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Methyl aminolevulinate hydrochloride, 168 mg/g, cream
Galderma Canada Inc.
Submission Control Number: 110853
Date Issued: 2009/07/17
Health Products and Food Branch
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On February 26, 2009, Health Canada issued a Notice of Compliance to Galderma Canada Inc. for the drug product, Metvix.
Metvix contains the medicinal ingredient methyl aminolevulinate (as methyl aminolevulinate hydrochloride), which is an antineoplastic agent.
Metvix in combination with 630 nm wavelength red light illumination using the Aktilite CL 128 lamp is indicated for the:
Metvix acts as a photosensitizer. Photosensitization occurs through the metabolic conversion of methyl aminolevulinate to photoactive porphyrins which accumulate in the skin lesions where Metvix cream has been applied. When exposed to light of appropriate wavelength and energy, the accumulated photoactive porphyrins produce a photodynamic reaction, resulting in an oxygen dependent cytotoxic process that kills precancerous and cancer cells.
The market authorization was based on quality, non-clinical, and clinical information submitted. In two, Phase III, placebo-controlled, double-blind, randomized, parallel-group studies in 211 patients with a total of 1555 non-hyperkeratotic actinic keratoses, Metvix was superior to placebo for the treatment of actinic keratosis lesions. In a pivotal Phase III study conducted with 196 patients with primary superficial BCC outside the facial H-zone, Metvix therapy was compared to excision surgery for the treatment of BCC lesions. Responses were evaluated 3 months and 12 months after treatment. The average reduction in lesion count by subject was 87% in the Metvix group versus 89% in the surgery group 3 months after treatment; and 79% versus 92%, respectively, 12 months after treatment. Longer-term efficacy data are not available. The cosmetic outcome in the Metvix group was superior to that of the surgery group at 3 and 6 months after the last treatment.
Metvix (168 mg/g, methyl aminolevulinate) is presented as a topical cream. This product should be administered in the physician's office by a trained physician only. Care should be taken by the physician when applying Metvix cream to avoid inadvertent skin contact. Dosing guidelines are available in the Product Monograph.
Metvix is contraindicated for patients who are hypersensitive to this drug or aminolevulinic acid, or to any ingredient in the formulation (including peanut and almond oil), or to any component of the container. Metvix is also contraindicated for patients with cutaneous photosensitivity/porphyria, or known allergies to porphyrins, or for patients with morpheaform BCC. Metvix should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Metvix are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Metvix is favourable for the indications stated above.
A New Drug Submission (NDS) for Metvix was submitted by Galderma Canada Inc. on December 27, 2006. During the review process, several deficiencies were found that precluded the appropriate benefit/risk assessment of Metvix. The original submission included data from studies using a light source which is no longer available in Canada, and did not contain sufficient efficacy and safety data to confirm equivalence with the Aktilite CL 128 lamp, which is marketed in Canada. The submission also failed to provide long-term efficacy data on patients with actinic keratosis lesions treated with Metivix. Due to these and other deficiencies, Health Canada issued a Notice of Deficiency on December 18, 2007. On March 17, 2008, the sponsor responded with additional data that was found to be adequate to support market authorization. A Notice of Compliance was subsequently issued by Health Canada for Metvix on February 26, 2009.
Methyl aminolevulinate (as methyl aminolevulinate hydrochloride) is the medicinal ingredient of Metvix. Methyl aminolevulinate is an antineoplastic agent which acts as a photosensitizer. Photosensitization occurs through the metabolic conversion of methyl aminolevulinate to photoactive porphyrins which accumulate in the skin lesions where Metvix cream has been applied. When exposed to light of appropriate wavelength and energy, the accumulated photoactive porphyrins produce a photodynamic reaction, resulting in an oxygen dependent cytotoxic process that kills precancerous and cancer cells.
Methyl aminolevulinate hydrochloride is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
The structure of methyl aminolevulinate hydrochloride has been adequately elucidated and the representative spectra have been provided. The proposed structure of methyl aminolevulinate hydrochloride was confirmed by different techniques.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified (for example within ICH limits and/or qualified from batch analyses or toxicological studies). Control of the impurities and degradation products is therefore considered acceptable.
