Astellas Pharma Co. Ltd

Difene Spray Gel 4% w/w Cutaneous Spray, Solution

Each 1g of solution contains 40 mg of diclofenac sodium.

Excipients: 150 mg propylene glycol (E1520) / gram solution

For a full list of excipients, see section 6.1.

Cutaneous spray, solution.

A golden-yellow, transparent solution, which turns to a gel-like consistency after administration.

For the local symptomatic relief of mild to moderate pain and inflammation following acute blunt trauma of small and medium-sized joints and periarticular structures.

For cutaneous use only.

Adults

Sufficient solution of Difene Spray Gel should be sprayed onto the skin of the affected site. Depending on the size of the area to be treated 4-5 pump strokes (0.8-1.0 g of spray containing 32-40 mg of diclofenac sodium) should be applied 3 times daily in regular intervals. A maximum single dose of 1.0 g of the product should not be exceeded. The maximum daily dose is 15 pump strokes (3.0 g of spray containing 120 mg of diclofenac sodium).

Difene Spray Gel should be massaged gently into the skin. After this the hands should be washed unless they are the site to be treated. After application some minutes for drying should be allowed before dressing or binding the treated area.

The treatment may be discontinued when the symptoms (pain and swelling) have subsided. Treatment should not be continued beyond 7-8 days without review. The patient is requested to consult the doctor if no improvement is seen after 3 days.

Elderly

The posology is the same as for adults.

Children and adolescents:

There are insufficient data on efficacy and safety available for the children and adolescents below 14 years of age (see also contraindications section 4.3).

In children aged 14 years and over, if this product is required for more than 7 days for pain relief or if the symptoms worsen the patient/parents of the adolescent is/are advised to consult a doctor.

Patients with hepatic or renal insufficiency

For the use of Difene Spray Gel in patients with hepatic or renal insufficiency see section 4.4.

• Hypersensitivity to the active substance or to any of the excipients.

• Hypersensitivity to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs)

• Patients with or without asthma in whom attacks of asthma, urticaria or acute rhinitis are precipitated by aspirin or other non-steroidal anti-inflammatory agents.

• The last trimester of pregnancy

• Application to the breast area of nursing mothers

• Children and adolescents: the use in children and adolescents aged less than 14 years is contraindicated.

Contact with eyes and mucous membranes as well as oral use should be avoided.

Difene Spray Gel should only be administered onto intact skin, not on open wounds or diseased skin areas.

Patients should be warned against excessive exposure to sunlight in order to reduce the incidence of photosensitivity. Discontinue if any rash develops. Not for use with occlusive dressings.

The concomitant use of Difene Spray Gel with oral NSAIDs should be cautioned as the incidence of systemic side effects may increase (see section 4.5).

Where Difene Spray Gel is applied to a relatively large area of skin (i.e. more than 600 square centimetres of the body surface) and over a prolonged period (i.e. more than 4 weeks), the possibility of systemic side-effects cannot be completely excluded. If such usage is envisaged, the data sheet on diclofenac oral dosage forms should be consulted (for example, there is the potential for hypersensitivity, asthmatic and renal adverse reactions).

Bronchospasm may be precipitated in patients suffering from or with previous history of bronchial asthma or allergenic disease.

Difene Spray Gel should only be used with caution in patients with a history of peptic ulcer, hepatic or renal insufficiency, bleeding diathesis or inflammatory bowel disease as isolated cases with topical diclofenac have been reported.

Difene Spray Gel contains propylene glycol which may cause skin irritation.

Difene Spray Gel contains peppermint oil which may cause allergic reactions.

The systemic availability of diclofenac from this pharmaceutical presentation is very low. Hence the risk of interactions with other medicinal products is small. Concurrent aspirin or other NSAIDs may result in an increased incidence of adverse reactions (see section 4.4).

There are no adequate data from the use of Difene Spray Gel in pregnant and nursing women. Therefore the use is not recommended.

Use in pregnancy: No evidence of a malformative effect was observed with diclofenac. However, additional epidemiological data is necessary to assess safety. During the last trimester of pregnancy, the use of prostaglandin synthetase inhibitors may result in:

- pulmonary and cardiac toxicity in the foetus (pulmonary hypertension with preterm closing of the ductus arteriosus)

- renal insufficiency in the foetus with oligohydramnios

- and increased possibility of bleeding in the mother and child.

