Ameluz 78 mg/g gel

One gram (g) gel contains 78 mg of 5-aminolaevulinic acid (as hydrochloride).

Excipients with known effect:

One gram gel contains 2.4 mg sodium benzoate (E211), 3.0 mg soybean phosphatidylcholine, and 10.0 mg propylene glycol.

For the full list of excipients, see section 6.1.

Gel.

White to yellowish gel.

Treatment of actinic keratosis of mild to moderate intensity on the face and scalp (Olsen grade 1 to 2; see section 5.1).

Ameluz should only be administered under the supervision of a physician, a nurse or other healthcare professionals experienced in the use of photodynamic therapy.

Posology in adults including the elderly

One session of photodynamic therapy should be administered for single or multiple lesions. Actinic keratosis lesions should be eva luated three months after treatment. Non- or partially responding lesions should be re-treated in a second session. The gel should cover the lesions and approximately 5 mm of the surrounding area with a film of about 1 mm thickness. 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 light dose is determined by factors such as 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.

Paediatric population

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

Method of administration

Preparation of the lesions: Before administration of Ameluz scales and crusts should be removed accurately. In addition, all lesion surfaces should be roughened gently. Care should be taken to avoid bleeding. Thereafter, all lesions should be carefully wiped-off with an ethanol or isopropanol-soaked cotton pad to ascertain degreasing of the skin.

Application of the gel: Ameluz should be applied to the entire lesion area using glove protected fingertips or a spatula. The gel can be administered to healthy skin around the lesions, whereas application near the eyes, nostrils, mouth, ears or mucosa should be avoided (keep a distance of 1 cm). Direct contact of Ameluz with the eyes or mucous membrane should be avoided. In case of accidental contact, rinsing with water is recommended. The gel should be allowed to dry for approximately 10 minutes, before an occlusive 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.

Illumination: Immediately after cleaning the lesions, the entire treatment area will be illuminated with a red light source. During illumination the lamp should be fixed at the distance from the skin surface that is indicated in the user manual. 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).

Each lamp should be used according to the user manual. Only CE marked lamps should be used, equipped with the necessary filters and/or reflecting mirrors to minimize exposure to heat, blue light and ultra violet (UV) radiation. The technical specifications of the device need to be checked before using a specific light source, and the requirements must be met for the intended light spectrum. Both the patient and the medical personnel conducting the photodynamic therapy should adhere to any safety instructions provided with the light source used. During illumination, patient and medical personnel should wear suitable protective goggles. There is no need to protect healthy untreated skin surrounding the treated actinic keratosis lesions.

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

• Hypersensitivity to the active substance, to porphyrins 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 erythematoides or phemphigus erythemtoides.

• No experience exists for the use of Ameluz in patients with inherited or acquired coagulation defects or in immunosuppressed patients.

• No experience exists for the treatment of BCC and Bowen's disease, which should therefore not be treated with the product.

• There is no experience of treating severe actinic keratoses or lesions which are pigmented or highly infiltrating.

• Ameluz should not be used on bleeding lesions.

• There is no experience of treating actinic keratosis lesions in patients with dark brown or black skin (skin sun sensitivity type V or VI according to Fitzpatrick).

• The success and assessment of treatment may be impaired if the treated area is affected by the presence of skin diseases (skin inflammation, located infection, psoriasis, excema, and benign or malignant skin cancers) as well as tattoos. No experience exists with these situations.

• 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. Concomitant use with other topical medicinal products should be avoided.

• 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.

• Ameluz contains soybean phosphatidylcholine and should not be applied to patients known to be allergic to peanut or soya. The excipient sodium benzoate may be mildly irritant to the skin, eyes and mucous membranes. Propylene glycol may cause irritation.

Ameluz does not increase 5-aminolaevulinic acid or protoprophyrin IX plasma levels following topical application.

No interaction studies have been performed.

There are no data from the use of 5-aminolaevulinic acid in pregnant women. Animal studies do not indicate reproductive toxicity (see section 5.3). As a precautionary measure, Ameluz is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether 5-aminolaevulinic acid is excreted in human or animal milk. As a precautionary measure, breast-feeding should be interrupted for 12 hours after application of Ameluz.