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of methyl aminolevulinate hydrochloride.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Based on the long-term and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered to be satisfactory.
Metvix cream is an oil-in-water emulsion, cream to pale yellow in colour.
Metvix cream contains methyl aminolevulinate hydrochloride equivalent to 168 mg/g of methyl aminolevulinate. Metvix cream also contains glyceryl monostearate, cetostearyl alcohol, polyoxyl stearate, cholesterol, and oleyl alcohol as emulsifying agents. It also contains glycerol, white soft paraffin, isopropyl myristate, arachis (peanut) oil, refined almond oil as emollients, edetate disodium as a chelating agent, methylparaben and propylparaben as preservatives, and purified water.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of methyl aminolevulinate hydrochloride with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Metvix cream is packaged in an aluminum tube sealed with an aluminum membrane and a screw cap.
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
The manufacturing process uses conventional manufacturing techniques. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Metvix is tested to verify that its identity, appearance, assay, pH, viscosity, globule size, and levels of preservatives, degradation products, drug-related impurities, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits for individual and total degradation products are within acceptable limits.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are considered satisfactory.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Based on the long-term and accelerated stability data submitted, the proposed 18-month shelf-life at 2-8°Celsius for Metvix is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
The design, operations, and controls of the facility and equipment that are involved in the production of Metvix are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
All excipients except cholesterol are derived from vegetable or synthetic sources. The cholesterol is manufactured from lanolin alcohols obtained from wool grease of sheep. In the Committee of Proprietary Medicinal Products guideline on transmissible spongiform encephalopathy, sheep's wool is defined as Category IV, tissues with no detectable infectivity.
The Chemistry and Manufacturing information submitted for Metvix has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
Metvix cream (methyl aminolevulinate hydrochloride) is an antineoplastic agent used as a photosensitizer for photodynamic therapy (PDT). The mode of action of methyl aminolevulinate in PDT was shown in the pharmacodynamic (PD) studies. In the target cells,methyl aminolevulinate was converted to photoactive porphyrins, including protoporphyrin IX (PpIX), which are the active photosensitizers. Upon light activation, the photosensitizers give rise to the production of cytotoxic singlet oxygen species which destroy the target cells.
Non-clinical PD studies were conducted in tumour cell lines in vitro and in a nude mouse normal skin model in vivo. In the in vitro studies, the relative concentrations of the photoreactive protoporphyrins were measured by the fluorescence technique and the cytotoxic singlet oxygen was studied by photoinactivation. PpIX, an endogenous photosensitizer formed within the mitochondria, was identified by high-performance liquid chromatography in the in vitro studies and was monitored in the in vivo studies. Detailed monitoring of PpIX in the mouse skin model demonstrated the mode of action of methyl aminolevulinate in PDT.
The pharmacokinetic (PK) investigations in rat models have demonstrated that systemic absorption of methyl aminolevulinate and its metabolites is minimal. Topical application of radiolabelled methyl aminolevulinate on rats for 48 hours resulted in 13.1% and 6.4% of the total dose being systemically absorbed through abraded and non-abraded skin, respectively. The major fraction of what was systemically absorbed was collected in excreta and the remaining fraction was concentrated to kidney/bladder and intestine content. The fraction remaining at the skin application site of the rats was quantified to be 6.3% (abraded) and 8.4% (non-abraded) after 24-hours exposure. In the mouse model, topically administered methyl aminolevulinate was readily absorbed into the epidermis, but systemic absorption was negligible.
An in vitro study showed that human skin had a much lower permeability for radiolabelled methyl aminolevulinate compared to rat skin. The systemic absorption through human cadaver skin was only 0.26% of the applied dose after a 24-hour application period. This amount would be considered negligible for the recommended human dose.
The metabolites were tested both locally in the skin and at the systemic level. Methyl aminolevulinate is converted to intracellular porphyrins, the functional metabolites of methyl aminolevulinate. The metabolites aminolevulinic acid (ALA) or protoporphyrin were not detected in rat tissue other than the skin application site after single-dose topical application of methyl aminolevulinate. With rats, it was only after repeated dosing that slightly elevated levels of ALA could be measured in the serum.
