Label: metvixia- methyl aminolevulinate hydrochloride cream

Mechanism of Action

Photosensitization following application of Metvixia Cream occurs through the metabolic conversion of methyl aminolevulinate (prodrug) to photoactive porphyrins (PAP), which accumulates in the skin lesions to which Metvixia Cream has been applied. When exposed to light of appropriate wavelength and energy, the accumulated photoactive porphyrins produce a photodynamic reaction, resulting in a cytotoxic process dependent upon the simultaneous presence of oxygen. The absorption of light results in an excited state of porphyrin molecules, and subsequent spin transfer from photoactive porphyrins to molecular oxygen generates singlet oxygen, which can further react to form superoxide and hydroxyl radicals. Photosensitization of actinic (solar) keratosis lesions using Metvixia Cream, plus illumination with a CureLight BroadBand Model CureLight 01 (a red light of 570 to 670 nm wavelength) at 75 J/cm2, is the basis for Metvixia photodynamic therapy (PDT). 

Pharmacokinetics

The time-course of PAPs after application of Metvixia Cream has been monitored by means of fluorescence. After application of Metvixia Cream to actinic keratosis lesions in 8 patients, fluorescence was measured at several time points over 28 hours. Three hours after the application of Metvixia Cream the fluorescence in the treated lesions was significantly greater than that seen in both treated and untreated normal skin, and after application of vehicle cream (not containing methyl aminolevulinate) to normal skin. After application of Metvixia Cream for 28 hours and subsequent illumination with red light of 570 to 670 nm wavelength at a total light dose of 75 J/cm2, complete photobleaching (photodegradation) of Protoporphyrin IX occurred with levels of Protoporphyrin IX returning to pre-treatment values within 1 hour after illumination. However, the fate of other photoactive porphyrins are unknown.

The clinical dose of methyl aminolevulinate cream and duration of application were derived from a study in which three different strengths of the cream (16, 80 and 160 mg/g methyl aminolevulinate, as hydrochloride), each applied for 3 hours or 18 hours, were tested in 16 patients.  

CLINICAL STUDIES

Metvixia Cream plus illumination with the CureLight BroadBand Model CureLight 01 (a red light of 570 to 670 nm wavelength) at 75 J/cm2 has been studied in 130 patients with non-hyperkeratotic actinic keratoses in two clinical trials. These trials were not identical; however, both were randomized, multicenter, and double-blinded with patients randomized to Metvixia-PDT and Vehicle-PDT study arms that required two treatment sessions (7 days apart). One study was conducted in the U.S. and patients were randomized 1:1 Metvixia to Vehicle and one study was conducted in Australia with patients randomized 4:1 Metvixia to Vehicle. In both studies treatment consisted of a multi-step process that was repeated after 7 days consisting of 1) Lesion preparation (debridement with sharp curette) to roughen the surface of the lesion. 2) Metvixia or Vehicle Cream application to lesions with occlusion with an adhesive, non-absorbent dressing, 3) Waiting at least 2.5 hours, but no more than 4 hours to allow for conversion of the methyl aminolevulinate, 4) Removal of cream with gauze and saline, 5) Red light Dosimetry and Illumination with the CureLight BroadBand Model CureLight 01 (a red light of 570 to 670 nm wavelength).

Study patients had previously untreated facial and scalp actinic keratoses (AKs) that were slightly palpable (better felt than seen). Hyperkeratotic actinic keratoses were excluded. In the U.S. study 100% of patients had 4 to 10 lesions at baseline. However, in the Australian study, 63% (70/111) of patients had less than 4 lesions at baseline, 31% (34/111) of the enrolled patients had 4 to 10 lesions, and 6% (7/111) had more than 10 lesions at baseline (a maximum of 6 treatment fields were allowed in this study).

A “Cleared” AK lesion was defined as being not visible and not palpable as assessed 3 months after the second treatment session. Patients with all treated lesions cleared at 3 months were defined as Complete Responders. 

