and niacin

Concomitant administration of fluvastatin with bezafibrate, gemfibrozil, ciprofibrate or niacin (nicotinic acid) has no clinically relevant effect on the bioavailability of fluvastatin or the other lipid-lowering agent. Since an increased risk of myopathy and/or rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors together with any of these molecules, the benefit and the risk of concurrent treatment should be carefully weighed and these combinations should only be used with caution (see section 4.4).

Colchicines

Myotoxicity, including muscle pain and weakness and rhabdomyolysis, has been reported in isolated cases with concomitant administration of colchicines. The benefit and the risk of concurrent treatment should be carefully weighed and these combinations should only be used with caution (see section 4.4).

Ciclosporin

Studies in renal transplant patients indicate that the bioavailability of fluvastatin (up to 40 mg/day) is not elevated to a clinically significant extent in patients on stable regimens of ciclosporin. The results from another study in which 80 mg fluvastatin was administered to renal transplant patients who were on stable ciclosporin regimen showed that fluvastatin exposure (AUC) and maximum concentration (C_max) were increased 2-fold compared to historical data in healthy subjects. Although these increases in fluvastatin levels were not clinically significant, this combination should be used with caution. Starting and maintenance dose of fluvastatin should be as low as possible when combined with ciclosporin.

Fluvastatin tablets had no effect on the bioavailability of ciclosporin when co-administered.

Warfarin and other coumarin derivatives

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

However, isolated incidences of bleeding episodes and/or increases prothrombin times have been reported very rarely in patients on fluvastatin receiving concomitant warfarin or other coumarin derivatives. It is recommended that prothrombin times are monitored when fluvastatin treatment is initiated, discontinued, or the dosage changes in patients receiving warfarin or other coumarin derivatives.

Rifampicin

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

Oral antidiabetic agents

For patients receiving oral sulfonylureas (glibenclamide (glyburide), tolbutamide) for the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), addition of fluvastatin does not lead to clinically significant changes in glycaemic control. In glibenclamide-treated NIDDM patients (n=32), administration of fluvastatin (40 mg twice daily for 14 days) increased the mean C_max, AUC, and t_1/2 of glibenclamide by approximately 50%, 69%, and 121%, respectively. Glibenclamide (5 to 20 mg daily) increased the mean C_max and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in glucose, insulin, and C-peptide levels. However, patients on concomitant therapy with glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 80 mg per day.

Bile acid sequestrants

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

Fluconazole

Administration of fluvastatin to healthy volunteers pre-treated with fluconazole (CYP 2C9 inhibitor) resulted in an increase in the exposure and peak concentration of fluvastatin by about 84% and 44%. Although there was no clinical evidence that the safety profile of fluvastatin was altered in patients pre-treated with fluconazole for 4 days, caution should be exercised when fluvastatin is administered concomitantly with fluconazole.

Histamine H2-receptor antagonists and proton pump inhibitors

Concomitant administration of fluvastatin with cimetidine, ranitidine or omeprazole results in an increase in the bioavailability of fluvastatin, which, however, is of no clinical relevance.

Phenytoin

The overall magnitude of the changes in phenytoin pharmacokinetics during co-administration with fluvastatin is relatively small and not clinically significant. Thus routine monitoring of phenytoin plasma levels is sufficient during co-administration with fluvastatin.

Cardiovasular agents

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

Itraconazole and erythromycin

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

Grapefruit juice

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

4.6 Pregnancy And Lactation

Pregnancy

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

Since HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly of other biologically active substances derived from cholesterol, they may cause foetal harm when administered to pregnant women. Therefore, fluvastatin is contraindicated during pregnancy (see section 4.3).

Women of childbearing potential have to use effective contraception.

If a patient becomes pregnant while taking fluvastatin, therapy should be discontinued.

