4.1. Therapeutic indications

Treatment of thin or non-hyperkeratotic and non-pigmented actinic keratoses on the face and scalp.

Only for treatment of superficial and/or nodular basal cell carcinoma unsuitable for other available therapies due to possible treatment related morbidity and poor cosmetic outcome; such as lesions on the mid-face or ears, lesions on severely sun damaged skin, large lesions, or recurrent lesions.

Treatment of squamous cell carcinoma in situ (Bowen´s disease) when surgical excision is considered less appropriate.

Metvix is indicated in adults above 18 years of age.

4.2. Posology and method of administration

Posology

Adults (including the older people)

AK, BCC and Bowen's disease using red light

For treatment of actinic keratoses (AK) one session of photodynamic therapy should be administered. Treated lesions should be evaluated after three months and if there has been an incomplete response, a second treatment may be given. For treatment of basal cell carcinoma (BCC) and Bowen's disease two sessions should be administered with an interval of one week between sessions. Before applying Metvix, the lesion surface should be prepared to remove scales and crusts and roughen the surface of the lesions. Nodular BCC lesions are often covered by an intact epidermal keratin layer which should be removed. Exposed tumour material should be removed gently without any attempt to excise beyond the tumour margins.

AK using daylight

The daylight treatment may be used to treat mild to moderate AK lesions. One treatment should be given. Treated lesions should be evaluated after three months and if there has been an incomplete response, a second treatment may be given.

Paediatric population

The safety and efficacy of Metvix in children below 18 years have not yet been established.

Method of administration

Treatment of AK lesions and/or field cancerization, BCC and Bowen's disease using red-light lamp:

a) Preparation of the lesions: Scales and crusts should be removed, and the skin surface roughened before applying a thin layer of Metvix to the lesion(s). Using a spatula, apply a layer of Metvix (about 1 mm thick) to the lesion area (for field cancerization up to 20 cm2, approximately) and approximately 5-10 mm of the surrounding area. Cover the treated area with an occlusive dressing for 3 hours. Remove the dressing and clean the area with saline.

b) Illumination: Immediately after cleaning the lesions, the entire treatment area will be illuminated with a red-light source, either with a narrow spectrum around 630 nm and a light dose of approximately 37 J/cm2 or a broader and continuous spectrum in a range between 570- and 670 nm with a light dose of approximately 75 J/cm². The light intensity at the lesion surface should not exceed 200 mW/cm2.Only CE marked lamps should be used, equipped with necessary filters and/or reflecting mirrors to minimize exposure to heat, blue light and UV radiation. It is important to ensure that the correct light dose is administered. The light dose is determined by factors such as the size of the light field, the distance between lamp and skin surface and illumination time. These factors vary with lamp type, and the lamp should be used according to the user manual. The light dose delivered should be monitored if a suitable detector is available. Patient and operator should adhere to safety instructions provided with the light source. During illumination patient and operator should wear protective goggles which correspond to the lamp light spectrum. Healthy untreated skin surrounding the lesion does not need to be protected during illumination. Multiple lesions may be treated during the same treatment session.

Lesion responses should be assessed after three months, and at this response evaluation, lesion sites showing non-complete response may be retreated if desired. It is recommended that the response of BCC and Bowen's disease lesions be confirmed by histological examination of biopsy material. Subsequently, close long term clinical monitoring of BCC and Bowen´s disease is recommended, with histology if necessary.