The percentage of patients in whom 75% or more of the treated lesions were clear and the percent of patients in whom 100% of the treated lesions were clear 3 months after the second Metvixia-PDT treatment session are shown in Table 1 for each of the two studies. 

Patients with 4 or more lesions had lower success rates than those with less than 4 lesions when treated with PDT using Metvixia Cream (see Table 2).

Lesions that were slightly palpable (Grade 1) had a better success rate than lesions that were visible and palpable (Grade 2) – See Table 3.

Response rate by lesion location is presented in Table 4.

The overall treatment effect as evidenced by the high vehicle response rate may include the contribution of lesion preparation, i.e. curettage. Adequate lesion preparation is an important component for AK therapy with Metvixia Cream.

Information regarding further treatments for residual or new AK lesions performed after 3 months is not available.

General

Metvixia Cream Application

During the time period between the application of Metvixia (methyl aminolevulinate) Cream and exposure to red light illumination, the treatment site will become photosensitive. After Metvixia Cream application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to red light treatment. Exposure to light may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. The treated site should be protected from extreme cold with adequate clothing or remaining indoors between application of Metvixia and PDT light treatment.

After illumination of Metvixia Cream, the area treated should be kept covered and away from light for at least 48 hours. 

Because of the potential for skin to become photosensitized, the Metvixia Cream should be used by a trained physician to apply drug only to non-hyperkeratotic actinic keratoses and perilesional skin within 5 mm of the lesion. Redness, swelling, burning, and stinging are expected as a result of therapy; however, if these symptoms increase in severity and persist longer than 3 weeks, the patient should contact their doctor.

Metvixia Cream has not been studied for more than two treatment sessions.

Information regarding further treatments for residual or new AK lesions performed after 3 months is not available.

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Photosensitivity and Device Precautions.

The patient, operator and other persons present should wear protective goggles that sufficiently screen out light with wavelengths from 570 to 670 nm during red light treatment.

If for any reason the patient cannot have the red light treatment after application of Metvixia Cream, the cream should be rinsed off, and the patient should protect the treated area from sunlight, prolonged or intense light for two days. Prolonged exposure for greater than 4 hours to Metvixia Cream should be avoided.

Coagulation defects

Metvixia Cream has not been tested on patients with inherited or acquired coagulation defects.

Hypersensitivity

Metvixia Cream is formulated with refined peanut and almond oil.

Metvixia (methyl aminolevulinate) Cream has not been tested in patients who are allergic to peanuts. Metvixia (methyl aminolevulinate) Cream has demonstrated a high rate of contact sensitization (allergenicity). 

Information for Patients

The physician should provide and discuss the attached Patient Package Insert with each patient.

Drug Interactions

There have been no studies of the interaction of Metvixia Cream with any other drugs, including local anesthetics. It is possible that concomitant use of other known photosensitizing agents might increase the photosensitivity reaction of actinic keratoses treated with Metvixia Cream.

Carcinogenesis, Mutagenesis, Impairment to Fertility

Long-term studies to evaluate the carcinogenic potential of Metvixia Cream have not been performed. 

Methyl aminolevulinate was negative for genetic toxicity in the Ames assay, and the chromosomal aberration assay in Chinese hamster ovary cells, tested with and without metabolic activation and in the presence and absence of light. Methyl aminolevulinate was also negative in the in vivo micronucleus assay in the rat. In contrast, at least one report in the literature has noted genotoxic effects in cultured rat hepatocytes after aminolevulinate (ALA) exposure with PpIX formation. Other studies have documented oxidative DNA damage in vivo and in vitro as a result of ALA exposure.

No animal fertility studies have been conducted.