Lactation

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

Fluvastatin is contraindicated in breastfeeding women.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

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

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Table 1 Adverse reactions

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

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares

• Memory loss

• Sexual dysfunction

• Depression

• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

Paediatric population

Children and adolescents with heterozygous familial hypercholesterolaemia

The safety profile of fluvastatin in children and adolescents heterozygous familial hypercholesterolaemia assessed in 114 patients aged 9-17 years treated in two open-label non-comparative clinical trials was similar to the one observed in adults. In both clinical trials no effect was observed on growth and sexual maturation. The ability of the trials to detect any effect of treatment in this area was however low.

Laboratory Findings

Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid-lowering agents. Based on pooled analyses of controlled clinical trials confirmed elevations of alanine aminotransferase or aspartate aminotranferase levels to more than 3 times the upper limit of normal occurred in 0.2% on fluvastatin capsules 20 mg/day, 1.5% to 1.8% on fluvastatin capsules 40 mg/day, 1.9% on fluvastatin 80 mg/day and in 2.7% to 4.9% on twice daily fluvastatin capsules 40 mg. The majority of patients with these abnormal biochemical findings were asymptomatic. Marked elevations of CK levels to more than 5x ULN developed in a very small number of patients (0.3 to 1.0%).

4.9 Overdose

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

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors

ATC code: C10AA04

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.

Fluvastatin reduces total-C, LDL-C, Apo B, and triglycerides, and increases HDL-C in patients with hypercholesterolaemia and mixed dyslipidaemia.

In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoproteinaemia, fluvastatin alone was administered to 1,621 patients in daily dose regimens of 20 mg, 40 mg and 80 mg (40 mg twice daily) for at least 6 weeks duration. In a 24-week analysis, daily doses of 20 mg, 40 mg and 80 mg produced dose-related reductions in total-C, LDL-C, Apo B and in triglycerides and increases in HDL-C (see Table 2).

Fluvastatin 80 mg was administered to over 800 patients in three pivotal trials of 24 weeks active treatment duration and compared to fluvastatin 40 mg once or twice daily. Given as a single daily dose of 80 mg, fluvastatin significantly reduced total-C, LDL-C, triglycerides (TG) and Apo B (see Table 2).

Therapeutic response is well established within two weeks, and a maximum response is achieved within four weeks. After four weeks of therapy, the median decrease in LDL-C was 38% and at week 24 (endpoint) the median LDL-C decrease was 35 %. Significant increases in HDL-C were also observed.

Table 2 Median percent change in lipid parameters from baseline to week 24

Placebo-controlled studies (fluvastatin 20 mg, 40 mg) and active-controlled trials (fluvastatin 80 mg)

	Total-C	TG	LDL-C	Apo-B	HDL-C
Dose	N	% Δ	N	% Δ	N	% Δ	N	% Δ	N	% Δ
All patients
Fluvastatin 20 mg1	747	-17	747	-12	747	-22	114	-19	747	+3
Fluvastatin 40 mg1	748	-19	748	-14	748	-25	125	-18	748	+4
Fluvastatin 40 mg twice daily1	257	-27	257	-18	257	-36	232	-28	257	+6
Fluvastatin 80 mg2	750	-25	750	-19	748	-35	745	-27	750	+7
Baseline TG
Fluvastatin 20 mg1	148	-16	148	-17	148	-22	23	-19	148	+6
Fluvastatin 40 mg1	179	-18	179	-20	179	-24	27	-18	179	7
Fluvastatin 40 mg twice daily1	76	-27	76	-23	76	-35	69	-28	76	+9
Fluvastatin 80 mg2	239	-25	239	-25	237	-33	235	-27	239	+11

¹Data for fluvastatin from 12 placebo-controlled trials

²Data for fluvastatin 80 mg tablet from three 24-week controlled trials.