In the single-dose toxicity studies, no serious toxicity was observed in rats and mice after oral administration of 2000 mg/kg Metvix (cream in purified water).
The intravenous lethal dose of Metvix (cream in physiological saline) in the rat ranged from 1430 to 1500 mg/kg.
In multiple-dose toxicity studies in rats, Metvix cream in physiological saline was injected intravenously at doses of 250 and 750 mg/kg/day in a 7-day study, and at doses of 50, 200, 600, or 800 mg/kg/day in a 14-day study. The No Observable Adverse Effect Level (NOAEL) was >250 mg/kg/day in the 7-day study, whereas the NOAEL was 200 mg/kg/day in the 14-day study.
In the 14-day study in rats, the liver was found to be the target organ of toxicity following the administration of 800 mg/kg/day doses of Metvix cream. The findings of the single-dose and multiple-dose studies indicate that very large amounts of Metvix cream are needed to produce toxicity in rats and mice. Additionally, very large amounts of impurities would be required to produce any meaningful toxic effects in these species.
Methyl aminolevulinate had no genotoxic effects in the Ames assay, the chromosomal aberration test, and in the in vivo micronucleus assay.
Long-term studies to evaluate the carcinogenic potential of Metvix cream were not performed.
A high dose of methyl aminolevulinate was teratogenic when injected intravenously to pregnant rabbits. The fetal NOAEL was quite high (1200 mg/m2) corresponding to 463 times the maximum topical human dose based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%.
The local tolerance studies showed no systemic toxicity after single or repeated dermal application of Metvix cream and photoactivation in rats, minipigs, or rabbits. No unexpected findings were reported on the nature of the local lesions both macroscopically and by histopathology after single or repeated dermal treatment. In addition, the skin lesions appeared to heal after repeated treatments.
The pharmacology and toxicology studies support the use of Metvix for the proposed indication. Overall, the results of the toxicology studies demonstrated no evidence of risk to the health of humans at the clinical dose.
No clinical studies of human pharmacodynamics were performed. See the non-clinical section 3.2.1 Pharmacodynamics.
Systemic PK data of Metvix in humans were not available due to the instability of the drug in human serum.
The PK studies that were performed provided important information, such as the depth of penetration of Metvix and the best dosage regimen. The application of Metvix cream compared to placebo resulted in a time-dependant and significant production of PpIX in the actinic keratosis and BCC lesions. The selected clinical regimen uses the concentration of cream producing the greatest concentration and depth of accumulation of photoactive porphyrins (PAP), the shortest time of application commensurate with the maximum efficacy (least number of lesions requiring re-treatment), good tolerability, and a light dose sufficient to cause photobleaching.
The PK study performed with the Aktilite CL128 lamp provided relevant information on the photobleaching of PAPs following illumination with Aktilite CL128. Results showed that a fluence of 37 J/cm2 with the Aktilite CL128 lamp reduced the fluorescence of skin lesions treated with Metvix but it did not result in complete photobleaching immediately after illumination. The study also showed that there was an increase in fluorescence 2 hours following the illumination. Complete photobleaching took place 24 hours after illumination.
Two pivotal multicentre, double-blind, randomized, vehicle-controlled, parallel-group, Phase III studies (PC T404/05 and PC T405/05) assessed the efficacy and safety of Metvix-PDT using the Aktilite CL128 lamp for the treatment of actinic keratosis lesions. A total of 211 patients with a total of 1555 non-hyperkeratotic actinic keratoses were studied; 106 of these patients with 781 lesions were treated with Metvix-PDT. Before administration, the lesions were prepared to facilitate the application of the Metvix cream or the vehicle cream. Three hours after the cream was applied, the cream was wiped-off and the treated skin area was then illuminated with the Aktilite CL128 lamp at a fluence of 37 J/cm2. Seven days later, a second treatment was performed. A detailed description of the administration of Metvix-PDT with the the Aktilite CL128 lamp is included in the Product Monograph.
