METVIXIA

METVIXIA- methyl aminolevulinate hydrochloride cream
Penn Pharmaceutical Services Ltd.

DESCRIPTION

Metvixia Cream is an oil in water emulsion. Metvixia Cream contains methyl aminolevulinate hydrochloride equivalent to168 mg/g of methyl aminolevulinate.

Methyl aminolevulinate hydrochloride is a white to slightly yellow powder that is freely soluble in water and methanol, soluble in ethanol and practically insoluble in most organic solvents.

The chemical formula for methyl aminolevulinate HCl is C6 H11 NO3 ·HCl (MW=181.62) and it has the following structural formula:

Image from Drug Label Content

Metvixia Cream contains glyceryl monostearate, cetostearyl alcohol, polyoxyl stearate, cholesterol and oleyl alcohol as emulsifying agents. It also contains glycerin, white petrolatum, isopropyl myristate, refined peanut oil, refined almond oil as emollients, edetate disodium as a chelating agent and methylparaben and propylparaben as preservatives.

CLINICAL PHARMACOLOGY

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.

Table 1. Patient Responses at 3-Month Post-Second Treatment Session
Australian Study U. S. Study
Patient Response Metvixia-PDT Vehicle PDT Metvixia -PDT Vehicle PDT
Patients with at least 75% of AK Lesions Cleared 76/88 (86%) 4/23 (17%) 35/42 (83%) 12/38 (32%)
Complete Responders (All Lesions clinically cleared at 3 months) 71/88 (81%) 3/23 (13%) 33/42 (79%) 8/38 (21%)

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).

Table 2. Complete Responders at 3-Month Post-Treatment for Different Baseline AK Lesion Counts
Australian Study U.S. Study
Baseline Lesion Count Metvixia-PDT Vehicle PDT Metvixia-PDT Vehicle PDT
Below 4 49/55 (89%) 3/15 (20%) N/A N/A
4 – 10 18/27 (67%) 0/7 33/42 (79%) 8/38 (21%)
More than 10 4/6 (67%) 0/1 N/A N/A
Total 71/88 (81%) 3/23 (13%) 33/42 (79%) 8/38 (21%)

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

Table 3. Lesion Complete Response at 3-Month Post-Treatment for Different Lesion Grades
Australian Study U.S. Study
Lesion Grade Metvixia-PDT Vehicle PDT Metvixia-PDT Vehicle PDT
Lesion Grade 1 (slightly palpable AK: better felt than seen) 198/209 (95%) 12/35 (34%) 172/196 (88%) 72/162 (44%)
Lesion Grade 2 (visible and palpable AK: easily seen and felt) 119/151 (79%) 9/39 (23%) 49/64 (77%) 20/80 (25%)
Total 317/360 (88%) 21/74 (28%) 221/260 (85%) 92/242 (38%)

Response rate by lesion location is presented in Table 4.

Table 4. Lesion Complete Response at 3-Month Post-Treatment for Different Lesion Locations
Australian Study U.S. Study
Lesion Location Metvixia-PDT Vehicle PDT Metvixia-PDT Vehicle PDT
Face 251/273 (92%) 15/62 (24%) 195/226 (86%) 73/204 (36%)
Scalp 66/87 (76%) 6/12 (50%) 26/34 (76%) 19/38 (50%)
Total 317/360 (88%) 21/74 (28%) 221/260 (85%) 92/242 (38%)

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.

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