- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Excipients with known effect:Metvix contains cetostearyl alcohol (40 mg/g), methyl parahydroxybenzoate (E 218; 2 mg/g), propyl parahydroxybenzoate (E 216; 1 mg/g) and arachis oil (30 mg/g).For the full list of excipients, see section 6.1.
Adults (including older people)
AK, BCC and Bowen's disease using red lightFor 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 daylightThe 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 populationThe safety and efficacy of Metvix in children below 18 years have not yet been established.
Method of administration
AK, BCC and Bowen's disease using red lightApply a layer of Metvix (about 1 mm thick) by using a spatula to the lesion and the surrounding 5-10 mm of normal skin. Cover the treated area with an occlusive dressing for 3 hours.Remove the dressing, and clean the area with saline and immediately expose the lesion to red light with a continuous spectrum of 570-670 nm and a total light dose of 75 J/cm2 at the lesion surface. Red light with a narrower spectrum of approximately 630 nm (and a total light dose of 37 J/cm2) giving the same activation of accumulated porphyrins may be used. 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.
AK using daylight
|Metvix 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 daylight treatment should not be used.|
PregnancyThere are no or limited amount of data from the use of methyl aminolevulinate in pregnant women. Studied 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.
BreastfeedingIt 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.
Metvix with red light in AK, BCC and Bowen's diseasea) 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|
|Eye disorders||Uncommon||Eye swelling, eye pain|
|Not known||Eyelid oedema|
|Vascular disorders||Uncommon||Wound haemorrhage|
|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|
Metvix with daylight in AKNo 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 reactionsReporting 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: www.mhra.gov.uk/yellowcard.
• Metvix with red light in AK, BCC and Bowen's diseaseAfter topical application of methyl aminolevulinate, porphyrins accumulate intracellularly in the treated skin lesions. The intracellular porphyrins (including PpIX) are photoactive, fluorescing compounds and, upon light activation in the presence of oxygen, singlet oxygen is formed which causes damage to cellular compartments, in particular the mitochondria. Light activation of accumulated porphyrins leads to a photochemical reaction and thereby phototoxicity to the light-exposed target cells. Metvix with daylight in AK After topical application of methyl aminolevulinate, porphyrins are produced intracellularly in the treated skin lesions. The intracellular porphyrins (including PpIX) are photoactive, fluorescing compounds and, upon daylight activation in the presence of oxygen, singlet oxygen is formed which causes damage to cellular compartments, in particular the mitochondria. When Metvix is used with daylight, PpIX is continuously being produced and activated within the target cells during the 2 hours of daylight exposure creating a constant micro-phototoxic effect. Daylight may not be sufficient for Metvix daylight treatment during winter months in certain parts of Europe. Metvix daylight photodynamic therapy is feasible all year long in southern Europe, from February to October in middle Europe, and from March to October in northern Europe.
Clinical efficacy Metvix with daylight in AK The efficacy and safety of Metvix daylight photodynamic therapy (DL-PDT) was compared to Metvix conventional photodynamic therapy (c-PDT) in two randomised, investigator-blinded, comparative, intra-individual clinical studies conducted in Australia and Europe, including a total of 231 patients. Patients were treated on one side of the face or scalp with Metvix DL-PDT and on the contralateral side with Metvix c-PDT. The results of both Phase III studies demonstrated that Metvix DL-PDT is similar (non-inferior) to Metvix c-PDT for treating AK lesions (on the percentage change from baseline in the number of treated lesions per side at 12 weeks after one treatment) and is significantly less painful. In the Australian study, the percentage change from baseline in the number of mild treated lesions was 89.2% versus 92.8% for DL-PDT versus c-PDT respectively (95% CI of the mean treatment difference: [-6.8; -0.3], per protocol population). In the European study, the percentage change from baseline in the number of total (mild and moderate) treated lesions was 70.1% versus 73.6% for DL-PDT versus c-PDT respectively (95% CI of the mean treatment difference: [-9.5; 2.4], per protocol population).Metvix DL-PDT was almost painless compared to Metvix c-PDT, with a pain score (on an 11-point scale ranging from 0 to 10) of 0.8 versus 5.7 (p<0.001) in the Australian study and 0.7 versus 4.4 (p<0.001) in the European study.In both studies, regardless of whether the weather was sunny or cloudy, efficacy was demonstrated. The maintenance of lesion response rate assessed in the Australian study was high with both treatments for patients presenting at week 24 (96% for DL-PDT and 96.6% for c-PDT).
Galderma (U.K) Ltd
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