The primary endpoint was the patient complete response (CR) rate determined by clinical assessment (visual inspection and palpation) 3 months after the last treatment. Secondary endpoints included the lesion CR rate 3 months after the last treatment, and the number of treatment site adverse events (AEs) at 3 months after the last treatment. In both studies that used the Aktilite CL128 lamp, Metvix-PDT was superior to vehicle-PDT in terms of patient CR rate for the treatment of actinic keratosis of the face and scalp. In Study PC T404/05 the patient CR rates were 59.2% and 14.9% in the Metvix-PDT group and the vehicle-PDT group, respectively. In Study PC T405/05 the patient CR rates were 68.4% and 6.9% in the Metvix-PDT group and the vehicle-PDT group, respectively. In both studies, the lesion CR rates in the Metvix-PDT group were higher than the vehicle-PDT group. Almost all patients treated with Metvix-PDT reported treatment site AEs. The majority of the AEs associated with Metvix-PDT were expected local phototoxicity events.
One pivotal, randomized, controlled Phase III study (Study 29040) compared Metvix-PDT in combination with the Aktilite CL128 lamp to excision surgery for the treatment of superficial basal cell carcinoma (sBCC) lesions outside the H-zone of the face (example, ears and nose). A total of 100 patients were treated with Metvix-PDT, and 96 patients were treated with excision surgery in the Intent to Treat (ITT) population. The lesion preparation, cream application, and illumination procedures were similar to the actinic keratosis studies described above.
The primary endpoint was the percent reduction in lesion count per patient, 3 months after the last treatment. The lesion response was defined as complete response (CR, complete clearance of lesion) or non-complete response (Non-CR; non-complete clearance of lesion). The secondary efficacy endpoints consisted of the cosmetic outcome assessed at 3, 6, and 12 months after the last treatment; and the reduction in lesion count per patient 6 and 12 months after the last treatment.
The percent reductions in lesion count per patient at 3 months after the last treatment were 92.2% and 99.2% for the Metvix-PDT group and the surgery group, respectively, for the Per Protocol (PP) population. For the ITT population, the percentages were similar; 87.4% and 89.4% for the Metvix-PDT group and the surgery group, respectively. The efficacy of Metvix-PDT decreased substantially at 12 months (92.2% at 3 months, 79.3% at 12 months). The clinical lesion response rates were only provided up to 12 months after treatment, and therefore, did not provide long-term efficacy data of Metvix-PDT with the Aktilite CL128 lamp.
A rationale for using the 12-month clinical clearance data from Study 29040 as a surrogate for 5-year long-term efficacy was provided. The validation of the surrogacy was based on data from the long-term follow-up reports of sBCC studies performed with an alternate light source for the same indication. The results from these studies strongly suggest that the complete clearance data at 12 months predict the 5-year long-term efficacy of Metvix-PDT in the treatment of sBCC lesions. Although the lamp characteristics were different, the mechanism of action of Metvix-PDT remains the same. The 12-month CR rate in Study 29040 is within the range of the 12-month CR rates obtained in the studies with the alternate lamp (lesion CR rates: 75.6% versus 71-87%, respectively). The studies with the alternate lamp showed that the lesion CR rates constantly decreased over time; a decrease of 29-60% at 60 months. The exact lesion CR rate in Study 29040 with the Aktilite CL128 lamp at 60 months is not known. However, it is fair to conclude that the CR rate is expected to decrease over time with a trend that would be similar to the one observed in the studies with the alternate lamp.
The cosmetic outcomes of the sBCC lesions were better with Metvix-PDT compared to surgery, when assessed at 3, 6 and 12 months after the last treatment.
The recurrence rate at 12 months after the last treatment was higher in the Metvix-PDT group compared to the surgery group (9.3% versus 0%).
The clinical safety evaluation was based on the safety data obtained from the three pivotal Phase III clinical studies, described in section 3.3.3 Clinical Efficacy, as well as data obtained from special tolerance studies in healthy volunteers and post-market pharmacovigilance data.
In the pivotal studies with actinic keratosis patients, 90% of the patients treated with Metvix-PDT reported treatment site AEs. The majority of these AEs were expected local phototoxicity events. The most common treatment site AEs reported with Metvix cream versus vehicle cream were skin burning (86% versus 36%), erythema (63% versus10%), scabbing/crusting/blister/erosions (29% versus 1%) and pruritus (22% versus 8%). Local symptoms were generally transient, and mild or moderate in severity. They occurred during and shortly after the period of illumination, although signs of erythema were more persistent.
