Diclovol^® 50mg tablets or Diclofenac Sodium 50mg tablets

The active substance is sodium- [o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate (= diclofenac sodium).

Each tablet contains 50mg diclofenac sodium.

Light brown, round, bioconvex, plain, film coated, gastro-resistant tablets.

Adults and Elderly:

Relief of all grades of pain and inflammation in a wide range of conditions including:

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

Route of administration: Oral

Adults: 75-150 mg daily in two or three divided doses after meals. The recommended maximum daily dose of diclofenac sodium is 150mg.

Children (aged 1-12 years): 1-3mg/kg per day in divided doses.

Elderly: Although the pharmacokinetics of diclofenac sodium are not impaired to any clinically relevant extent in elderly patients, non-steroidal anti-inflammatory drugs should be used with particular caution in such patients who are generally more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also Precautions) and the patient should be monitored for GI bleeding during NSAID therapy.

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

• Patients who have previously shown hypersensitivity reactions (e.g. asthma, angioedema, urticaria or acute rhinitis) to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.

• Patients with a history of, or active, gastro-intestinal ulcers, bleeding or perforation (two or more distinct episodes of proven ulceration or bleeding).

• Severe hepatic, renal and heart failure (see section 4.4 Special warnings and precautions for use).

• During the last trimester of pregnancy.

• History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy.

• Acute porphyria.

Warnings:

In all patients: Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 Posology and method of administration and GI and cardiovascular risks below).

The use of diclofenac with concomitant NSAIDs including cyclo-oxygenase-2-selective inhibitors should be avoided (see section 4.5 Interactions with other medicaments and other forms of interaction).

Elderly: The elderly have increased frequency of adverse reactions to NSAIDs especially to gastrointestinal bleeding and perforation which may be fatal (see section 4.2 Posology and method of administration).

Gastro-intestinal: Close medical surveillance is imperative in patients with symptoms indicative of gastro-intestinal disorders, with a history suggestive of gastro-intestinal ulceration, with ulcerative colitis or with Crohn's disease as these conditions may be exacerbated (see section 4.8 Undesirable effects).

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

Gastro-intestinal bleeding or ulceration/perforation: Haematemesis, melaena, ulceration or perforation which can be fatal has been reported with all NSAIDs. They can occur at any time during treatment with or without warning symptoms or a previous history of serious GI events. In the rare instances where gastro-intestinal bleeding or ulceration occurs in patients receiving diclofenac sodium the drug should be withdrawn.

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 Contraindications), 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 Interactions with other medicaments and other forms of interaction).

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as aspirin (see section 4.5 Interaction with other medicaments and other forms of interaction).

Hepatic: Close medical surveillance is also imperative in patients suffering from impairment of hepatic function.

Hypersensitivity reactions: As with other non-steroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug (see Section 4.8 Undesirable effects).

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (ie nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions with NSAIDs such as exacerbation of asthma (so called intolerance to analgesics / analgesics-asthma), Quincke's oedema (angioedema) or urticaria are more frequent than in other patients. Therefore special precautions are recommended in such patients (readiness for emergency). This is also applicable to patients who are allergic to other substances, for example those with skin reactions, pruritis or urticaria.

As with other NSAIDs, diclofenac sodium may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Precautions:

Renal: Patients with renal, cardiac or hepatic impairment, a history of hypertension and the elderly, should be kept under surveillance, since the use of NSAIDs may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored.

The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, those being treated with diuretics or other products that can significantly impact renal function, or those recovering from major surgery. Effects on renal function are usually reversible on withdrawal of diclofenac sodium.

Long-term treatment: All patients who are receiving non-steroidal anti-inflammatory agents should be monitored as a precautionary measure e.g. renal function, hepatic function (elevation of liver enzymes may occur) and blood counts. This is particularly important in the elderly.

Hepatic: If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), diclofenac sodium should be discontinued. Hepatitis may occur without prodromal symptoms.

