4.1. Therapeutic indications

Treatment of actinic keratosis of mild to moderate severity (Olsen grade 1 to 2; see section 5.1) and of field cancerization in adults.

Treatment of superficial and/or nodular basal cell carcinoma unsuitable for surgical treatment due to possible treatment-related morbidity and/or poor cosmetic outcome in adults.

4.2. Posology and method of administration

Posology in adults

For treatment of actinic keratoses (AK) of the face or scalp, one session of photodynamic therapy (with natural daylight or a red-light or artificial daylight lamp) shall be administered for single or multiple lesions or entire fields with cancerization (areas of skin where multiple AK lesions are surrounded by an area of actinic and sun-induced damage within a limited field).

For treatment of actinic keratoses (AK) in the body region trunk, neck or extremities, one session of narrow spectrum red-light photodynamic therapy shall be administered.

Actinic keratosis lesions or fields shall be evaluated three months after treatment. Treated lesions or fields that have not completely resolved after 3 months shall be retreated.

For treatment of basal cell carcinoma (BCC), two sessions of photodynamic therapy with red-light lamp shall be administered for one or multiple lesions with an interval of about one week between sessions. Basal cell carcinoma lesions shall be evaluated three months after last treatment. Treated lesions that have not completely resolved after 3 months shall be retreated.

Paediatric population

There is no relevant use of Ameluz in the paediatric population. No data are available.

Method of administration

Ameluz is for cutaneous use.

Ameluz should be administered under the guidance of a physician, a nurse or other healthcare professional experienced in the use of photodynamic therapy. When a red-light or an artificial daylight lamp is required, the treatment should be performed by a healthcare professional.

Treatment of AK, field cancerization and BCC using a red-light lamp:

a) Preparation of the lesions: Before administration of Ameluz, all lesions should be carefully wiped with an ethanol or isopropanol-soaked cotton pad to ensure degreasing of the skin. Scales and crusts should be removed accurately and all lesion surfaces roughened gently. Care should be taken to avoid bleeding. 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.

b) Application of the gel: Ameluz should be applied to the lesion area or entire cancerized fields and approximately 5 mm of the surrounding area in a film of about 1 mm thickness (about 20 cm2 area per tube). The gel should be applied using glove-protected fingertips or a spatula, and it should be allowed to dry for approximately 10 minutes, before a light-tight dressing is placed over the treatment site. Following 3 hours of incubation, the dressing should be removed and the remnant gel wiped off. The gel can be administered to healthy skin around the lesions. Direct contact of Ameluz with the eyes or mucous membranes should be avoided (keep a distance of 1 cm). In case of accidental contact, rinsing with water is recommended.

c) Illumination: 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 the range between 570 and 670 nm with a light dose between 75 and 200 J/cm2. It is important to ensure that the correct light dose is administered. The total light dose is determined by factors such as the irradiance (or equivalent), the size of the light field, the distance between lamp and skin surface, and the illumination time. These factors vary with lamp type. The light dose delivered should be monitored if a suitable detector is available. During illumination the lamp should be fixed at the distance from the skin surface that is indicated in the user manual. See also section 6.6.A narrow-spectrum lamp is recommended to achieve higher clearance rates. Symptomatic treatment of transient adverse site reactions may be considered. A broader and continuous spectrum may be used if narrow-spectrum light sources are not tolerated (see sections 4.8 and 5.1).

Note: Efficacy of Ameluz in the treatment of AK in the body regions trunk, neck and extremities has been demonstrated only in the scope of narrow-spectrum PDT. There are no data for these body regions with broader spectrum lamps PDT or with natural or artificial daylight PDT.

Lesions should be re-assessed after three months, at which point any residual lesions or fields may be retreated. It is recommended that the response of BCC lesions may be confirmed by histological examination of biopsy material, if considered necessary. Subsequently, close long-term clinical monitoring of BCC is recommended, with histology if necessary.

Treatment of AK and field cancerization of the face and scalp with natural or artificial daylight:

a) Considerations before treatment: Natural daylight PDT should only be used if the conditions are suitable to stay comfortably outdoors for two hours (with temperatures > 10 ºC). If the weather is rainy, or is likely to become so, natural daylight treatment should not be used.

