Motifene 75 mg Capsules

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.

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.

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.

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.

• 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.

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).

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases without previous exposure to the drug. Motifene may mask the signs and symptoms of infection due to its pharmacodynamic properties.

The use of Motifene with concomitant NSAIDs including cyclo-oxygenase-2 selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects. (See section 4.5).

Elderly:

Caution is indicated on basic medical grounds.The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (See section 4.2). It is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight.

Respiratory disorders:

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions to NSAIDs like asthma exacerbations (so-called intolerance to analgesics / analgesics-asthma), Quincke's oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for a medicalemergency). This is also applicable to patients who are known to be allergic to other substances and have previously presented with skin reactions, pruritus or urticaria.

Cardiovascular, Renal and Hepatic Impairment:

Close medical surveillance is required when prescribing Diclofenac to patients with impaired hepatic function, as their condition may be exacerbated.

As with other NSAIDs, , treatment with Diclofenac can be associated with a rise in liver enzymes . During prolonged treatment with Diclofenac, regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, or if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), Diclofenac should be discontinued. Hepatitis may occur without prodromal symptoms. Caution is called for in patients with hepatic porphyria, since it may trigger an attack.

Fluid retention and oedema have been reported with NSAID therapy, including diclofenac; particular caution is called for in patients with impaired cardiac or renal function, a history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see 4.3). Monitoring of renal function is recommended as a precautionary measure when using Diclofenac in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.

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-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for 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. Motifene should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

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.

Haematological Effects:

Diclofenac, in common with other NSAIDs, can reversibly inhibit platelet aggregation and with such patients, careful monitoring is advised.

Other analgesics including cyclo-oxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (See section 4.4).

Diuretics and Anti-hypertensives : Reduced diuretic and anti-hypertensive effect may be seen

The combination should be administered with caution, and patients, especially the elderly, should have their blood pressure monitored. Patients should be adequately hydrated and renal function monitored after initiation of concomitant therapy and periodically thereafter, particularly for those patients on diuretics and ACE inhibitors, due to the increased risk of nephrotoxicity.

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.

Digoxin: A Rise in plasma concentrations of dixogin may be seen, therefore monitoring of serum digoxin levels recommended.

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

Lithium: Decreased elimination of lithium, may occur and monitoring of serum lithium levels recommended.

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

Diclofenac can inhibit the tubular renal clearance of methotrexate thereby increasing methotrexate levels, leading to toxicity

Ciclosporin: Increased risk of nephrotoxicity, therefore Diclofenac should be given at doses lower than those that would be used in patients not receiving ciclosporin.

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).

Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding (see 4.4). Although clinical studies do not appear to indicate that diclofenac affects the action of anticoagulants, there are isolated reports of an increased risk of haemorrhage in patients receiving concomitant diclofenac and anticoagulants. Close monitoring of such patients is therefore recommended.

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.

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.

Phenytoin: Monitoring of phenytoin plasma concentrations recommended due to an expected increase in phenytoin levels.

Colestipol and cholestyramine: These agents can induce a delay or decrease in absorption, therefore,it is recommended that diclofenac is administered at least one hour before or 4 to 6 hours after administration of colestipol/ cholestyramine.

Potent CYP2C9 inhibitors: Caution recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentration and exposure to diclofenac due to inhibition of diclofenac metabolism.

Antidiabetics: Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of both hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. Therefore, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Pregnancy:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal death.

In addition, increased incidences of various malformations, including cardiovascular malformations, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, Motifene should not be given unless absolutely necessary. If Motifene is used by a woman when attempting to conceive, or during the first and second trimester of pregnancy, the dose and durations should be kept as low and as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause the following in the foetus:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

In the mother and the neonate, at the end of pregnancy:

, an anti-aggregating effect which may occur even at very low doses leading to possible prolongation of bleeding times

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, Motifene is contraindicated during the third trimester of pregnancy.

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.

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

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

The most commonly reported adverse reactions are gastrointestinal in nature.

Adverse reactions from Motifene in clinical trials and epidemiological data are summarised in the table below.

The following terminologies have been used in order to classify the occurrence of adverse reactions:

Very common (1/10)

Common (1/100 to <1/10)

Uncommon (1/1,000 to <1/100)

Rare (1/10,000 to <1/1,000)

Very rare (<1/10,000)

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.

Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.

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).

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.

Not applicable

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

Triethyl citrate

Talc

Capsule shell:

Indigocarmine E132

Titanium dioxide E171

Gelatin

Capsule body:

Gelatin

Ink, containing:

Shellac

Soy lecithin (food grade)

Antifoam DC 1510

Titanium dioxide E171

None known.

4 years.

Do not store above 25°C.

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.

Not applicable.

Daiichi Sankyo UK Limited

Chiltern Place

Chalfont Park

Gerrards Cross

Buckinghamshire

SL9 0BG

UK

PL 08265/0003

5 August 1994/9 September 2004

9 March 2012