Astellas Pharma Co. Ltd

Difene 1% w/w Gel

Diclofenac sodium 1% w/w.

For excipients, see 6.1

Gel.

A slightly turbid, colourless gel with the odour of isopropyl alcohol.

For local symptomatic relief of pain and inflammation in

1. Trauma of the tendons, ligaments, muscles and joints e.g. due to sprains, strains and bruises.

2. Localised forms of soft tissue rheumatism.

Topical administration.

Adults: Diclofenac Gel should be rubbed gently into the skin. Depending on the size of the site to be treated, 2 to 4 g (a circular shaped mass approximately 2 to 2.5 cm in diameter) should be applied 2 to 4 times daily. After the application the hands should be washed unless they are the site being treated.

It is recommended that the treatment be reviewed after 14 days. These indications should not warrant treatment for more than 6 weeks.

Elderly: NSAIDs should be used with particular caution in elderly patients who are more prone to adverse events. The lowest dose compatible with adequate safe clinical control should be employed.

Children: Not recommend

Patients with active peptic ulceration.

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

Use in patients hypersensitive to propylene glycol or isopropanol.

Application over extensive areas for prolonged periods or application in excess of recommended dosage may give rise to systemic effects. These include gastrointestinal disturbances, irritability, fluid retention, rash, renal dysfunction, anaphylaxis and rarely gastrointestinal bleeding, hepatitis, blood dycrasis, bronchospasm and erythema multiform.

The product should be applied only to intact skin and not to skin wounds or open injuries. It should not be allowed to come into contact with the eyes or mucous membranes and should never be taken by mouth.

The product should not be used with occlusion.

Undesirable effects may be reduced by using the minimum effective dose for the shortest possible duration. Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.

Diclofenac should be used with great caution in patients with a history of peptic ulceration or inflammatory bowel disease, gastrointestinal bleeding, hepatic or oral insufficiency or bleeding diathesis. Circulating levels of active drug are low but the theoretical increased risk in patients should be considered.

The following interactions occur with oral forms of diclofenac.

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-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 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 bleeding.

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.

Quinolone antimicrobials: Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking Difene Suppositories concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

To date, no drug interactions during treatment with Difene Gel have been reported but the theoretical risk of the above interactions occurring should be borne in mind.

The product should not be used in pregnancy or lactation unless considered essential by the physician. Use of PG synthetase inhibitors in the third trimester may result in premature closure of the ductus arteriosus. Traces of drug are detectable in breast milk following oral doses of 50 mg after 8 hours but are not clinically significant.

None known.

Difene Gel is usually well tolerated. Local allergic skin reactions (exanthema, erosion, erythema, eczema and ulceration) may occasionally occur. Photosensitivity reactions have been observed in isolated cases with other topical diclofenac preparations.

Although systemic absorption of Difene Gel is low in comparison to oral forms of diclofenac, the possibility of systemic side-effects cannot be excluded.

Asthma has been rarely reported in patients using topical NSAID preparations.

The low systemic absorption of topical diclofenac renders over-dosage extremely unlikely. In the event of over-dosage by ingestion, general therapeutic measures normally adopted to treat poisoning with NSAIDs should be used.

Management of acute poisoning NSAIDs essentially consists of supportive and symptomatic measures. There is no typical clinical picture resulting from diclofenac sodium over-dosage. The therapeutic measures that can be taken are: absorption should be prevented as soon as possible after over-dosage by means of gastric lavage and treatment with activated charcoal; supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastro-intestinal irritation and respiratory depression; specific therapies such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism.

Diclofenac sodium is a non-steroidal agent with marked analgesic, antipyretic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthesis (cyclo-oxygenase).

The use of a topical application of diclofenac sodium allows the percutaneous absorption of therapeutic concentrations of the active to penetrate to, and accumulate at, the target site of action. The dose to be delivered in a concentration of a 1% gel, is comparable to the normal daily doses of oral administration. As with other percutaneously applied NSAIDs, it is the concentration reached at the target area that is important for the therapeutic action rather than the plasma concentration. Hence the systemic load produced by oral or parenteral administration can be avoided through local application.

The comparison of the excretion of diclofenac and its metabolities after oral and cutaneous administration gave almost the same pattern of metabolities.

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.

Hypromellose

Propylene glycol

PEG-7-glyceryl-cocoate

Isopropyl alcohol

Purified water.

Not applicable.

2 years.

Do not store above 25°C.

30g/50g/100g: Conical flexible tubes with membrane, tube nozzle with treads with internal protection and end seal lacquer or latex seal.

Not all pack sizes may be marketed.

No special requirements.

Astellas Pharma Co. Ltd

25 The Courtyard

Kilcarbery Business Park

Clondalkin

Dublin 22

Ireland

P.A. 1241/12/5

6th July 1995/28th August 2005

June 2006