Treatment of AK using lesions and/or field cancerization with natural daylight

a) Considerations before treatment: Metvix natural daylight treatment can be used if the temperature conditions are suitable to stay comfortably outdoors for 2 hours. If the weather is rainy, or is likely to become so, Metvix natural daylight treatment should not be used (see section 5.1).

b) Preparation of the lesions: A sunscreen should be applied, please see section 4.4. Once sunscreen has dried, scales and crusts should be removed and the skin surface roughened before applying a thin layer of Metvix to the lesion(s) or field of cancerization. No occlusion is necessary.

c) Illumination using daylight for AK treatment: Patients should go outside after Metvix application or, at the latest, 30 minutes later in order to avoid excessive protoporphyrin IX accumulation which would lead to greater pain on light exposure. In order to minimize pain and ensure maximum efficacy the patient should then stay outdoors for 2 continuous hours in full natural daylight and avoid going indoors. On sunny days, should the patient feel uncomfortable in direct sunlight, shelter in the shade may be taken. Following the 2 hour exposure period, Metvix should be washed off.

Multiple lesions may be treated during the same treatment session

Treated lesions should be evaluated after three months and if there has been an incomplete response, a second treatment may be given.

Treatment of AK lesions and/or field cancerization using artificial daylight device

Preparation of the lesions: Scales and crusts should be removed, and the skin surface roughened before applying a thin layer of Metvix to the areas to be treated.

a) Occlusion is not necessary. Sunscreen is not needed, as patients are not exposed to ultraviolet light.

Illumination using artificial daylight for AK treatment: Lesion should be exposed after Metvix application or, at the latest, 30 minutes later in order to avoid excessive protoporphyrin IX accumulation which would lead to greater pain on light exposure. In order to minimize pain and ensure maximum efficacy, the patient should be exposed to artificial daylight for 2 continuous hours in a comfortable position. Following the 2-hour exposure period, Metvix should be washed off.

Only CE marked devices should be used. The devices should have a continuous light spectrum of 400 to 750 nm and an illuminance greater than 12,000 lux at the lesion surface. It is important to ensure that the correct light dose is administered. The light dose is determined by factors such as the illuminance (or equivalent), the size of the light field, the distance between lamp and skin surface and illumination time. These factors vary with lamp type, and the lamp should be used according to the user manual. Patient and operator should adhere to safety instructions provided with the light source.

b) Healthy untreated skin surrounding the lesion does not need to be protected during illumination. Multiple lesions may be treated during the same treatment session

Lesion responses should be assessed after three months, and at this response evaluation, lesion sites showing incomplete response may be retreated if desired.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, including arachis oil or peanut or soya.

Morpheaform basal cell carcinoma.

Porphyria.

4.4. Special warnings and precautions for use

The usage of Metvix requires a specific knowledge in photodynamic therapy as it may necessitate the use of a red-light lamp or an artificial daylight lamp . Accordingly, it should be administered in the presence of a physician, a nurse or other health care professional trained in the use of photodynamic therapy.

When using Metvix with natural daylight, a sunscreen should be applied to all areas exposed to daylight, including the treatment areas, prior to lesion preparation. Sunscreen used should offer adequate protection (SPF30 or higher) and must not include physical filters (e.g. titanium dioxide, zinc oxide, iron oxide) as these inhibit absorption of visible light which may impact efficacy. Only sunscreens with chemical filters should be used with daylight treatment.

Metvix is not recommended during pregnancy (see section 4.6).

Thick (hyperkeratotic) actinic keratoses should not be treated with Metvix. There is no experience of treating lesions which are pigmented, highly infiltrating or located on the genitalia with Metvix. There is no experience of treating Bowen´s disease lesions larger than 40 mm. As with cryotherapy and 5-FU therapy of Bowen´s disease, response rates of large lesions (>20 mm in diameter) are lower than those of small lesions.

There is limited experience from post-authorisation exposure in treating actinic keratoses and Bowen´s disease in transplant patients on immunosuppressive therapy. A close monitoring of these patients, with re-treatment if necessary is recommended in this population.

There is no experience of treating Bowen´s disease in patients with a history of arsenic exposure.

Methyl aminolevulinate may cause sensitization by skin contact resulting in angioedema, application site eczema or allergic contact dermatitis. The excipient cetostearyl alcohol may cause local skin reactions (e.g. contact dermatitis), methyl- and propyl parahydroxybenzoate (E218, E216) may cause allergic reactions (possibly delayed).

