Regulatory Decision Summary for Metvix

This Supplement to a New Drug Submission (SNDS) was filed with the purpose of updating some wording included in the Indications and Dosage and Administration sections of the Product Monograph (PM) to add clarity on the appropriateness of using Metvix in the first-line treatment of Actinic Keratosis (AK) and specify modalities for treating affected areas of skin.

In addition, the sponsor proposed the inclusion of the adverse event "Transient Global Amnesia" (TGA) in the Warnings and Precautions section and incorporated format changes according to the Health Canada Guidance Document: Product Monograph (2020).

The efficacy of Metvix-photodynamic therapy (PDT) for Actinic Keratosis (AK) treatment was demonstrated in two Phase III, multicenter, double-blind, randomized, vehicle-controlled, parallel-group trials (PC T404/05 and PC T405/05) that included patients with “multiple, untreated, non-pigmented, non-hyperkeratotic AK lesions on the face and/or scalp for whom other standard therapies (e.g. surgery of cryotherapy at that time), were considered medically less appropriate.” Since its approval in 2009, several studies have evaluated the efficacy of Metvix as a first-line alternative, especially for multiple lesions (field-directed treatment) with no notable safety concerns.

In this submission, the Sponsor proposed to remove the statement "when other therapies are considered less appropriate" from the AK indications and to add the term “and/or field cancerization” to the dosage and administration section of the PM with the purpose of clarifying that Metvix-PDT can be used not only to treat single isolated lesions but also for multiple lesions or “field of cancerization.” Based on the evidence provided, Pharmaceutical Drugs Directorate (PDD) agreed with the company that the statement "when other therapies are considered less appropriate" should be removed from the AK indications. The final recommended AK indication is the following: “Metvix topical cream in combination with 630 nm wavelength red light illumination using the Aktilite CL 128 lamp (conventional photodynamic therapy [c-PDT]) or in combination with daylight (daylight photodynamic therapy [DL-PDT]) is indicated for the treatment of thin or non-hyperkeratotic and non-pigmented actinic keratosis on the face and scalp.”

The sponsor proposed that the addition of the term “and/or field cancerization” to the Dosage and Administration section of the PM with the purpose of clarifying that Metvix-PDT can be used not only to treat single isolated lesions but also for multiple lesions or “field of cancerization.” This change was supported by evidence from a pharmacokinetic (PK) study and the literature. The PDD agreed with the sponsor in the importance of providing clarification on Metvix-PDT administration modalities. However, the term "field cancerization” was considered imprecise, as no standard definition is available. To avoid the use of vague concepts in the PM, PDD recommended replacing the term "field of cancerization" by the term "field-directed treatment," which was accepted by the sponsor.

The association between Transient Global Amnesia (TGA) and Metvix-PDT has been known since 2017, and no increase in the number or seriousness of reports was noted in the last 5 years. PDD therefore agreed with the sponsor regarding the inclusion of TGA in the PM; not only to raise awareness of this adverse event, but also to align the safety information between the PM, the CCDS, and the PM of similar products.

In summary, PDD considers that the PM changes proposed in this SNDS do not affect the way in which this product is being used, but rather incorporate some clarifications on the appropriateness of using Metvix as a first-line alternative not only for treating single but for multiple AK lesions, which is in line with well-known and widely recommended clinical practice.

Based on the evidence reviewed, it can be concluded that the benefit-risk profile of Metvix remains favorable.

For further details about Metvix, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.