Rheumatac Retard 75

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Rheumatac Retard 75

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Rheumatac 75 Retard. Each tablets contains 75mg diclofenac sodium BP.

3 PHARMACEUTICAL FORM

Modified Release Tablets

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Rheumatoid arthritis, osteoartbritis, acute gout, low back pain, relief of pain in fractures, acute musculo-skeletal disorders and trauma including periarthritis (particularly frozen shoulder), bursitis, tendinitis, tenosynovitis, dislocations, sprains and strains, ankylosing spondylitis, and the control of pain and inflammation in orthopaedic, dental and other minor surgery.

4.2 Posology and method of administration

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

For oral administration. Tablets should be swallowed whole preferably with or after food.

Adults: One 75 mg tablet once or twice a day.

Children: Not suitable for use in children.

Elderly: Care should be used when treating patients who are frail or have a low body weight, as they will in general be more susceptible to adverse reactions. The elderly are at an 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 any of the other constituents.

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.

Severe hepatic failure, renal failure and heart 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 possible duration necessary to control symptoms (see Section 4.2, and GI and cardiovascular risks below).

Monitoring of renal function, hepatic function (elevation of liver enzymes may occur) and blood counts should be performed on long-term NSAID patients, as a precautionary measure.

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

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, the elderly and those recovering from major surgery. Renal function should be monitored in these patients (Also 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 a 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).

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 disease (e.g. 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 diclofenac, 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).

Patients with a history of haematemesis, or melaena, should be carefully observed.

Haematological disorders:

Care should be taken when treating patients with haematological abnormalities, or bleeding diathesis.

Hepatic Disorders:

Diclofenac must be stopped if liver function tests show abnormalities, which persist or worsen, or if liver disease develops or if other symptoms such as eosinophilia or rash occur.

Diclofenac may trigger an attack in patients with hepatic porphyria.

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. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Impaired Female fertility:

The use of diclofenac 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 diclofenac should be considered.

4.5 Interaction with other medicinal products and other forms of interaction

Other analgesics (including cycloxygenase-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).

Anti-hypertensives: Reduced anti-hypertensive effect.

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. The activity of diuretics may be inhibited by some NSAIDs. Increased serum potassium levels may result when diclofenac is given concomitantly with potassium-sparing diuretics. Serum potassium levels should therefore be monitored.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: Decreased elimination of lithium.

Methotrexate: Decreased elimination of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity as a result of the effect of NSAIDs on renal prostaglandins.

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 GI ulceration or bleeding (See section 4.4).

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4). Monitoring is recommended to ensure the desired response to the anticoagulant is maintained, as there are rare reports of increased risk of haemorrhage with combined diclofenac and anticoagulant therapy.

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.

Antiplatelet 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.

Anti-diabetics: It has been reported that hypo- and hyperglycaemic effects have occurred rarely when diclofenac and oral antidiabetic agents have been given together and adjustment of the hypoglycaemic may be required.

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.

4.6 Fertility, 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 discernable 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 Contra-Indications). 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 breastfeeding.

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: 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, anorexia, 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, glossitis and oesophageal lesions have 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. Hypotension, chest pains and palpitations have been rarely reported.

Other adverse events reported less commonly include:

Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure. Other occasional effects on the kidney include acute renal insufficiency, urinary abnormalities (e.g. haematuria, proteinuria), nephritic syndrome and papillary necrosis.

Hepatic: Abnormal liver function for example occasional reports of elevation of serum aminotransferase enzymes (ALT, AST), hepatitis and jaundice.

Neurological and special senses: Visual disturbances, optic nephritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing autoimmune 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), depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Other isolated effects on the central nervous system include tiredness, impaired hearing, insomnia, convulsions, irritability, anxiety, psychotic reactions, tremor, memory disturbance, disturbance of sensation, nightmares and taste alterations.

Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia. Leucopoenia has been rarely reported.

Dermatological: Bullous reactions including Stevens Johnson Syndrome, Lyells syndrome and Toxic Epidermal Necrolysis (including erythroderma) (very rare). Photosensitivity, eczema, hair loss.

Other: Impotence has been reported rarely.

4.9 Overdose

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. Other complications that might be encountered include hypotension, respiratory depression, and gastro-intestinal irritation.

b) 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 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

Diclofenac sodium is a non-steroidal, anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It is an inhibitor of prostaglandin synthetase.

5.2 Pharmacokinetic properties

Diclofenac 75 Retard Tablets are extended release preparations designed to release diclofenac over a period of time. Following a pharmacokinetic study with the 100 mg tablet in volunteers it was found that the average time to reach maximum plasma concentration was 6.05 hours.

The average elimination half life was found to be 6.75 hours. The average maximum plasma concentrations were found to be 262ng/ml.

General characteristics of the active substance

Diclofenac sodium is almost totally absorbed after oral administration and it is subject to significant first-pass metabolism with only approximately 60% of an oral dose reaching the systemic circulation.

Diclofenac sodium is highly protein bound (>99%). It is mainly excreted in the form of metabolites via the urine but also in the bile.

The main metabolite has minimal anti-inflammatory activity compared with the parent drug.

Characteristics in patients

Plasma concentration of unchanged diclofenac are not reported to be significantly affected by age, renal or hepatic impairment. The metabolite concentrations may be increased by severe renal impairment.

5.3 Preclinical safety data

No relevant information additional to that already included elsewhere in the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Purified talc EP

Ethylcellulose EP

Magnesium Stearate EP

Povidine

Stearic acid	USP
Hydroxypropylmethlcellulose	EP
Ethylcellulose	EP
Diethyl phthalate	USP
Titanium dioxide E171	EP
Polyethylene glycol 4000	BP
Incompatibilities
Not applicable.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store in a dry place below 25°C. Protect from light.

6.5 Nature and contents of container

PVdC/PVC/aluminiumlPVdC blister strip.

Number of tablets per carton 28, 30, 50, 56, 60, 84, 100, 250, 500, 1000

6.6 Special precautions for disposal

None stated.

7 MARKETING AUTHORISATION HOLDER

Amdipharm UK Limited

Capital House, 85 King William Street,

London EC4N 7BL, UK

MARKETING AUTHORISATION NUMBER(S)

PL 20072/0219

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27 March 1998

DATE OF REVISION OF THE TEXT

08/04/2014