Any UV-therapy should be discontinued before treatment. As a general precaution, sun exposure of the treated lesion sites and surrounding skin should be avoided for about 2 days following treatment. Direct eye contact with Metvix should be avoided. Metvix cream should not be applied to the eyelids and mucous membranes.

Pain during illumination with red light may induce increased blood pressure. It is thus recommended to measure blood pressure in all patients prior to treatment with red light. If severe pain occurs during treatment with red light, the blood pressure should be checked. In case of severe hypertension, the illumination with red light should be interrupted in addition to taking appropriate symptomatic measures.

Conventional Photodynamic Therapy (PDT) with a red-light lamp may be a precipitating factor for transient global amnesia in very rare instances. Although the exact mechanism is not known, stress and pain associated with illumination with the lamp may increase the risk to develop transient amnesia. If signs of confusion or disorientation are observed, PDT must be discontinued immediately

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of methyl aminolevulinate in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Metvix is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breastfeeding

It is unknown whether methyl aminolevulinate/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Metvix therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Metvix with red light in AK, BCC and Bowen's disease

a) Summary of the safety profile: approximately 60% of patients experience reactions localised to the treatment site that are attributable to toxic effects of the photodynamic therapy (phototoxicity) or to preparation of the lesion.

The most frequent symptoms are painful and burning skin sensation typically beginning during illumination or soon after and lasting for a few hours with resolving on the day of treatment. The symptoms are usually of mild or moderate severity and rarely require early termination of illumination. The most frequent signs of phototoxicity are erythema and scab. The majority are of mild or moderate severity and persist for 1 to 2 weeks or occasionally longer.

Local phototoxic reactions may be reduced in frequency and severity with repeated treatment of Metvix.

b) Tabulated list of adverse reactions: the incidence of adverse reactions in a clinical trial population of 932 patients receiving the standard treatment regimen with red light and adverse reactions reported from the post marketing surveillance are shown in the table below.

The adverse reactions are classified by System Organ Class and frequency, 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), not known (cannot be estimated from the available data) (see Table 1).

Table 1: tabulated list of adverse reactions

System organ class (MedDRA)

Frequency*

Adverse reaction

Nervous system disorders

Common

Paraesthesia, headache

Not Known

Transient global amnesia (including confusional state and disorientation)

Eye disorders

Uncommon

Eye swelling, eye pain

Not known

Eyelid oedema

Vascular disorders

Uncommon

Wound haemorrhage

Not known

Hypertension

Gastrointestinal disorders

Uncommon

Nausea

Skin and subcutaneous tissue disorders

Very common

Pain of skin, skin burning sensation, scab, erythema

Common

Skin infection, skin ulcer, skin oedema, skin swelling, blister, skin hemorrhage, pruritus, skin exfoliation, skin warm

Uncommon

Urticaria, rash, skin irritation, photosensitivity reaction, skin hypopigmentation, skin hyperpigmentation, heat rash, skin discomfort

Not known

Angioedema, face oedema (swelling face), application site eczema, allergic contact dermatitis, rash pustular (application site pustule)

General disorders and administration site conditions

Common

Application site discharge, feeling hot

Uncommon

Fatigue

Metvix with daylight in AK

No new local adverse reactions were reported in the two phase III Metvix daylight studies compared to the already known local adverse reactions with Metvix red light. Metvix DL-PDT was almost painless compared to Metvix c-PDT (refer to section 5.1).

In the two Phase III studies, including a total of 231 patients, local related adverse events were reported less frequently on Metvix DL-PDT than on c-PDT treated sides (45.0% and 60.1% of subjects, respectively).

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 national reporting system via Yellow Card Scheme at https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The severity of local phototoxic reactions such as erythema, pain and burning sensation may increase in case of prolonged application time and/or very high red light intensity.