In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of fluvastatin on coronary atherosclerosis was assessed by quantitative coronary angiography in male and female patients (35 to 75 years old) with coronary artery disease and baseline LDL-C levels of 3.0 to 4.9 mmol/l (115 to 190 mg/dl). In this randomised, double-blind, controlled clinical study, 429 patients were treated with either fluvastatin 40 mg/day or placebo. Quantitative coronary angiograms were evaluated at baseline and after 2.5 years of treatment and were evaluable in 340 out of 429 patients. Fluvastatin treatment slowed the progression of coronary atherosclerosis lesions by 0.072 mm (95% confidence intervals for treatment difference from -0.1222 to -0.022 mm) over 2.5 years as measured by change in minimum lumen diameter (fluvastatin -0.028 mm vs. placebo -0.100 mm). No direct correlation between the angiographic findings and the risk of cardiovascular events has been demonstrated.

In the Fluvastatin Intervention Prevention Study (LIPS), the effect of fluvastatin on major adverse cardiac events (MACE; i.e. cardiac death, non-fatal myocardial infarction and coronary revascularisation) was assessed in patients with coronary heart disease who had first successful percutaneous coronary intervention. The study included male and female patients (18 to 80 years old) and with baseline total-C levels ranging from 3.5-7.0mmol/L (135 to 270 mg/dl).

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). The primary endpoint of MACE occurred in 21.4 % of patients treated with fluvastatin vs 26.7 % of patients treated with placebo (absolute risk difference: 5.2 %; 95 % CI: 1.1 to 9.3). These beneficial effects were particularly noteworthy in patiens with diabetes mellitus and in patiens with multivessel disease.

Paediatric population

Children and adolescents with heterozygous familial hypercholesterolaemia

The safety and efficacy of fluvastatin in children and adolescent patients aged 9-16 years of age with heterozygous familial hypercholesterolaemia has been evaluated in 2 openlabel, uncontrolled clinical trials of 2 years' duration. 114 patients (66 boys and 48 girls) were treated with fluvastatin administered as either fluvastatin capsules (20 mg/day to 40 mg twice daily) or fluvastatin 80 mg prolonged-release tablets once daily using a dose-titration regimen based upon LDL-C response.

The first study enrolled 29 pre-pubertal boys, 9-12 years of age, who had an LDL-C level> 90^th percentile for age and one parent with primary hypercholesterolaemia and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226mg/dL equivalent to 5.8 mmol/L (range: 137–354mg/dL equivalent to 3.6–9.2 mmol/L). All patients were started on fluvastatin capsules 20mg daily with dose adjustments every 6 weeks to 40mg daily then 80mg daily (40mg twice daily) to achieve an LDL-C goal of 96.7 to 123.7mg/dL (2.5mmol/L to 3.2 mmol/L).

The second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C> 190mg/dL (equivalent to 4.9mmol/L) or LDL-C > 160 mg/dL (equivalent to 4.1mmol/L) and one or more risk factors for coronary heart disease, or LDL-C > 160mg/dL (equivalent to 4.1mmol/L) and a proven LDL-receptor defect. The mean baseline LDL-C was 225mg/dL equivalent to 5.8 mmol/L (range: 148–343mg/dL equivalent to 3.8–8.9mmol/L). All patients were started on fluvastatin capsules 20mg daily with dose adjustments every 6 weeks to 40mg daily then 80mg daily (fluvastatin 80mg prolonged release tablet) to achieve an LDL-C goal of < 130mg/dL (3.4mmol/L). 70 patients were pubertal or postpubertal (n=69 evaluated for efficacy).

In the first study (in prepubertal boys), fluvastatin 20 to 80mg daily doses decreased plasma levels of total-C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161mg/dL equivalent to 4.2mmol/L (range: 74–336mg/dL equivalent 1.9– 8.7mmol/L). In the second study (in pubertal or postpubertal girls and boys), fluvastatin 20 to 80mg daily doses decreased plasma levels of total-C and LDL-C by 22% and 28% respectively. The mean achieved LDL-C was 159mg/dL equivalent to 4.1mmol/L (range: 90–295mg/dL equivalent to 2.3–7.6mmol/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 80mg. At study endpoint, 26 to 30% of patients in both studies achieved a targeted LDL-C goal of < 130mg/dL (3.4mmol/L).

