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METVIXIA™ (methyl aminolevulinate) Cream, 16.8%
For Topical Use Only.
Not for Ophthalmic, Oral, or Intravaginal Use
Must be dispensed to and applied by a physician.
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 C6H11NO3·HCl (MW=181.62) and it has the following structural formula:
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.
| 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).
| 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.
| 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.
| 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.
INDICATIONS AND USAGE
Metvixia Cream in combination with 570 to 670 nm wavelength red light illumination using the CureLight BroadBand Model CureLight 01 lamp is indicated for treatment of non-hyperkeratotic actinic keratoses of the face and scalp in immunocompetent patients when used in conjunction with lesion preparation (debridement using a sharp dermal curette) in the physician’s office when other therapies are unacceptable or considered medically less appropriate.
CONTRAINDICATIONS
Metvixia Cream is contraindicated in patients with cutaneous photosensitivity, or known allergies to porphyrins, and in patients with known sensitivities to any of the components of Metvixia Cream, which includes peanut and almond oil (See WARNINGS regarding sensitivity to Metvixia Cream).
This product contains refined peanut oil (See PRECAUTIONS).
WARNINGS
Metvixia Cream is intended for topical use in the physician’s office by trained physicians only. Do not apply to the eyes or to mucous membranes.
Metvixia Cream has demonstrated a high rate of contact sensitization (allergenicity) (See ADVERSE REACTIONS). Care should be taken by the physician applying Metvixia Cream to avoid inadvertent skin contact. Nitrile gloves should be worn when applying and removing the cream. Vinyl and latex gloves do not provide adequate protection when using this product.
Metvixia Cream when used with CureLight BroadBand Model CureLight 01 lamp must be used with appropriate protective sleeves obtained from the product manufacturer to decrease the risk of blood-borne transmitted diseases (hepatitis, HIV, etc.). Change the disposable covers for the device (probe and horseshoe positioning device) between patients. Universal Precautions should be used with this treatment.
PRECAUTIONS
The safety and efficacy have not been established for the treatment of cutaneous malignancies and for skin lesions other than non-hyperkeratotic face and scalp actinic keratoses using PDT with Metvixia Cream. Thick (hyperkeratotic) actinic keratoses should not be treated with Metvixia Cream. The safety and efficacy of Metvixia Cream has not been established in patients with immunosuppression, porphyria or pigmented actinic keratoses.
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.
.
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.
ADVERSE REACTIONS
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.
| Events | Metvixia-PDT (n=130) | Vehicle PDT* (n=61) |
| n (%) of patients with AEs | n (%) of patients with AEs | |
| Burning sensation skin | 65 (50.0%) | 9 (14.8%) |
| Erythema | 60 (46.2%) | 12 (19.7%) |
| Skin pain | 27 (20.8%) | 6 (9.8%) |
| Stinging skin | 25 (19.2%) | 2 (3.3%) |
| Crusting | 20 (15.4%) | 6 (9.8%) |
| Edema skin | 20 (15.4%) | 1 (1.6%) |
| Skin peeling | 14 (10.8%) | 2 (3.3%) |
| Bulers | 14 (10.8%) | 2 (3.3%) |
| Bleeding skin | 11 (8.5%) | 2 (3.3%) |
| Pruritus/Itching | 17 (13.1%) | 2 (3.3%) |
| Skin ulceration | 7 (5.4%) | 0 (0%) |
| Skin infection | 3 (2.3%) | 1 (1.6%) |
| Skin hyper-pigmentation | 1 (0.8%) | 0 (0%) |
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.
OVERDOSAGE
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.
DOSAGE AND ADMINISTRATION
Photodynamic therapy for non-hyperkeratotic actinic keratoses with Metvixia Cream is a multi-stage process as described below: Two treatment sessions 7 days apart should be conducted. Not more than one gram (half a tube) of Metvixia Cream should be applied per treatment session.
One Metvixia -PDT session consists of:
1) Lesion debriding –
Before applying Metvixia Cream, the surface of the lesions should be prepared with a small dermal curette to remove scales and crusts and roughen the surface of the lesion. This is to facilitate access of the cream and light to all parts of the lesion.
Figure 1 A Lesion debriding
Only nitrile gloves should be worn during this and subsequent steps and Universal Precautions should be taken. Vinyl and latex gloves do not provide adequate protection when using this product.
Figure 1B Lesion debriding
2) Application of Metvixia Cream –
Using a spatula, apply a layer of Metvixia Cream about 1 mm thick to the lesion and the surrounding 5 mm of normal skin. Do not apply more than one gram of Metvixia Cream for each patient per treatment session.
Figure 2: Cream application
The area to which the cream has been applied should then be covered with an occlusive, non-absorbent dressing for 3 hours. Multiple lesions may be treated during the same treatment session. Each treatment field is limited to a diameter of 55 mm. Only nitrile gloves should be worn by the qualified healthcare provider in order to avoid skin contact with the cream. This product is not intended for application by patients or unqualified medical personnel.
Figure 3: Occlusive dressing application
3) Wait for 3 hours - (at least 2.5 hours, but no more than 4 hours).
After 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. Patients should protect treated areas 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. It has not been determined if perspiration can spread the Metvixia Cream outside the treatment site to the eyes or surrounding skin. The treated site should be protected from extreme cold with adequate clothing or remaining indoors between application of Metvixia Cream and PDT light treatment.
4) Removal of Dressing and Rinse Off Excess Cream - Following removal of the occlusive dressing, clean the area with saline and gauze. Nitrile gloves should be worn at this step by the trained physician.
Figure 4: Cream removal
5) Illumination of Metvixia Treated Lesion - It is important to ensure that the correct light dose is administered. The light intensity at the lesion surface should not be higher than 200 mW/cm2. Patient and operator should adhere to safety instructions and Universal Precautions provided with the lamp. The patient and operator should wear protective goggles during illumination. Patients should be advised that transient stinging and/or burning at the target lesion sites may occur during the period of light exposure.
Figure 5: Illumination
The CureLight BroadBand Model CureLight 01 lamp is approved for the use in Metvixia -PDT. The lamp should be carefully calibrated so that dosing is accurate and immediately thereafter the lesion should be exposed to red light with a continuous spectrum of 570 to 670 nm and a total light dose of 75 J/cm2. To avoid direct contact between lamp parts and patient skin, always use disposable protective plastic sleeves on the positioning device and on the light measuring probe. Following each patient treatment, the disposable protective plastic sleeves should be removed from the positioning device and from the light measuring probe and discarded.
If red light treatment is interrupted or stopped for any reason, it may be restarted. 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. Metvixia Cream is not intended for use with any device other than the approved lamp: CureLight BroadBand Model CureLight 01.
Use of Metvixia Cream without subsequent red light illumination is not recommended.
No more than 1 gram (half a tube) of product should be used for each of the two weekly treatment sessions. Multiple lesions may be treated during the same treatment session using a total of 1 gram of Metvixia Cream. Lesion response should be assessed 3 months after the last treatment session.
This product is not intended for application by patients or unqualified medical personnel, therefore, this product is only dispensed to physicians.
HOW SUPPLIED
Metvixia Cream, 16.8%, is available as the following:
NDC 63069-401-01, 2 gram aluminum tube, box of 1
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 spans within one week after opening.
Should not be used after 24 hours out of refrigerator.
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.