For natural daylight PDT, sunscreen should be applied 15 min prior to lesion pretreatment in order to protect sun exposed skin. Only sunscreen with chemical filters and SPF 30 or higher should be used. Sunscreens with physical filters such as titanium dioxide, zinc oxide, etc. should not be used, as these inhibit light absorption and may therefore impact efficacy.For artificial daylight PDT, sunscreen is not needed, as patients are not exposed to ultraviolet light during illumination.

b) Preparation of the lesions: Before administration of Ameluz, all lesions should be carefully wiped with an ethanol or isopropanol-soaked cotton pad to ensure degreasing of the skin. Scales and crusts should be removed accurately and all lesion surfaces roughened gently. Care should be taken to avoid bleeding.

c) Application of the gel: A thin layer of Ameluz should be applied to the lesion area or entire cancerized fields and approximately 5 mm of the surrounding area using glove protected fingertips or a spatula. No occlusive dressing is necessary during incubation. It can be used optionally for artificial daylight PDT, but it should be removed before illumination at the latest. The gel can be administered to healthy skin around the lesions. Direct contact of Ameluz with the eyes or mucous membrane should be avoided (keep a distance of 1 cm). In case of accidental contact, rinsing with water is recommended. The gel should not be wiped off during the entire daylight PDT.

d) Incubation and Illumination using daylight for AK treatment: Natural daylight PDT: If conditions are suitable (see section a. Considerations before treatment), patients shall go outside within 30 minutes after application of the gel and stay for 2 continuous hours in full daylight. Taking shelter in the shade in hot weather is acceptable. Interruption of the time outdoors should be compensated by a longer illumination time. Remaining gel should be removed after completion of light exposure.Artificial daylight PDT: To ensure sufficient protoporphyrin IX (PpIX) synthesis, the total treatment time (covering incubation and illumination) should be 2 hours and should not exceed 2.5 hours. However, illumination should start within 0.5 to 1 hour after gel application to avoid excessive PpIX accumulation, which might lead to increased pain sensation. The illumination time may vary due to different characteristics (e.g. irradiance and light spectrum) of the CE marked medical devices for artificial daylight PDT. The devices should have either a continuous or an intermittent spectrum covering one or more of the PpIX absorption peaks/bands in the range between 400 and 750 nm. All studied artificial daylight devices with proven PpIX activating activity at least addressed the red PpIX absorption peak at about 631 nm. In order to ensure that the correct light dose is administered, light dose and illumination conditions recommended in the user manuals of the artificial daylight devices should be considered. However, the minimal applied dose at the lesions surface should not be less than ~14 J/cm2. Patient and operator should adhere to safety instructions provided with the light source. Remaining gel should be removed after completion of light exposure.

Lesions should be re-assessed after three months, at which point any residual lesions or fields may be retreated.

4.3. Contraindications

• Hypersensitivity to the active substance, to porphyrins, to soya or peanuts, or to any of the excipients listed in section 6.1.

• Porphyria.

• Known photodermatoses of varying pathology and frequency, e.g. metabolic disorders such as aminoaciduria, idiopathic or immunological disorders such as polymorphic light reaction, genetic disorders such as xeroderma pigmentosum, and diseases precipitated or aggravated by exposure to sun light such as lupus erythematosus or pemphigus erythematosus.

4.4. Special warnings and precautions for use

Risk of Transient Global Amnesia (TGA)

Photodynamic therapy (PDT) 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 PDT may increase the risk to develop transient amnesia. If amnesia is observed, the PDT must be discontinued immediately (see section 4.8).

Use of immunosupressants

As inflammatory response is important for the effect of PDT, the trials investigating the efficacy and safety of Ameluz excluded patients who were undergoing treatment with immunosuppression therapy. No experience exists for the use of Ameluz in patients taking immunosuppressants. Therefore, the use of immunosuppressants during treatment with Ameluz is not recommended.

Ameluz should not be used on bleeding lesions

Any bleeding must be stopped before application of the gel. No experience exists for the use of Ameluz in patients with inherited or acquired coagulation defects. Special care should be taken to avoid bleeding during lesion preparation in such patients (see section 4.2).

Risk of mucous membrane and eye irritation

Ameluz can cause mucous membrane or eye irritation. The excipient sodium benzoate may be mildly irritant to the skin, eyes, and mucous membranes.

Special care should be taken to avoid applying Ameluz into eyes or to mucous membranes. In case of accidental contact, the site must be rinsed with water.

Ameluz should not be used on skin areas affected by other diseases or tattoos.

The success and assessment of treatment may be impaired if the treated area is affected by the presence of skin diseases (e.g. skin inflammation, located infection, psoriasis, eczema, and malignant skin cancers other than indicated) as well as tattoos. No experience exists with these situations.