5.2 Pharmacokinetic Properties

Absorption

Fluvastatin is absorbed rapidly and completely (98%) after oral administration of a solution to fasted volunteers. After oral administration of fluvastatin prolonged-release tablets, and in comparison with the capsules, the absorption rate of fluvastatin is almost 60% slower while the mean residence time of fluvastatin is increased by approximately 4 hours. In a fed state, the substance is absorbed at a reduced rate,

Distribution

Fluvastatin exerts its main effect in the liver, which is also the main organ for its metabolism. The absolute bioavailability assessed from systemic blood concentrations is 24%. The apparent volume of distribution (Vz/f) for the drug is 330 litres. 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 or glyburide.

Biotransformation

Fluvastatin is mainly metabolised 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. There are multiple, alternative cytochrome P450 (CYP450) pathways for fluvastatin biotransformation and thus fluvastatin metabolism is relatively insensitive to CYP450 inhibition.

Fluvastatin inhibited only the metabolism of compounds that are metabolised 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 (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 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 presystemic metabolism, the potential exists for drug accumulation in patients with hepatic insufficiency (see sections 4.3 and 4.4).

Children and adolescents with heterozygous familial hypercholesterolaemia

No pharmacokinetic data in children are available.

5.3 Preclinical Safety Data

The conventional studies, including safety pharmacology, genotoxicity, repeated dose toxicity, carcinogenicity and toxicity on reproduction studies did not indicate other risks for the patient than those expected due to the pharmacological mechanism of action. A variety of changes were identified in toxicity studies that are common to HMG-CoA reductase inhibitors. Based on clinical observations, liver function tests are already recommended (see section 4.4). Further toxicity seen in animals was either not relevant for human use or occurred at exposure levels sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Despite the theoretical considerations concerning the role of cholesterol in embryo development, animal studies did not suggest an embryotoxic and teratogenic potential of fluvastatin.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core

Carrageenan

Magnesium stearate

Film-coating

Hydroxypropyl cellulose

Hypromellose 6cP

Iron oxide yellow

Titanium dioxide

Macrogol 8000

Iron oxi

Amoxicilina Clav Ardineclav

Amoxicilina Clav Ardineclav may be available in the countries listed below.

Ingredient matches for Amoxicilina Clav Ardineclav

Clavulanate

Clavulanic Acid potassium (a derivative of Clavulanic Acid) is reported as an ingredient of Amoxicilina Clav Ardineclav in the following countries:

• Spain

International Drug Name Search

Solian 100mg Tablets

1. Name Of The Medicinal Product

SOLIAN 100

2. Qualitative And Quantitative Composition

Amisulpride 100 mg per tablet

For excipients, see 6.1.

3. Pharmaceutical Form

Tablet

White to off-white, round, flat-faced tablet engraved AMI 100 on one face and with a breakable bar on the other face.

4. Clinical Particulars

4.1 Therapeutic Indications

Solian is indicated for the treatment of acute and chronic schizophrenic disorders, in which positive symptoms (such as delusions, hallucinations, thought disorders) and/or negative symptoms (such as blunted affect, emotional and social withdrawal) are prominent, including patients characterised by predominant negative symptoms.

4.2 Posology And Method Of Administration

For acute psychotic episodes, oral doses between 400 mg/d and 800 mg/d are recommended. In individual cases, the daily dose may be increased up to 1200 mg/d. Doses above 1200 mg/d have not been extensively evaluated for safety and therefore should not be used. No specific titration is required when initiating the treatment with Solian. Doses should be adjusted according to individual response.

For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms.

Maintenance treatment should be established individually with the minimally effective dose.

For patients characterised by predominant negative symptoms, oral doses between 50 mg/d and 300 mg/d are recommended. Doses should be adjusted individually.