Not relevant.

In clinical trials with Ameluz, local skin reactions at the application site were observed in about 90% of the subjects. 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 narrow spectrum lamps (see section 5.1).

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. In rare cases, the adverse reactions may require interruption or discontinuation of the illumination.

The incidence of adverse reactions in a clinical trial population of 357 subjects exposed to treatment with Ameluz is listed below. 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.

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.

Pharmacotherapeutic group: Antineoplastic agent, Sensitizers used in photodynamic/radiation therapy, ATC code: L01XD04

Mechanism of action

Following topical application of 5-aminolaevulinic acid, the substance is metabolized to protoporphyrin IX, a photoactive compound which accumulates intracellularly in the treated actinic keratosis lesions. Protoporphyrin IX is activated by illumination with red light of a suitable wavelength and energy. In the presence of oxygen, reactive oxygen species are formed. The latter causes damage of cellular components and eventually destroys the target cells.

Clinical data

Efficacy and safety of Ameluz has been eva luated in 357 patients enrolled in clinical trials. In clinical phase III, all patients had 4 to 8 mild to moderate actinic keratosis lesions on the face and/or scalp. The application site preparation and duration of incubation followed the description under section 4.2. If not completely cleared 12 weeks after initial treatment, lesions were treated a second time with an identical regimen.

In a randomised, observer blinded clinical trial with 571 patients and a follow-up duration of 6 and 12 months, photodynamic therapy with Ameluz was tested for non-inferiority to a commercially registered cream containing 16% methyl-aminolevulinate (MAL, methyl-[5-amino-4-oxopentanoate]) and superiority over placebo. The red light source was either a narrow light spectrum lamp (Aktilite CL 128 or Omnilux PDT) or a lamp with a broader and continuous light spectrum (Waldmann PDT 1200 L, or Hydrosun Photodyn 505 or 750). The primary endpoint was complete patient clearance 12 weeks after the last photodynamic therapy. Ameluz (78.2%) was significantly more effective than MAL (64.2%, [97.5%- confidence interval: 5.9; ∞]) and placebo (17.1%, [95%- confidence interval: 51.2; 71.0]). Total lesion clearance rates were higher for Ameluz (90.4%) compared to MAL (83.2%) and placebo (37.1%). Clearance rates and tolerability were dependent on the illumination source. The following table presents the efficacy and the adverse reactions transient pain and erythema occurring at the application site during photodynamic therapy with different light sources:

Clinical efficacy was re-assessed at follow-up visits 6 and 12 months after the last photodynamic therapy. Recurrence rates after 12 months were slightly better for Ameluz (41.6%, [95%-confidence interval: 34.4; 49.1]) as compared to MAL (44.8%, [95%-confidence interval: 36.8; 53.0]) and dependent on the light spectrum used for illumination, in favour of narrow spectrum lamps. Prior to the decision to undergo photodynamic therapy it should be taken into consideration that the probability of a subject to be completely cleared 12 months after the last treatment was 53.1% or 47.2% for treatment with Ameluz and 40.8% or 36.3% for MAL treatment with narrow spectrum lamps or all lamp types, respectively. The probability of patients in the Ameluz group to require only 1 treatment and remain completely cleared 12 months after the photodynamic therapy was 32.3%, that of patients in the MAL group 22.4% on average with all lamps.

Cosmetic outcome assessed 12 weeks after the last photodynamic therapy (with baseline sum score 0 excluded) was judged as: very good or good in 43.1% of subjects in the Ameluz group, 45.2% in the MAL group and 36.4% in the placebo group; and unsatisfactory or impaired in 7.9%, 8.1% and 18.2% of subjects, respectively.

