Astellas Pharma Co. Ltd

Difene 75 mg Dual Release Capsules

Each capsule contains Diclofenac Sodium 75 mg in a modified release formulation (25 mg in the form of enteric coated release pellets and 50 mg in the form of sustained release pellets).

For a full list of excipients, see section 6.1.

Modified release capsule, hard

Size 2, gelatin capsules with light blue opaque caps and colourless transparent bodies, containing white to cream-coloured spherical pellets. The capsules are printed “D75M” in white.

As a non-steroidal anti-inflammatory analgesic in the symptomatic management of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, acute musculo-skeletal disorders such as periarthritis, tendinitis, tenosynovitis, bursitis, sprains, strains and dislocations, relief of pain in fractures, low back pain, acute gout, psoriatic arthropathy. In the management of pain and inflammation associated with orthopaedic, dental and minor surgery.

In the management of dysmenorrhoea and associated menorrhagia.

For oral use only. The capsules should be swallowed whole with liquid.

Adults: One or two capsules (75 - 150 mg) in divided doses, daily. The daily dose should not exceed 150 mg.

Elderly: NSAIDs should be used with particular caution in elderly patients who are more prone to adverse events.

Children: Not recommended.

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

Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

Patients with a history of hypersensitivity reactions (e.g. bronchospasm, rhinitis, urticaria) in response to diclofenac, aspirin or nonsteroidal anti-inflammatory drugs.

Severe heart failure.

Warnings:

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 longterm should undergo regular medical supervision to monitor for adverse events.

The use of Difene Capsules with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). Prolonged use of NSAIDs in the elderly is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.

Gastrointestinal: Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of previous 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 4.5).

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

When GI bleeding or ulceration occurs in patients receiving Difene Capsules, 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 – undesirable effects).

Cardiovascular and cerebrovascular effects

Caution and 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 dose (150mg initiating 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 longer- term treatment of patient with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Serious skin reaction, 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 (see 4.8). 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. Difene capsules should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The use of Difene Capsules may impair the 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 Difene Capsules should be considered.

In patients with renal, cardiac or hepatic impairment, caution is required since the use of NSAIDs may result in deterioration of renal function. Assessment of renal function should occur prior to the initiation of therapy and regularly thereafter.

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).

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

It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

Care should be taken in patients treated with any of the following drugs as interactions have been reported:

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Anti-hypertensives: reduced anti-hypertensive effect.

Diuretics: reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate (GFR) and increase plasma cardiac glycoside levels.

Lithium: decreased elimination of lithium.

Methotrexate: decreased elimination of methotrexate.

Cyclosporin: increased risk of nephrotoxicity with NSAIDs.

Other NSAIDs: avoid concomitant use of two or more NSAIDs.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Aminoglycosides: reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Probenecid: reduction in metabolism and elimination of NSAID and metabolites.

Oral hypoglycemic agents: inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Although animal studies have not demonstrated teratogenic effects, Difene should not be used in pregnancy or lactation unless considered essential by the physician and if so the lowest effective dose should be used. Use of prostaglandin synthetase inhibitors in the third trimester may result in premature closure of the ductus arteriosus. Traces of drug are detectable in breast milk but are not clinically significant.

Isolated cases of disorientation and blurred vision have been reported with diclofenac sodium, if affected refrain from driving or operating machinery.

If serious side-effects occur, Difene should be withdrawn.

Gastrointestinal tract:

Occasional: epigastric pain, other gastrointestinal disorders (e.g. nausea, vomiting, diarrhoea, abdominal cramps/pain, dyspepsia, flatulence, anorexia, gastritis).

Rare: gastro-intestinal bleeding (which can be fatal), peptic ulcer (with or without bleeding or perforation), bloody diarrhoea, haematemesis.

Isolated cases: lower gut disorders (e.g. non-specific haemorrhagic colitis and exacerbations of ulcerative colitis or Crohn's disease), pancreatitis, aphthous stomatitis, glossitis, oesophageal lesions, constipation.

Central Nervous System:

Occasional: headache, dizziness or vertigo.

Rare: drowsiness, tiredness.

Isolated cases: disturbances of sensation (paraesthesiae, memory disturbance, disorientation, disturbance of vision, blurred vision, diplopia), impaired hearing, tinnitus, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions. Taste alteration disorders.

Skin:

Occasional: rashes or skin eruptions.