Solian can be administered once daily at oral doses up to 300 mg, higher doses should be administered bid.

The minimum effective dose should be used.

Elderly: Solian should be used with particular caution because of a possible risk of hypotension or sedation.

Children: The efficacy and safety of amisulpiride from puberty to the age of 18 years have not been established. There are limited data available on the use of amisulpiride in adolescents in schizophrenia. Therefore, the use of amisulpiride from puberty to the age of 18 years is not recommended; in children up to puberty amisulpiride is contraindicated (see Section 4.3).

Renal insufficiency: Solian is eliminated by the renal route. In renal insufficiency, the dose should be reduced to half in patients with creatinine clearance (CR_CL) between 30-60 ml/min and to a third in patients with CR_CL between 10-30 ml/min.

As there is no experience in patients with severe renal impairment (CR_CL < 10 ml/min) particular care is recommended in these patients (see Section 4.4).

Hepatic insufficiency: since the drug is weakly metabolised a dosage reduction should not be necessary.

4.3 Contraindications

Hypersensitivity to the active ingredient or to other ingredients of the medicinal product

Concomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas or breast cancer

Phaeochromocytoma

Children before the onset of puberty

Lactation

Combination with levodopa (see Section 4.5)

4.4 Special Warnings And Precautions For Use

As with other neuroleptics, Neuroleptic Malignant Syndrome, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK, may occur. In the event of hyperthermia, particularly with high daily doses, all antipsychotic drugs including Solian should be discontinued.

Hyperglycaemia has been reported in patients treated with some atypical antipsychotic agents, including amisulpride, therefore patients with an established diagnosis of diabetes mellitus or with risk factors for diabetes who are started on amisulpride, should get appropriate glycaemic monitoring.

Solian is eliminated by the renal route. In cases of renal insufficiency, the dose should be decreased or intermittent treatment could be considered (see Section 4.2).

Solian may lower the seizure threshold. Therefore patients with a history of epilepsy should be closely monitored during Solian therapy.

In elderly patients, Solian, like other neuroleptics, should be used with particular caution because of a possible risk of hypotension or sedation.

As with other antidopaminergic agents, caution should be also exercised when prescribing Solian to patients with Parkinson's disease since it may cause worsening of the disease. Solian should be used only if neuroleptic treatment cannot be avoided.

Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.

Prolongation of the QT interval

Caution should be exercised when amisulpride is prescribed in patients with known cardiovascular disease or family history of QT prolongation.

Concomitant antipsychotics should be avoided.

Stroke:

In randomized clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic drugs, or other populations of patients cannot be excluded. Solian should be used with caution in patients with stroke risk factors.

Increased Mortality in Elderly people with Dementia:

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Solian is not licensed for the treatment of dementia-related behavioural disturbances.

Venous thromboembolism:

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Solian and preventive measures undertaken.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

COMBINATIONS WHICH ARE CONTRAINDICATED

Levodopa : reciprocal antagonism of effects between levodopa and neuroleptics.

COMBINATIONS WHICH ARE NOT RECOMMENDED

Solian may enhance the central effects of alcohol.

COMBINATIONS TO BE TAKEN INTO ACCOUNT

CNS depressants including narcotics, anaesthetics, analgesics, sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytic drugs, clonidine and derivatives

Antihypertensive drugs and other hypotensive medications

Caution is advised when prescribing amisulpride with medicines known to prolong the QT interval, e.g., class IA antiarrythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g. amiodarone, sotalol), some antihistaminics, some other antipsychotics and antimalarials (e.g., mefloquine) (see Section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

In animals, Solian did not show reproductive toxicity. A decrease in fertility linked to the pharmacological effects of the drug (prolactin mediated effect) was observed. No teratogenic effects of Solian were noted.

Very limited clinical data on exposed pregnancies are available. Therefore, the safety of Solian during human pregnancy has not been established.