Therefore, during the first six months of pregnancy, Difene Spray Gel should not be used unless clearly necessary and must not be applied to a large area of the skin (i.e. more than 600 square centimetres of the body surface). It must not be used for long-term treatment (> three weeks). Difene Spray Gel is contraindicated (see 4.3) during the last trimester of pregnancy.

Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans is unknown.

Use during lactation: It is not expected that any measurable amount of diclofenac will occur in breast milk following topical application. However, NSAIDs are excreted in human milk. Therefore Difene Spray Gel is not recommended for use in nursing mothers. An application to the breast area of nursing mothers is contraindicated.

Patients who experience dizziness or other central nervous disturbances while taking NSAIDs should refrain from driving or operating machinery, but this would be very unlikely using topical preparations.

Skin disorders are commonly reported.

Skin: Application site reactions, rashes, pruritus and urticaria, drying, reddening, burning sensations, contact dermatitis.

In a clinical trial 236 patients with ankle distortions were treated with 4-5 pump strokes of Difene Spray Gel t.i.d. (120 patients) or placebo (116 patients) for 14 days. The following adverse drug reactions were reported:

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),

not known (cannot be estimated form the available data).

Undesirable effects may be reduced by using the minimum effective dose for the shortest possible duration. The total single dose of product should not exceed 1.0 g (equivalent to 5 pump strokes) of spray.

Nevertheless during long term treatment (> three weeks) and/or when treating large areas (i.e. more than 600 square centimetres of the body surface) there is a possibility of systemic adverse reactions. Reactions like abdominal pain, dyspepsia, gastric and renal disorders may occur.

In patients using topical NSAID preparations asthma has been reported rarely. In isolated cases generalised skin rash, hypersensitivity reactions such as angioedema and photosensitivity reactions have been reported.

During recommended use there is practically no risk due to overdosage. It is recommended to wipe off the surplus Difene Spray Gel. If, accidentally, Difene Spray Gel has been administered orally symptomatic treatment should be given.

Pharmacotherapeutic group: Antiinflammatory preparations, non-steroids for topical use.

ATC code: M02AA 15

Sodium diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which has also analgesic properties. The inhibition of prostaglandin synthesis is considered to be an essential part of its mode of action.

After cutaneous application of 1.5 g Difene Spray Gel a rapid onset of diclofenac absorption can be observed leading to measurable plasma levels of about 1 ng/ml as early as 30 minutes and to maximum levels of about 3 ng/ml at about 24 hours after application.

The achieved systemic concentrations of diclofenac are about 50 times lower than those achieved following oral administration of equivalent amounts of diclofenac. Systemic plasma levels are not supposed to contribute to the efficacy of Difene Spray Gel.

Diclofenac is extensively bound to plasma proteins (about 99 %).

In rabbit skin, Difene Spray Gel is classified as non-irritant.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential of diclofenac.

In rats and rabbits oral doses of diclofenac were not teratogenic but caused embryotoxicity at maternally toxic doses.

Diclofenac did not affect fertility in rats but inhibited ovulation in rabbits and reduced implantation in rats.

In rats, diclofenac resulted in dose-dependent constriction of the fetal ductus arteriosus, dystocia and delayed parturition.

Isopropyl alcohol

Soy bean lecithin

Ethanol

Disodium phosphate dodecahydrate

Sodium dihydrogen phosphate dihydrate

Disodium edetate

Propylene glycol (E1520)

Peppermint oil

Ascorbyl palmitate

Hydrochloric acid concentrated (w/w) for pH-adjustment

Sodium hydroxide 10% (w/w) for pH-adjustment

Purified water.

Not applicable.

Unopened bottle (25g solution in 30 ml bottle and 12.5g solution in 15 ml bottle): 3 years

Unopened bottles (7.5g solution in 10 ml bottle): 2 years

In-use: 6 months.

Store in the original package.

Glass bottle with metering pump/nozzle/spray valve and cap.

Pack sizes of 7.5 g (10 ml bottle), 12.5 g (15 ml bottle) and 25 g (30 ml bottle) solution.

Not all pack sizes may be marketed.

No special requirements.

Astellas Pharma Co. Ltd.

25 The Courtyard

Kilcarbery Business Park

Clondalkin

Dublin 22

Ireland

PA 1241/012/008

Date of first authorisation: 02 May 2003

Date of last renewal: 13 May 2007

June 2011