SIDE EFFECTS

Dermal Safety Studies

Studies in healthy volunteer subjects and subjects with actinic keratoses previously treated with Metvixia (methyl aminolevulinate cream) -PDT on at least 4 previous occasions have demonstrated that Metvixia (methyl aminolevulinate cream) Cream has the potential to cause irritancy and sensitization. A cumulative irritancy and sensitization (allergenicity) study of Metvixia (methyl aminolevulinate cream) Cream with a cross-sensitization challenge with aminolevulinic acid (ALA) was performed in 156 subjects. Metvixia (methyl aminolevulinate cream) Cream was applied 3 times each week for 3 weeks (total of 9 applications), to separate sites on the back of healthy volunteers. After each application, the area was covered by an aluminum Finn Chamber. After the 3-week continuous treatment period and a 2-week interval without further applications, subjects were challenged with Metvixia (methyl aminolevulinate cream) Cream, Metvixia (methyl aminolevulinate cream) vehicle, ALA, and ALA-vehicle creams for 48 hours. Assessment of skin reactions was performed 48, 72, and 96 h after start of the challenge cream application. Only 98 of the 156 subjects tested entered the challenge phase because of a high incidence of local irritancy evident as erythema. Of the 58 subjects who were challenged with Metvixia (methyl aminolevulinate cream) Cream, 30 (52 %) showed contact sensitization. Of the 98 subjects who were challenged with ALA, only 2 (2 %) showed equivocal reactions the remaining subjects having negative responses.

The potential for sensitization was also assessed by patch testing a total of 21 patients with actinic keratoses previously treated with Metvixia (methyl aminolevulinate cream) -PDT on at least 4 previous occasions. Metvixia (methyl aminolevulinate cream) Cream 16.8 % and vehicle cream were applied to different sites on the lower back for 48 hours. Three of the 21 patients (14%) showed contact sensitization associated with erythema scores ≥ 4 (strong erythema spreading outside the patch) and edema, vesiculation, papules and glazing.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 231 subjects, each with 4 - 10 actinic keratoses were enrolled in 2 double-blind, randomized, vehicle-controlled clinical trials. Subjects were randomized to receive Aktilite PDT with Metvixia (methyl aminolevulinate cream) Cream 16.8 % or Vehicle cream on 2 occasions 1 week apart. Cream was applied for approximately 3 hours under occlusion followed immediately by illumination using the Aktilite CL128 lamp, delivering red light at a dose of 37 J/cm².

Table 1 shows the incidence and severity of local (treatment site) adverse reactions in these two trials. The most frequent adverse reactions were associated with phototoxicity at the treatment site. Pain and burning sensation typically begin during illumination and generally resolve completely within a few minutes or hours, but may last up to a few days. Erythema and other signs generally resolve within a few days to 3 weeks.

In these two studies, out of 126 subjects treated with Metvixia (methyl aminolevulinate cream) Cream, six Metvixia (methyl aminolevulinate cream) Aktilite PDT subjects did not complete the full two treatment session regimen due to adverse reactions such as headache, pain, or burning. These subjects either stopped illumination early or did not have the second treatment. In addition, 12 Metvixia (methyl aminolevulinate cream) PDT subjects paused illumination due to pain, burning or stinging but did subsequently complete treatment.

Table 1: Incidence of Treatment Site Adverse Reactions in ≥ 1% of Subjects in Studies 1 and 2 (Safety Population)

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Metvixia (methyl aminolevulinate cream) Cream outside of the United States. Because these reactions are reported voluntary from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Reports of serious adverse reactions at or near the application site include pain, erythema, edema, pustules, scab, crusting, and hyperpigmentation. Allergic reactions reported include eczema, allergic contact dermatitis and urticaria. Most cases were localized to the treatment area; rarely erythema and swelling have been more extensive. At sites distant from the application site there have been reports of squamous cell carcinoma of the skin, as expected in this population. There have been occasional reports of eye disorders including edema, eyelid swelling, macular edema, vitreous detachment and keratitis.

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