Rare: urticaria

Isolated cases: bullous eruptions, eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome, (acute toxic epidermolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reactions, purpura including allergic purpura.

Kidney:

Isolated cases: acute renal insufficiency, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis.

Liver:

Occasional: elevation of serum aminotransferase enzymes (SGOT, SGPT).

Rare: liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice.

Blood:

Isolated cases: thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.

Cardiovascular system:

Isolated cases: Oedema, palpitations, chest pain, hypertension, congestive heart failure.

Clinical and epidemiological data suggest that use of diclofenac, particularly at high dose (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).

Other organ systems:

Rare: oedema, hypersensitivity reactions (e.g. bronchospasm, anaphylactic/anaphylactoid systemic reactions including hypotension).

Isolated cases: impotence (association with Diclofenac sodium intake is doubtful), palpitation, chest pain, hypertension.

Management of acute poisoning with diclofenac and other non-steroidal anti-inflammatory drugs consists of supportive and symptomatic measures.

Therapeutic measures that can be taken include; supportive and symptomatic treatment for the complications of overdosage such as hypotension, renal failure, convulsions, gastro-intestinal irritation and respiratory depression; Forced diuresis or dialysis are probably of no help in eliminating diclofenac and other non-steroidal anti-inflammatory medicines due to their high rate of protein binding.

For the capsules additional measures include gastric lavage and treatment with activated charcoal. Difene 75 mg Dual Release is a controlled release system which will continue to release diclofenac for some hours.

M01A B05 Anti-inflammatory and antirheumatic products, non-steroids, acetic acid derivatives and related substances, diclofenac.

Diclofenac sodium is a phenyl acetic acid derivative and a non-steroidal anti-inflammatory agent with analgesic, anti-inflammatory and anti-pyretic properties. Diclofenac is an inhibitor of cyclo-oxygenase and therefore reduces prostaglandin synthesis. Reduction in prostaglandin levels reduces the inflammatory response by the body.

The enteric coated pellet component of the preparation ensures quick availability, following rapid gastric passage, of the active component in the blood stream and the sustained release pellet causes a delayed release of the active component.

At therapeutic concentrations, diclofenac is extensively bound (more than 99%) to plasma proteins. It is subject to first pass metabolism and extensively metabolised in the liver (50-60%).

Diclofenac is excreted mostly through the urine with a small amount excreted in the bile; it also enters the synovial fluid and is excreted in breast milk.

Diclofenac has a short half-life of about 1-4 hours.

Animal studies have been carried out in a number of species to determine the toxicity of diclofenac sodium. Acute toxicity studies have been carried out in the rat and when administered orally an LD50 of 53 mg/kg produced behavioural effects and respiratory stimulation. Acute oral toxicity studies in the rabbit showed no toxic effect at a dose of 157 mg/kg.

Toxicity by the intravenous route has been measured in the rat. An administered dose of 117 mg/kg has been shown to have no adverse effect. Intraperitoneal studies have shown a no adverse effect level of 25 mg/kg in the rat, and subcutaneous toxicity in the rat shows a no toxic effect level of 83 mg/kg.

Rectal toxicity has been measured in the rat. An administered dose of 85 mg/kg has been shown to have no adverse effect.

Reproductive toxicity has been studied in both the rat and the rabbit; a dose of 1 mg/kg/day for 21 days in rats has been shown to produce developmental abnormalities of the cardiovascular system. In the rabbit a dose of 10 mg/kg has been shown to reduce fertility.

Pellets

Microcrystalline Cellulose

Povidone

Methacrylic Acid Ethyl Acrylate Copolymer

Talc

Ammonio Methacrylate Copolymer Type A

Ammonio Methacrylate Copolymer Type B

Colloidal Anhydrous Silica

Propylene Glycol

Triethyl citrate

Sodium Hydroxide

Capsule Shell

Gelatin

Titanium Dioxide E171

Indigo Carmine E132

Printing Ink

Titanium Dioxide E171

Shellac

Propylene Glycol

Not applicable.

4 years.

Do not store above 25°C.

PVC/PVDC/aluminium blister.

Pack size: 4 (sample pack), 20 & 56 capsules.

Not all pack size may be marketed.

No special requirements.

Astellas Pharma Co. Ltd

25 The Courtyard

Kilcarbery Business Park

Clondalkin

Dublin 22

Ireland

PA 1241/12/3

Date of first authorization: 16 June 1994

Date of last renewal: 30 May 2007

August 2011