AMELUZ

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.

6. A narrow-spectrum lamp is recommended to achieve higher clearance rates. Symptomatic treatment of transient adverse site reactions may be considered. 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 °C).

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 […]

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. 1). 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 At application site: Pustules Infections and infestations Uncommon Not at application site: Rash pustular Psychiatric disorders Uncommon Nervousness Common Headache Nervous system disorders 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 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 General disorders and administration site conditions Uncommon At application site: Discoloration, ulcer, swelling, inflammation, eczema infected, hypersensitivity*1 System organ class Frequency Adverse reaction 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 national reporting system listed in Appendix V.

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.

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.

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. g. skin inflammation, located infection, psoriasis, eczema, and malignant skin cancers other than indicated) as well as tattoos.

No experience exists with these situations. 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.

3).

1. • Porphyria. 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 erythemtosus.