Use of the drug is not recommended during pregnancy unless the benefits justify the potential risks. If amisulpride is used during pregnancy, neonates may show adverse effects of amisulpride and thus appropriate monitoring should be considered.

For women of childbearing potential, effective contraception should be fully discussed with the physician prior to treatment.

Neonates exposed to antipsychotics (including Solian) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Lactation

It is not known whether Solian is excreted in breast milk, breast-feeding is therefore contra-indicated.

4.7 Effects On Ability To Drive And Use Machines

Even used as recommended, Solian may cause somnolence so that the ability to drive vehicles or operate machinery can be impaired (see Section 4.8 Undesirable effects).

4.8 Undesirable Effects

Adverse effects have been ranked under headings of frequency 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); frequency not known (cannot be estimated from the available data).

Clinical trials data

The following adverse effects have been observed in controlled clinical trials. It should be noted that in some instances it can be difficult to differentiate adverse events from symptoms of the underlying disease.

• Nervous system disorders:

Very common: Extrapyramidal symptoms may occur: tremor, rigidity, hypokinesia, hypersalivation, akathisia, dyskinesia. These symptoms are generally mild at optimal dosages and partially reversible without discontinuation of amisulpride upon administration of antiparkinsonian medication. The incidence of extrapyramidal symptoms which is dose related, remains very low in the treatment of patients with predominantly negative symptoms with doses of 50-300 mg/day.

Common: Acute dystonia (spasm torticollis, oculogyric crisis, trismus) may appear. This is reversible without discontinuation of amisulpride upon treatment with an antiparkinsonian agent. Somnolence.

Uncommon: Tardive dyskinesia characterized by rhythmic, involuntary movements primarily of the tongue and/or face have been reported, usually after long term administration. Antiparkinsonian medication is ineffective or may induce aggravation of the symptoms. Seizures.

• Psychiatric disorders:

Common: Insomnia, anxiety, agitation, orgasmic dysfunction

• Gastrointestinal disorders

Common: Constipation, nausea, vomiting, dry mouth

• Endocrine disorders:

Common: Amisulpride causes an increase in plasma prolactin levels which is reversible after drug discontinuation. This may result in galactorrhoea, amenorrhoea, gynaecomastia, breast pain, and erectile dysfunction.

• Metabolism and nutrition disorders

Uncommon: Hyperglycemia (see Section 4.4).

• Cardiovascular disorders

Common: Hypotension

Uncommon: Bradycardia

• Investigations:

Common: Weight gain

Uncommon: Elevations of hepatic enzymes, mainly transaminases

• Immune system disorders

Uncommon: Allergic reaction

Post Marketing data

In addition, cases of the following adverse reactions have been reported through spontaneous reporting only:

• Nervous system disorders:

Frequency not known: Neuroleptic Malignant Syndrome (see Section 4.4).

• Cardiac disorders:

Frequency not known: QT interval prolongation and ventricular arrhythmias such as torsade de pointes, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest, sudden death (see Section 4.4).

• Vascular disorders:

Frequency not known: Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs.

• Skin and subcutaneous tissue disorders:

Frequency not known: Angioedema, urticaria

• Pregnancy, puerperium and perinatal conditions:

Frequency not known: Drug withdrawal syndrome neonatal (see section 4.6)

4.9 Overdose

Experience with Solian in overdosage is limited. Exaggeration of the known pharmacological effects of the drug have been reported. These include drowsiness and sedation, coma, hypotension and extrapyramidal symptoms. Fatal outcomes have been reported mainly in combination with other psychotropic agents.

In cases of acute overdosage, the possibility of multiple drug intake should be considered.

Since Solian is weakly dialysed, hemodialysis is of no use to eliminate the drug.

There is no specific antidote to Solian.

Appropriate supportive measures should therefore be instituted with close supervision of vital functions including continuous cardiac monitoring due to the risk of prolongation of the QT interval until the patient recovers.