Ameluz was also compared with placebo treatment in a randomised, double-blind clinical trial enrolling 122 patients. The red light source provided either a narrow spectrum around 630 nm at a light dose of 37 J/cm² (Aktilite CL 128) or a broader and continuous spectrum in the range between 570 and 670 nm at a light dose of 170 J/cm² (Photodyn 750). The primary endpoint was complete patient clearance after 12 weeks following the last photodynamic therapy. Photodynamic therapy with Ameluz (66.3%) was significantly more effective than with placebo (12.5%, p < 0.0001). Total lesion clearance was higher for Ameluz (81.1%) compared to placebo (20.9%). Clearance rates and tolerability were dependent on the illumination source in favour of the narrow spectrum light source. Clinical efficacy was maintained during the follow-up periods of 6 and 12 months after the last photodynamic therapy. Prior to the decision to undergo photodynamic therapy it should be taken into consideration that the probability of a subject to be completely cleared 12 months after the last treatment was 67.5% or 46.8% for treatment with Ameluz with narrow spectrum lamps or all lamp types, respectively. The probability to require only one treatment with Ameluz and remain completely cleared 12 months later was 34.5% on average with all lamps.

In both studies the clearance rates were higher after illumination with narrow light spectrum devices but the incidence and intensity of administration site disorders (e.g. transient pain, erythema) increased in patients illuminated with these devices (see tables above and section 4.8).

The cosmetic outcome was assessed as very good or good in 47.6% of the subjects in the Ameluz group compared to 25.0% of subjects in the placebo group. An unsatisfactory or impaired cosmetic outcome was judged for 3.8% of the subjects in the Ameluz group and in 22.5% of the subjects in the placebo group.

Actinic keratosis lesion intensity was graded according to the scale described by Olsen et al., 1991 (J Am Acad Dermatol 1991; 24: 738-743):

 Grade   Clinical description of intensity grading
0  none  no AK lesion present, neither visible nor palpable
1  mild  flat, pink maculae without signs of hyperkeratosis and erythema, slight palpability, with AK felt better than seen
2  moderate  pink to reddish papules and erythematous plaques with hyperkeratotic surface, moderately thick AK that are easily seen and felt
3  severe  very thick and / or obvious AK

The European Medicines Agency has waived the obligation to submit the results of studies with Ameluz in all subsets of the paediatric population in Actinic Keratosis (see section 4.2 for information on paediatric use).

In vitro dermal absorption into human skin was studied using Ameluz containing radiolabelled 5- aminolaevulinic acid. After 24 hours, the mean cumulative absorption (including accumulation in the dermis) through human skin was 0.2% of the administered dose. Corresponding studies in human skin with actinic keratosis lesions and/or roughened surface were not performed.

In a phase II clinical trial, 5-aminolaevulinic acid and protoporphyrin IX serum levels and 5- aminolaevulinic acid urine levels were measured before, 3 and 24 hours after administration of Ameluz for photodynamic treatment. None of the post-dose levels were increased in comparison to the naturally occuring pre-dose levels, showing absence of a relevant systemic absorption after topical administration.

Non-clinical data reveal no special hazard for humans based on dermal toxicity studies or studies reported in the literature of repeated dose toxicity, genotoxicity and reproductive toxicity.

Carcinogenicity studies have not been performed with ALA.

Xanthan gum

Soybean phosphatidylcholine

Polysorbate 80

Triglycerides, medium-chain

Isopropyl alcohol

Disodium phosphate dihydrate

Sodium dihydrogen phosphate dihydrate

Propylene glycol

Sodium benzoate (E211)

Purified water

Not applicable.

Unopened tube: 18 months

After first opening: 12 weeks

Store in a refrigerator (2°C – 8°C).

Keep the tube tightly closed after first opening.

Aluminium tube with epoxyphenol inner lacquer and a latex seal and a screw cap of high density polyethylene. Each tube contains 2 g of gel.

Any unused contents have to be discarded.

Biofrontera Bioscience GmbH

Hemmelrather Weg 201

51377 Leverkusen

Germany

Tel: +49-214-87632-66

Fax: +49-214-87632-90

Email: ameluz@biofrontera.com

EU/1/11/740/001

Date of first authorisation: 14 December 2011

April 2016

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.