For the treatment of actinic keratosis (AK) in adults.

Use in Adults: Solaraze is applied locally to the affected area twice daily, with the gel smoothed into the skin gently. The amount needed depends on the size of the affected area. Normally 0.5 grams (the size of a pea) of the gel is used on a 5 cm × 5 cm lesion site. The maximum daily amount of 8 grams of gel allows simultaneous treatment of up to 200 cm² skin surface area.

The usual duration of therapy is from 60 to 90 days. Maximum efficacy has been observed with treatment duration towards the upper end of this range. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy.

Use in the Elderly: The usual adult dose may be used.

Paediatric Population: AK is a condition not generally seen within the paediatric population and was not studied. Therefore, dosage recommendations and indications for the use of Solaraze have not been established for use in children and adolescents. No data are available.

Method of administration

For cutaneous use.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Because of cross-reactions, the gel must not be used by patients who have experienced hypersensitivity reactions such as symptoms of asthma, allergic rhinitis or urticaria, to acetylsalicylic acid or other non-steroidal anti-inflammatory agents.

The use of the medicinal product is contraindicated during the third trimester of pregnancy (see Section 4.6).

The likelihood of systemic adverse reactions occurring following the topical application of <Invented name> is very small compared to the frequency of adverse reactions with oral diclofenac, owing to low systemic absorption with Solaraze. However, the possibility of systemic adverse events from application of topical diclofenac cannot be excluded if the preparation is used on large areas of skin and over a prolonged period (see product information on systemic forms of diclofenac). This medicinal product should be used with caution in patients with a history of and/or active gastrointestinal ulceration or bleeding, or reduced heart, liver or renal function, since isolated cases of systemic adverse reactions consisting of renal affection, has been reported with topically administered antiphlogistics.

It is known that nonsteroidal anti-inflammatory drugs (NSAIDs) can interfere with platelet function. Although the likelihood of systemic side effects is very low, caution should be used in patients with intracranial haemorrhage and bleeding diathesis.

Direct sunlight, including solarium, should be avoided during treatment. If sensitivity skin reactions occur, discontinue use.

Solaraze should not be applied to skin wounds, infections or exfoliative dermatitis. It should not be allowed to come into contact with the eyes or mucous membranes and should not be ingested.

The treatment should be discontinued if a generalised skin rash develops after applying the medicinal product.

Topical diclofenac can be used with non-occlusive bandages but should not be used with an airtight occlusive dressing.

This medicinal product contains 10 mg benzyl alcohol in each g. Benzyl alcohol may cause allergic reactions and mild local irritation.

Since systemic absorption of diclofenac from a topical application is very low such interactions are very unlikely.

Pregnancy: The systemic concentration of diclofenac 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 the dose and duration of therapy.

• Animal studies have shown reproductive toxicity. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and postimplantation 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, diclofenac should not be given unless clearly necessary. If diclofenac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low (< 30 % of the body surface) and duration of treatment as short as possible (not longer than 3 weeks).

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

• Functional renal injury in the foetus. From the 12^th week: oligohydramnios (usually reversible after the end of treatment), or anamnios (particularly with prolonged exposure). After birth: kidney failure may persist (particularly with late or prolonged exposure).

• Pulmonary and cardiac toxicity in the foetus (pulmonary hypertension with premature closure of the ductus arteriosus). This risk exists from the beginning of the 6^th month and increases if administration is close to full term.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the mother and the neonate, 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.

• Increased risk of oedema formation in the mother.

Consequently, Solaraze is contraindicated during the third trimester of pregnancy (see section 4.3).

Breastfeeding:

Like other NSAIDs, diclofenac passes into breast milk in small amounts. However, at the recommended therapeutic doses of Solaraze 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, Solaraze 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).

Solaraze has no influence on the ability to drive and use machines.

Most frequently reported adverse reactions include skin reactions such as contact dermatitis, erythema and rash or application site reactions such as inflammation, irritation, pain and blistering. In studies there appeared to be no age specific increase or pattern of reactions.

Adverse reactions are listed in Table 1 according to Medical Dictionary for Regulatory Activities (MedDRA) system organ class and in decreasing frequency defined as follows: very common: (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1,000, <1/100); rare (≥ 1/10,000, <1/1,000); very rare (<1/10,000); Not known: frequency cannot be estimated from the available data.

Table 1: Treatment-related adverse reactions reported by body system and frequency

Temporary hair discolouration at the application site has been reported. This is usually reversed on stopping treatment.

Patch testing of previously treated patients indicate a 2.18 % probability of allergic contact dermatitis sensitisation (type IV) to diclofenac with as yet unknown clinical relevance. Cross-reactivity to other NSAIDs is not likely. Serum testing more than 100 patients indicated no presence of type I anti-diclofenac antibodies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Due to the low systemic absorption of Solaraze, overdose is extremely unlikely as a result of topical use. However, the skin should be rinsed with water. There have been no clinical cases of ingestion of Solaraze inducing overdosage.

