Diclomax SR

1. Name Of The Medicinal Product

Diclomax SR.

2. Qualitative And Quantitative Composition

Each Diclomax SR capsule contains diclofenac sodium 75mg.

For excipients, see 6.1.

3. Pharmaceutical Form

Modified release capsules for oral use.

4. Clinical Particulars

4.1 Therapeutic Indications

For rheumatoid arthritis; osteoarthritis; 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 use.

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 or two 75mg capsules daily taken whole in single or divided doses preferably with food or after food.

Children

Not recommended.

Elderly

The elderly are at an increased risk of serious consequences of adverse reactions. Studies indicate the pharmacokinetics of diclofenac sodium are not impaired to any clinical extent in the elderly, however, as with all non-steroidal anti-inflammatory drugs, Diclomax should be used with caution in elderly patients and the lowest effective dose used for the shortest possible duration. These patients should be monitored regularly for GI bleeding during NSAID therapy.

4.3 Contraindications

Diclomax is contraindicated in patients with a known hypersensitivity to diclofenac sodium or to any of the excipients, patients with a history of/or active peptic ulcer, history of/or upper gastro-intestinal bleeding or perforation related to previous NSAID therapy. 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.

Diclomax is contraindicated in patients with acute porphyria.

Diclomax should not be used in patients with severe hepatic, renal or cardiac failure (see section 4.4) or during the last trimester of pregnancy (see section 4.6).

As Diclomax contains lactose and sucrose, patients with rare hereditary problems of fructose/galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.4 Special Warnings And Precautions For Use

As with all non-steroidal anti-inflammatory drugs (NSAIDs) Diclomax should only be given to the elderly after other forms of treatment have been carefully considered, as the elderly have an increased frequency of adverse reactions to NSAIDs especially gastro-intestinal bleeding and perforation which may be fatal (see section 4.2).

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 Diclomax SR with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

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).

All patients who are receiving long-term treatment with NSAIDs should be monitored as a precautionary measure, e.g. renal, hepatic function (elevation of liver enzymes may occur) and blood counts.

If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Diclomax should be discontinued.

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 (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, smoking).

Respiratory disorders:

Cautions is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to cause bronchospasm in such patients.

Gastro-intestinal bleeding, ulceration and perforation:

Diclomax should be used with caution in patients with gastro-intestinal disorders or haematological abnormalities, as GI bleeding, ulceration or perforation, which can be fatal, has been reported with NSAID therapy 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 GI risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution is advised in patients receiving concomitant medications that could increase the risk of ulceration or bleeding, such as corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving Diclomax, the treatment should be withdrawn.

NSAIDs should be given with care to patients with a history of gastro-intestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

Haematological:

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

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 reaction occurring in the majority of cases within the first month of treatment. Diclomax should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired Female fertility:

The use of Diclomax 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 Diclomax should be considered.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Lithium: Diclomax may increase plasma concentrations and decrease elimination of lithium.

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

Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, such as warfarin (see section 4.4)

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

Ciclosporin: Ciclosporin nephrotoxicity may be increased by 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.

Methotrexate: Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours of each other, since NSAIDs may increase methotrexate plasma levels with decreased elimination, resulting in increased toxicity.

Quinolone antibiotics: Animal data indicate that the 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 GI bleeding (see section 4.4).

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

Corticosteroids: Corticosteroids can increase the risk of GI ulceration or bleeding (see section 4.4).

Diuretics: Various NSAIDs are liable to inhibit the activity of diuretics. 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.

Anti-hypertensives: Reduced anti-hypertensive effect.

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.

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 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 with traces of diclofenac sodium found in breast milk following oral doses of 50mg every 8 hours. NSAIDs should, if possible, be avoided when breastfeeding (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

The following adverse events have been reported with NSAIDs:

Gastro-intestinal:

The most commonly observed adverse events are gastro-intestinal 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, angioedema 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 (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) (see section 4.4).

Other adverse events reported less commonly include:

Renal:

Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.

Hepatic:

Abnormal liver function, hepatitis and jaundice.

Neurological and special senses:

Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune 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.

Haematological:

Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological:

Photosensitivity.

4.9 Overdose

(a) Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastro-intestinal 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.

(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 agent with marked analgesic/anti-inflammatory and anti-pyretic 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. Capsules give peak plasma concentrations after approximately 2.5 hours. The active substance is 99.7% protein bound and 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. About 30% of the dose is excreted via the bile in metabolised form.

The Diclomax slow release preparation:

• Increases the duration of action of the drug

• Maintains relatively constant rate of absorption in the gastro-intestinal tract over a longer period of time

• Increases the fraction of the ingested dose absorbed in the GI tract

• Regulates the rate at which the drug is made available for absorption, thereby reducing the possibility of malabsorption and occurrence of side-effects.

5.3 Preclinical Safety Data

The results of the preclinical tests do not add anything of further significance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sucrose

Maize starch

Polyethylene glycol 6000

Ammonio methacrylate copolymer type A

Talc

Lactose

Polysorbate 80

Purified water

Ethanol 96%

Acetone

Capsule Shell Constituents:

Gelatin

Yellow iron oxide (E172)

Titanium dioxide (E171)

Overprint Ink Constituents:

Shellac glaze

Propylene glycol

Black iron oxide (E172)

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months – PVC/PE/PVDC blister packs.

18 months – PVC blister packs.

60 months – Polyamide/Al/PVC-Al blister packs.

6.4 Special Precautions For Storage

PVC/PE/PVDC and PVC blister packs: Store between 10^oC and 25^oC. Protect from moisture. Do not refrigerate.

Polyamide/Al/PVC-Al blister packs: This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

White opaque PVC blister pack with hard tempered foil or white opaque PVC/PE/PVDC/hard tempered foil blister strips or Polyamide/Al/PVC-Al blister strips.

Packs of 4 and 56 capsules.

6.6 Special Precautions For Disposal And Other Handling

No special instructions needed.

7. Marketing Authorisation Holder

Galen Limited

Seagoe Industrial Estate

Craigavon

BT63 5UA

UK.

8. Marketing Authorisation Number(S)

PL 27827/0004.

9. Date Of First Authorisation/Renewal Of The Authorisation

12 January 1995.

10. Date Of Revision Of The Text

29 December 2009.