Astellas Pharma Co. Ltd

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

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

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 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 diclofenac, peanut, soya or to any of the excipients contained in Difene Spray Gel.

• 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 (NSAIDs).

• During the third 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 not recommended.

The possibility of systemic adverse events from application of Difene Spray Gel cannot be excluded if the preparation is used on large areas of skin and over a prolonged period (see the product information on systemic forms of diclofenac).

Difene Spray Gel should be applied only to intact non-diseased 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 not be ingested.

Difene Spray Gel can be used with non-occlusive bandages but should not be used with an airtight occlusive dressing.

Patients should be warned against excessive exposure to sunlight in order to reduce the incidence of photosensitivity.

Discontinue the treatment if a skin rash develops after applying the product.

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 in some people.

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

Since systemic absorption of diclofenac from a topical application of Difene Spray Gel is very low such interactions are very unlikely. Concurrent acetylsalicylic acid or other NSAIDs may result in an increased incidence of adverse reactions (see section 4.4).

Pregnancy

The systemic concentration of Difene Spray Gel is lower after topical administration, compared to oral formulations. With reference to experience from treatment with NSAIDs with systemic uptake, the following is recommended:

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 lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

During the first and second trimester of pregnancy, Difene Spray Gel should not be given unless clearly necessary. If Difene Spray Gel is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

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

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

The mother and the neonate, at the end of pregnancy, to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

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

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

Lactation

Like other NSAIDs, diclofenac passes into breast milk in small amounts. However, at therapeutic doses of Difene Spray Gel no effects on the suckling child are anticipated. Because of a lack of controlled studies in lactating women, the product should only be used during lactation under advice from a healthcare professional. Under this circumstance, Difene Spray Gel should not be applied on the breasts of nursing mothers, nor elsewhere on large areas of skin or for a prolonged period of time (see section 4.4).

Cutaneous application of Difene Spray Gel has no influence on the ability to drive and use machines.

Skin disorders are commonly reported.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: 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), or not known (can not to be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1

* Pruritus has been reported at a frequency of 0.9% 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.

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.

The low systemic absorption of topical diclofenac renders overdose very unlikely.

However undesirable effects similar to those observed following an overdose of diclofenac tablets can be expected if Difene Spray Gel is inadvertently ingested (i.e. a 15 ml spray bottle containing 500 mg of diclofenac sodium).

In the event of accidental ingestion resulting in significant systemic adverse effects, general therapeutic measures normally adopted to treat poisoning with non-steroidal anti-inflammatory medicines should be used. Gastric decontamination and the use of activated charcoal should be considered, especially within a short time of ingestion.

Pharmacotherapeutic group: Anti-inflammatory 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 10% (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 24

Ireland

PA 1241/12/8

Date of first authorisation: 13/05/2002

Date of latest renewal: 13/05/2007

09/2012

Not applicable.

Not applicable.