Motifene 75mg

1. Name Of The Medicinal Product

Motifene 75 mg Capsules

2. Qualitative And Quantitative Composition

Each capsule contains 75 mg diclofenac sodium (25 mg as gastro-resistant pellets and 50 mg as prolonged release pellets).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsule, hard.

Size 2 hard gelatin capsule with a light blue opaque cap and colourless transparent body, containing white to cream-coloured pellets. The capsules are printed “D75M” in white.

4. Clinical Particulars

4.1 Therapeutic Indications

Motifene is indicated for the treatment of rheumatoid arthritis; osteoarthrosis; low back pain; acute musculo-skeletal disorders and trauma such as periarthritis (especially frozen shoulder), tendinitis, tenosynovitis, bursitis, sprains, strains and dislocations; relief of pain in fractures; ankylosing spondylitis; acute gout; control of pain and inflammation in orthopaedic, dental and other minor surgery.

4.2 Posology And Method Of Administration

For oral administration.

The capsules should be swallowed whole with a liberal quantity of liquid.

To be taken preferably with or after food.

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

Adults:

One capsule daily. Dose may be increased to two capsules daily if necessary. The first dose should be taken in the morning with breakfast and the second if required 8-12 hours later.

Children:

Not for use in children.

Elderly:

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

4.3 Contraindications

• Hypersensitivity to diclofenac sodium or to any of the excipients.

• Previous hypersensitivity reactions (eg asthma, urticaria, angioedema or rhinitis) in response to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.

• Severe hepatic, renal and cardiac failure (See section 4.4).

• During the last trimester of pregnancy (See section 4.6).

• Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

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

4.4 Special Warnings And Precautions For Use

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, and GI and cardiovascular risks below).

The use of Motifene with concomitant NSAIDs including cyclo-oxygenase

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).

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.

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 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 diclofenac, particularly at high dose (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).

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 (eg hypertension, hyperlipidaemia, diabetes mellitus, smoking).

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 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 Motifene, 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 these conditions may be exacerbated (See section 4.8).

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).

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens

Female fertility:

The use of Motifene 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 Motifene should be considered.

Motifene, in common with other NSAIDs, can reversibly inhibit platelet aggregation.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Other analgesics including cyclo-oxygenase Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (See section 4.4).

Anti-hypertensives: Reduced anti-hypertensive effect.

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, hence serum potassium should be monitored.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduced GFR (Glomerular Filtration Rate) and increase plasma glycoside levels.

Lithium: Decreased elimination of lithium.

Methotrexate: Decreased elimination of methotrexate.

Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours of each other.

Ciclosporin: Increased risk of nephrotoxicity.

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

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (See section 4.4).

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

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.

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

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.

Pharmacodynamic studies have shown no potentiation of oral hypoglycaemic drugs, but caution and adequate monitoring are nevertheless advised.

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. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the 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). NSAIDs 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.

Lactation:

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breast-feeding.

See section 4.4 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

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

Gastrointestinal: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly may occur (See section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (See section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of:

(a) non-specific allergic reactions and anaphylaxis

(b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea

or

(c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

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

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).

Other adverse events reported less commonly include:

Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, renal failure and urinary abnormalities (e.g. haematuria).

Hepatic: Abnormal liver function, hepatitis (in isolated cases fulminant) and jaundice.

Neurological and special senses: Visual disturbances (blurred vision, diplopia), optic neuritis, headache, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4), depression, confusion, hallucinations, tinnitus, dizziness, vertigo, malaise, fatigue and drowsiness.

Isolated cases of memory disturbance, disorientation, impaired hearing, insomnia, irritability, convulsions, anxiety, nightmares, tremor, psychotic reactions.

Dermatological: Photosensitivity reactions, rashes, skin eruptions, urticaria.

Isolated cases of bullous eruptions, eczema, erythema multiforme, Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (very rare), Lyell's syndrome, loss of hair.

Haematological: Thrombocytopenia, neutropenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.

4.9 Overdose

Symptoms:

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

Treatment:

Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures.

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 closely monitored 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. Specific therapies such as forced diureses, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Acetic acid derivatives and related substances

ATC code: M01AB05

Motifene is a non-steroidal agent with marked analgesic/anti-inflammatory properties.

It is an inhibitor of prostaglandin synthetase (cyclo-oxygenase).

5.2 Pharmacokinetic Properties

Diclofenac sodium is rapidly absorbed from the gut and is subject to first-pass metabolism. Therapeutic plasma concentrations occur about ½ hour after administration of Motifene. The active substance is 99.7% protein bound and the plasma half-life for the terminal elimination phase is 1-2 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.

Following rapid gastric passage, the gastro-resistant pellet component of Motifene ensures quick availability of the active component in the blood stream. The prolonged release pellets cause a delayed release of the active component, which means one single daily dose is usually sufficient.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars

6.1 List Of Excipients

Gastro-resistant pellets:

Microcrystalline cellulose

Povidone K25

Colloidal anhydrous silica

Methacrylic acid ethyl acrylate copolymer

Propylene glycol

Talc

Prolonged release pellets:

Microcrystalline cellulose

Povidone K25

Colloidal anhydrous silica

Ammonio methacrylate copolymer A and B

Dibutyl phthalate

Talc

Capsule shell:

Indigo carmine E132

Titanium dioxide E171

Gelatin

Capsule body:

Gelatin

Ink, containing:

Shellac

Soy lecithin (food grade)

Antifoam DC 1510

Titanium dioxide E171

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25ºC.

6.5 Nature And Contents Of Container

The capsules are blister packed in PVC/PDVC and aluminium foil and are packed into folding cardboard cartons.

Motifene is available in packs of 2, 4, 28 and 56 capsules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Daiichi Sankyo UK Limited

Chiltern Place

Chalfont Park

Gerrards Cross

Buckinghamshire

SL9 0BG

UK

8. Marketing Authorisation Number(S)

PL 08265/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

5 August 1994/9 September 2004

10. Date Of Revision Of The Text

28 September 2010