Use of diclofenac sodium in patients with hepatic porphyria may trigger an attack. Use in acute porphyria is contraindicated.

Haematological: Diclofenac sodium may reversibly inhibit platelet aggregation (see anticoagulants in Section 4.5 Interaction with other medicaments and other forms of interactions). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Respiratory disorders: Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of, bronchial asthma.

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 diclofenac, particularly at high doses (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

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

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 NSAIDs, including diclofenac (see section 4.8 Undesirable effects). Patients appear to be at the 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. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

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

Lithium: Diclofenac sodium may increase plasma concentrations of lithium.

Anticoagulants: Although clinical investigations do not appear to indicate that diclofenac sodium has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage with the combined use of diclofenac and anticoagulant therapy. Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other non-steroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.

Antidiabetic agents: Clinical studies have shown that diclofenac sodium can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects which have required adjustment to the dosage of hypoglycaemic agents.

Ciclosporin and tacrolimus: Cases of nephrotoxicity have been reported in patients receiving concomitant ciclosporin and NSAIDs, including diclofenac sodium. Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through combined renal anti-prostaglandin effects of both the NSAID and calcineurin inhibitor.

Methotrexate: Cases of serious toxicity have been reported when methotrexate and NSAIDs are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.

Quinolone antimicrobials: Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients already receiving an NSAID.

Other NSAIDs including cyclo-oxygenase-2 selective inhibitors and corticosteroids: Co-administration of diclofenac sodium with these agents may increase the risk of gastro-intestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4 Special warnings and precautions for use).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).

Diuretics: Like other NSAIDs, diclofenac sodium may inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently.

Antihypertensives: Concomitant use of NSAIDs with antihypertensive drugs (i.e. beta-blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics) may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.

Baclofen: NSAIDs possibly reduce excretion of baclofen (increased risk of toxicity).

Drospirenone: Risk of hyperkalaemia when given with drospirenone (monitor serum potassium during first cycle).

Ketorolac: Increased side effects and haemorrhage if used with NSAIDs.

Penicillamine: Possible increased risk of nephrotoxicity.

Erlotinib, iloprost, pentoxifylline, sibutramine, venlafaxine: Possible increased risk of bleeding.

Phenytoin: NSAIDS possibly enhance effects of phenytoin.

Ritonavir: Plasma concentration of NSAIDs possibly increased by ritonavir.

Zidovudine: Increased risk of haematological toxicity when NSAIDs given with zidovudine.

Pregnancy

Congenital abnormalities have been reported in association with the administration of NSAIDs in man, however, these are low in frequency and do not appear to follow any discernible pattern.

In view of the known effects of NSAIDs on the foetal cardiovascular system (e.g. a premature closure of the ductus arteriosus) and in causing uterine inertia, 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 Contraindications). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit outweighs the potential risk to foetus. The lowest effective dose should be used and duration kept as short as possible.

Lactation

Following doses of 50mg enteric coated tablets every 8 hours, traces of active substance have been detected in breast milk, but in quantities so small that no adverse effects on the breast fed infant are to be expected.

NSAIDs should if possible be avoided when breast-feeding.

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

Patients who experience visual disturbances, dizziness, drowsiness, fatigue or other central nervous system disturbances while taking NSAIDs should refrain from driving or operating machinery.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.

The following undesirable effects include those reported with diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use.

Blood and lymphatic system disorders

Very rare: Thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.

Immune system disorders

Rare: Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).

Very rare: Angioneurotic oedema (including face oedema).

Psychiatric disorders

Very rare: Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder/reactions, confusion, hallucinations.

Nervous system disorders

Common: Headache, dizziness.

Rare: Somnolence, drowsiness, tiredness, hypotension.

Very rare: Paraesthesia, memory impairment/disturbance, convulsion, anxiety, tremor, taste disturbances, cerebrovascular accident, disturbances of sensation, taste disturbances, malaise, aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus and mixed tissue disease) with symptoms such as fever, stiff neck, headache, nausea and vomiting.