Pregnancy

Nursing Mothers

The amount of methyl aminolevulinate secreted into human breast milk following topical administration of Metvixia Cream is not known. Because many drugs are secreted in human milk, caution should be exercised when Metvixia Cream is administered to a nursing mother. If Metvixia Cream is used in a nursing mother, a decision should be made whether or not to stop nursing.

Pediatric Use

It is not recommended that Metvixia Cream be used in pediatric patients. Actinic keratosis is rarely found in pediatric patients. 

Geriatric Use

Seventy percent (269 among 383) of the patients treated with Metvixia Cream in all clinical studies of actinic keratosis were 65 years of age or older. No overall differences in safety and efficacy were observed between patients aged 65 years and older and those who were younger.

Dermal Safety Studies

Provocative studies to evaluate irritancy and sensitization have demonstrated that Metvixia Cream is an irritant and sensitizer. A provocative cumulative irritancy and sensitization (allergenicity) study of Metvixia Cream with a cross-sensitization challenge with ALA was performed in 156 subjects. Only 98 of the 156 subjects tested entered the challenge phase. Fifty-two percent of the subjects (30/58), who agreed to challenge with Metvixia Cream, were positive (sensitized). Forty subjects refused challenge with Metvixia Cream and 60 withdrew. At least 58 of the 60 subjects who withdrew from the study discontinued due to irritation/sensitization.

Ninety-eight subjects agreed to challenge with ALA. Two percent of the ALA challenged subjects (2/98) were scored as equivocal reactions and 2% in the paraffin vehicle group were scored as positive.

Adverse Events

In vehicle-controlled phase 3 studies of actinic keratosis, 88% of patients treated with Metvixia Cream reported one or more adverse events.

Burning was the most frequent complaint, reported by 50% of patients (ranging from mild, to severe) and 9% of those patients reported severe burning sensation. Pain in the skin was reported by 21% of patients and 7% had severe pain. Local erythema lasting up to two weeks and edema up to one week after treatment were reported by 31% and 6% of patients.

Symptoms and signs of local phototoxicity were observed in 88% of patients treated with Metvixia Cream in all clinical studies of Metvixia -PDT for actinic keratoses.

The majority of patients in all the clinical trials had local pain or discomfort upon illumination. There were 4 (1.0%) withdrawals/discontinuations among 383 patients treated with Metvixia Cream in all the clinical trials of actinic keratosis, all of which were due to the adverse event of local pain on illumination.

There have been reported instances of patients treated with Metvixia Cream (2 out of 130) who have developed squamous cell and basal cell carcinoma at the site of treatment. The relationship to treatment with Metvixia Cream is unknown.

Serious erythema and facial edema have been described in European post-marketing reports.

Metvixia Cream Overdose

Metvixia Cream overdose has not been reported. If the patient for any reason cannot have the red light treatment during the prescribed period after application (the 3 hour timespan), the cream should be rinsed off, and the patient should protect the exposed area from sunlight, prolonged or intense light for two days.  

Red Light Overdose

There is no information on overdose of red light following Metvixia Cream application.

In case of red light overexposure and skin burn occurs, the patient should be treated according to standard of practice guidelines for treatment of cutaneous burns.

Product Package

Keep out of reach of children

For topical use only by physicians in the physician’s office.

Rx Only

Storage Conditions

Store refrigerated, 2-8°C (36-46°F).
Use contents within one week after opening.
Should not be used after 24 hours out of refrigerator.

Metvixia Cream is a registered trade name of PhotoCure ASA.
PhotoCure ASA, Hoffsveien 48, N-0377 Oslo, Norway
USA Contact: Cato Research, Westpark Corporate Center, 4364 South Alston Avenue, Durham NC 27713

Revision: September 5, 2007

PATIENT INFORMATION

Metvixia™ Cream 16.8% (phonetic)
Generic name: methyl aminolevulinate hydrochloride

Read this Patient Information before you get treated with Metvixia Cream and each time you get a treatment. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment. Ask your healthcare provider about anything you do not understand about Metvixia Cream.