In the event of accidental ingestion (100 g Solaraze gel contain the equivalent of 3000 mg diclofenac sodium) resulting in significant systemic adverse reactions, general therapeutic measures normally adopted to treat poisoning with non-steroidal anti-inflammatories should be used.

Supporting and symptomatic treatment should be given for complications such as renal failure, convulsions, gastrointestinal irritation and respiratory depression. Gastric decontamination and the use of activated charcoal should be considered, especially within a short time of ingestion.

Specific therapies such as forced diuresis and dialysis will probably not be therapeutic in eliminating NSAIDs due to their high rate of protein binding.

Pharmacotherapeutic group: dermatologicals, other dermatologicals ATC code: D11AX18

Mechanisms of action: Diclofenac is a non-steroidal anti-inflammatory drug. The mechanism of action of diclofenac in AK may be related to the inhibition of the cycloxygenase pathway leading to reduced prostaglandin E₂ (PGE₂) synthesis. In addition, immunohistochemistry (IHC) from skin biopsies revealed that the clinical effects of diclofenac in AK are primarily due to anti-inflammatory, anti-angiogenic and possibly anti-proliferative effects and apoptosis-inducing mechanisms.

Pharmacodynamic Effects: Solaraze has been shown to clear AK lesions with maximum therapeutic effect seen 30 days after cessation of drug therapy.

Clinical efficacy and safety: Data from 3 company-sponsored, randomised, double-blind clinical trials in which Solaraze was used as a comparator arm (Studies 0908, 1004 and 0702) provide further evidence on the efficacy of Solaraze in the treatment of AK lesions (including hyperkeratotic lesions) across a number of endpoints. Specifically the Solaraze arm showed histological clearance rates between 47.6 % and 54.1 % while these were between 33.9 % and 42.7 % for vehicle. Complete clinical clearance of AK lesions was achieved in 37.9 % and 23.4 % of patients at 30 (n=11/29) and 60 days post-treatment (n= 76/380).

In a three arm study comparing 0.5 % 5-FU, diclofenac 3 % gel and vehicle, both active arms were superior to vehicle in histological and complete cure rates, whereas 0.5 % 5-FU was not inferior to diclofenac 3 % gel and showed higher histological clearance compared to it (70.1 % vs. 54.1 %).

Moderate-to-significant improvements were reported using investigator and patient Global Improvement Index following Solaraze treatment.

Observational 1-year follow-up data indicate that following treatment with diclofenac 3 % gel, complete clearance was achieved by 28.8 % and 36.8 % at 6 and 12 months post treatment respectively (18.9 % and 25.0 % with placebo at similar time points).

The efficacy of Solaraze has been investigated in 32 patients (24 on diclofenac 3 % gel, 8 on placebo) who had previously undergone organ transplantation, and now had a currently stable graft. diclofenac 3 % gel was superior to vehicle in both complete clearance of AK lesions (41 % vs. 0%) and lesion count reduction (53 % vs. 17 %).

Absorption: Mean absorption through the skin varies between <1-12 % with large inter-individual variability. Absorption is dependent on the amount of the topical dose applied and the site of application.

Distribution: Diclofenac binds highly to serum albumin.

Biotransformation: Biotransformation of diclofenac involves partly conjugation of the intact molecule, but mainly single and multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however to a much lesser extent than diclofenac. Metabolism of diclofenac following percutaneous and oral administration is similar.

Elimination: Diclofenac and its metabolites are excreted mainly in the urine. Systemic clearance of diclofenac from plasma is 263 ± 56 ml/min (mean value ± standard deviation) following oral administration. Terminal plasma half-life is short (1-2 hours). For the metabolites also have short terminal half-lives of 1-3 hours.

Pharmacokinetics in special patient populations: After topical application, the absorption of diclofenac in normal and compromised epidermis are comparable although there is a large inter-individual variation. Systemic absorption of diclofenac is approximately 12 % of the administered dose for compromised skin and 9 % for intact skin.

Published animal studies have shown that when given orally, the principal adverse effect is on the gastrointestinal tract. Diclofenac inhibited ovulation in the rabbit and impaired implantation, as well as early embryonic development in the rat. The embryo/foeto-toxic potential of diclofenac was evaluated in three animal species (rat, mouse and rabbit). Foetal death and growth retardation occurred at maternal toxic doses, however, on the basis of the available data, diclofenac is not considered to be teratogenic. The gestation period and the duration of parturition were extended by diclofenac. Doses lower than maternal toxic ones did not affect the postnatal development. Results from extensive genotoxicity and carcinogenicity testing suggest that it is unlikely that diclofenac would pose a significant carcinogenic hazard to humans.

Sodium hyaluronate, benzyl alcohol, macrogol monomethyl ether 350 and purified water

Not applicable.

2 years

After 1^st opening: 6 months

Do not store above 25 ° C.

The product is supplied in an epoxy-phenolic lined sealed aluminium tube with a white polypropylene screw on cap with a pierced tip, in 25 g, 50 g, 60 g, 90 g and 100 g sizes.

Not all pack sizes may be marketed.

No special requirements.