Eye disorders

Very rare: Visual disturbance, vision blurred, diplopia, optic neuritis.

Ear and labyrinth disorders

Common: Vertigo.

Very rare: Tinnitus, hearing impaired.

Cardiac disorders

Very rare: Palpitations, chest pain, cardiac failure/congestive heart failure, myocardial infarction.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150 mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events, for example, myocardial infarction or stroke (see section 4.4 Special warnings and special precautions for use).

Vascular disorders

Very rare: Hypertension, vasculitis.

Respiratory, thoracic and mediastinal disorders

Rare: Asthma (including dyspnoea), alveolitis, pulmonary eosinophilia.

Very rare: Pneumonitis.

Aggravated asthma or bronchospasm have also been reported.

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain or cramps, flatulence, anorexia.

Rare: Gastritis, gastrointestinal haemorrhage or bleeding, haematemesis, diarrhoea haemorrhagic/bloody, melaena, gastrointestinal ulcer, with or without bleeding or perforation (sometimes fatal, particularly in the elderly).

Very rare: Lower gut disorders such as colitis (including colonic damage, non specific haemorrhagic colitis/ haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease/Crohn's proctocolitis), constipation, stomatitis/aphthous stomatitis, glossitis, oesophageal disorder/lesions, diaphragm-like intestinal strictures/stricture formation, pancreatitis.

Hepatobiliary disorders

Common: Transaminases (serum aminotransferase enzymes) increased (eg AST, ALT).

Rare: Hepatitis, jaundice, liver disorder.

Very rare: Fulminant hepatitis.

Skin and subcutaneous tissue disorders.

Common: Rash, skin eruptions.

Rare: Urticaria.

Very rare: Bullous eruptions/dermatoses, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis/acute toxic epidermolysis (Lyell's syndrome), dermatitis exfoliative (erythroderma), loss of hair, photosensitivity reactions, purpura, allergic purpura, pruritus.

Renal and urinary disorders

Rare: Interstitial fibrosis has been reported with NSAIDs and may lead to renal failure.

Very rare: Acute renal failure or insufficiency, urinary abnormalities (eg haematuria, proteinuria), nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders and administration site conditions

Rare: Oedema.

Very rare: Impotence.

Symptoms:

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

Therapeutic measures:

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 potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.

Pharmacotherapeutic group

Non-steroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

Diclofenac sodium is a non-steroidal agent with marked analgesic/anti- inflammatory and anti-pyretic properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase).

Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

Diclofenac sodium is rapidly absorbed from the gut and is subject to first-pass metabolism. Tablets give peak plasma concentrations after 1-4 hours. The active substance is 99.7% protein bound and plasma half-life for the terminal elimination phase is 1-2 hours.

Diclofenac sodium enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been obtained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma, and they remain higher for up to 12 hours.

Approximately 60% of the administered dose is excreted via the kidneys in the form of metabolites and less than 1% in unchanged form. The remainder of the dose is excreted via the bile in metabolised form. In patients with impaired renal function no accumulation of diclofenac sodium has been reported.

None relevant.

The tablets also contain silicon dioxide, lactose, maize starch, sodium starch glycollate, povidone, microcrystalline cellulose, magnesium stearate, hydroxypropylmethylcellulose, polyethoxylated castor oil, yellow iron oxide (E172), red iron oxide (E172), purified talc special, titanium dioxide (E171), methacrylic acid copolymer, polyethylene glycol, silicone, ammonia and purified water.

None known.

5 years.

Protect from moisture. Store below 30^oC.

The tablets come in PVC/PVdC blister packs of 84 and 100.

The tablets should be swallowed whole.

Sandoz Limited

37 Woolmer Way

Bordon

Hampshire GU35 9QE

United Kingdom

PL 04416/0644

25^th April 2005

12/2008