The safety profile of sBCC patients treated with Metvix-PDT was worse than with surgery, but most of the AEs were transient and local. Most treatment-related AEs were dermatologic. The most commonly reported related AEs were photosensitivity in the Metvix group and wound infection in the surgery group. The local skin pain associated with Metvix-PDT was generally well managed by the sBCC patients.
Cumulative irritancy and sensitization studies were conducted with Metvix cream. In a study with 25 healthy subjects, signs of mild to moderate skin irritancy were seen in 12 subjects after 4 days of continuous exposure. Challenge applications at previously untested sites following a two-week induction period, resulted in 5 subjects with contact sensitization. In another study with 156 healthy subjects, Metvix cream was applied 3 times each week for 3 weeks 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 Metvix cream, Metvix vehicle, ALA, and ALA-vehicle creams for 48 hours. Assessment of skin reactions was performed 48, 72, and 96 hours 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 Metvix 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.
Four cases of squamous cell carcinoma (SCC) were reported during the post-market pharmacovigilance period, which is expected in the treated population. Although the incidence of SCC in the post-market database is unknown, a higher incidence of SCC was found in patients with sBCC treated with Metvix-PDT in Study 290240. However, the other safety studies with actinic keratosis patients did not report an increase of SCC in the Metvix-PDT group. In fact, some of the submitted studies suggest that the long-term number of skin lesions in Metvix-treated areas is lower than in the control-treated areas. The long-term safety of Metvix-PDT for the treatment of actinic keratosis lesions appears acceptable. However, all patients with a history of actinic keratosis should be followed-up for new lesions at regular intervals, which should be treated to prevent the development of SCC.
The clinical benefit of Metvix-PDT with the Aktilite CL128 lamp for the treatment of actinic keratosis lesions on the face and scalp has been demonstrated. The risks attributed to Metvix-PDT for the treatment of actinic keratosis are few and are related mainly to moderate pain during and shortly after treatment. The treatment was well-tolerated by patients. The benefit/risk profile of Metvix-PDT in combination with the Aktilite CL128 lamp for the treatment of actinic keratosis is acceptable.
The clinical benefit of Metvix-PDT with the Aktilite CL128 lamp for the treatment of sBCC lesions outside the H-zone of the face has been demonstrated. However, the long term efficacy (at 60 months) has not been provided but studies performed with an alternate lamp suggest that the efficacy decreases over time. The Product Monograph indicates that patients with sBCC treated with Metvix-PDT are required to have regular follow-up of the treatment site because the efficacy is generally less than with surgery. Superficial BCC is generally not life-threatening and the morbidity associated with the disease can be well managed with a regular follow-up and with treatment of recurrent lesions with other available therapies, such as surgery. The sponsor indicated that the Metvix treatment does not affect the outcome of subsequent therapies. The risks attributed to Metvix-PDT for the treatment of sBCC are few and related mainly to moderate pain during and shortly after treatment. The treatment was well tolerated by the patients. The benefit/risk profile of Metvix-PDT in combination with the Aktilite CL128 lamp for the treatment of sBCC is acceptable.
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Metvix in combination with 630 nm wavelength red light illumination using the Aktilite CL 128 lamp is favourable for the treatment of thin or non-hyperkeratotic and non-pigmented actinic keratosis on the face and scalp when other therapies are considered less appropriate; and for the treatment of primary sBCC (confirmed by biopsy) outside the H-zone of the face when other therapies are considered less appropriate. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
|Screening Acceptance Letter issued:||2007/02/21|
|Notice of Deficiency (NOD) issued by Director General (safety and efficacy issues):||2007/12/18|
|Screening Acceptance Letter issued:||2008/05/02|
|Quality Evaluation complete:||2009/02/26|
|Clinical Evaluation complete:||2009/02/25|
|Labelling Review complete:||2009/02/26|
|NOC issued by Director General:||2009/02/26|