Intensive lesion preparation might lead to increased pain

Some intensive lesion preparation protocols (e.g. chemical peel followed by ablative laser) might increase the frequency and intensity of pain sensation during PDT. This was noticed in the scope of artificial daylight PDT but should also be considered for red-light PDT and natural daylight PDT.

Ameluz transiently increases phototoxicity

Any UV-therapy should be discontinued before treatment. As a general precaution, sun exposure on the treated lesion sites and surrounding skin should be avoided for approximately 48 hours following treatment. Concomitant use of medicinal products with known phototoxic or photoallergic potential such as St. John's wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones and tetracyclines may enhance the phototoxic reaction to photodynamic therapy.

Risk of allergic reaction

Ameluz contains soybean phosphatidylcholine and should not be applied to patients known to be allergic to peanut or soya (see section 4.3).

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

Ameluz does not significantly increase the natural plasma levels of 5-aminolaevulinic acid or protoporphyrin IX following topical application (see section 5.2).

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of 5 aminolaevulinic acid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Ameluz during pregnancy.

Breast-feeding

It is unknown whether 5-aminolaevulinic acid/metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued for 12 hours after treatment with Ameluz.

Fertility

There are no data available on the effect of 5-aminolaevulinic acid on fertility.

4.7. Effects on ability to drive and use machines

Ameluz has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

In clinical trials with Ameluz, local skin reactions at the application site were observed in most of the subjects treated for actinic keratosis and basal cell carcinoma. This is to be expected as the therapeutic principle of photodynamic therapy is based on phototoxic effects of protoporphyrin IX which is synthesized from the active ingredient 5-aminolaevulinic acid.

The most common signs and symptoms are application site irritation, erythema, pain, and oedema. The intensity of these effects is dependent on the type of illumination used for photodynamic therapy. The increased effects correlate with the higher clearance rate of red-light narrow spectrum lamps (see section 5.1). In rare cases, adverse reactions, e.g. pain required interruption or discontinuation of the illumination.

The study of Ameluz using natural and artificial daylight showed similar types of side effects. However, intensity of some adverse reactions, particularly pain, was lower when Ameluz was used in combination with daylight PDT.

Most adverse reactions occur during illumination or shortly afterwards. The symptoms are usually of mild or moderate intensity (investigator's assessment on a 4-point scale), and last for 1 to 4 days in most cases; in some cases, however, they may persist for 1 to 2 weeks or even longer.

Tabulated list of adverse reactions

The incidence of adverse reactions in 624 subjects exposed to photodynamic therapy with Ameluz in pivotal clinical trials is listed below. All these adverse reactions were non serious. The table additionally includes serious adverse reactions reported post-marketing. Frequencies are defined as 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), and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Summary of related adverse drug reactions (ADRs) reported in patients treated with photodynamic therapy with 5-aminolaevulinic acid

System organ class

Frequency

Adverse reaction

Infections and infestations

Uncommon

At application site: Pustules

Not at application site: Rash pustular

Psychiatric disorders

Uncommon

Nervousness

Nervous system disorders

Common

Headache

Uncommon

Transient global amnesia (incl. confusion and disorientation)*, Dysaesthesia

Eye disorders

Uncommon

Eyelid oedema, vision blurred, visual impairment

Skin and subcutaneous disorders

Uncommon

Blister, dry skin, petechiae, skin tightness

Musculoskeletal and connective tissue disorders

Uncommon

Back pain

General disorders and administration site conditions

Very common

At application site: Erythema, pain (incl. burning pain), irritation, pruritus, oedema, scab, exfoliation, induration, paraesthesia

Common

At application site: Vesicles, discharge, erosion, reaction, discomfort, hyperalgesia, haemorrhage, warmth

Uncommon

At application site: Discoloration, ulcer, swelling, inflammation, eczema infected, hypersensitivity*1

Not at application site: Chills, feeling hot, pyrexia, pain, fatigue, ulcer, swelling

Injury, poisoning and procedural complications

Uncommon

Wound secretion

Vascular disorders

Uncommon

Hot flush

* Data from post-marketing period.

1 This reaction also occurs before illumination.

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.yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose following topical administration is unlikely and has not been reported in clinical studies. If Ameluz is accidentally ingested, systemic toxicity is unlikely. Protection from sun light exposure for 48 hours and observation are nevertheless recommended.