If severe extrapyramidal symptoms occur, anticholinergic agents should be administered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antipsychotics, ATC code N05A L05

Amisulpride binds selectively with a high affinity to human dopaminergic D₂/D₃ receptor subtypes whereas it is devoid of affinity for D₁, D₄ and D₅ receptor subtypes.

Unlike classical and atypical neuroleptics, amisulpride has no affinity for serotonin, ₁ and cholinergic receptors. In addition, amisulpride does not bind to sigma sites.

In animal studies, at high doses, amisulpride blocks dopamine receptors located in the limbic structures in preference to those in the striatum.

At low doses it preferentially blocks pre-synaptic D₂/D₃ receptors, producing dopamine release responsible for its disinhibitory effects.

This pharmacological profile explains the clinical efficacy of Solian against both negative and positive symptoms of schizophrenia.

5.2 Pharmacokinetic Properties

In man, amisulpride shows two absorption peaks: one which is attained rapidly, one hour post-dose and a second between 3 and 4 hours after administration. Corresponding plasma concentrations are 39 ± 3 and 54 ± 4 ng/ml after a 50 mg dose.

The volume of distribution is 5.8 l/kg, plasma protein binding is low (16%) and no drug interactions are suspected.

Absolute bioavailability is 48%. Amisulpride is weakly metabolised: two inactive metabolites, accounting for approximately 4% of the dose, have been identified. There is no accumulation of amisulpride and its pharmacokinetics remain unchanged after the administration of repeated doses. The elimination half-life of amisulpride is approximately 12 hours after an oral dose.

Amisulpride is eliminated unchanged in the urine. Fifty percent of an intravenous dose is excreted via the urine, of which 90% is eliminated in the first 24 hours. Renal clearance is in the order of 20 l/h or 330 ml/min.

A carbohydrate rich meal (containing 68% fluids) significantly decreases the AUCs, Tmax and Cmax of amisulpride but no changes were seen after a high fat meal. However, the significance of these findings in routine clinical use is not known.

Hepatic insufficiency: since the drug is weakly metabolised a dosage reduction should not be necessary in patients with hepatic insufficiency.

Renal insufficiency: The elimination half-life is unchanged in patients with renal insufficiency while systemic clearance is reduced by a factor of 2.5 to 3. The AUC of amisulpride in mild renal failure increased two fold and almost tenfold in moderate renal failure (see chapter 4.2). Experience is however limited and there is no data with doses greater than 50 mg.

Amisulpride is very weakly dialysed.

Limited pharmacokinetic data in elderly subjects (> 65 years) show that a 10-30 % rise occurs in Cmax, T1/2 and AUC after a single oral dose of 50 mg. No data are available after repeat dosing.

5.3 Preclinical Safety Data

An overall review of the completed safety studies indicates that Solian is devoid of any general, organ-specific, teratogenic, mutagenic or carcinogenic risk. Changes observed in rats and dogs at doses below the maximum tolerated dose are either pharmacological effects or are devoid of major toxicological significance under these conditions. Compared with the maximum recommended dosages in man, maximum tolerated doses are 2 and 7 times greater in the rat (200 mg/kg/d) and dog (120 mg/kg/d) respectively in terms of AUC. No carcinogenic risk, relevant to man, was identified in the rat at up to 1.5 to 4.5 times the expected human AUC.

A mouse carcinogenicity study (120 mg/kg/d) and reproductive studies (160, 300 and 500 mg/kg/d respectively in rat, rabbit and mouse) were performed. The exposure of the animals to amisulpride during these latter studies was not evaluated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium starch glycolate, lactose monohydrate, microcrystalline cellulose, hypromellose, magnesium stearate.

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

No special precautions.

6.5 Nature And Contents Of Container

PVC/aluminium foil blister packs containing 60 tablets

6.6 Special Precautions For Disposal And Other Handling

No special precautions

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0651

9. Date Of First Authorisation/Renewal Of The Authorisation

7 February 2009

10. Date Of Revision Of The Text

7 November 2011

LEGAL STATUS

POM