2.1 Lesion preparation

• 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 1A 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

2.2 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 (half tube) of METVIXIA Cream per treatment session.

Figure 2: Cream application

2.3 Occlusive Dressing Cover

• The area where 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 an area of 80 x 180 mm.

Figure 3: Occlusive dressing application

2.4 Occlusion 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 Aktilite 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 Aktilite PDT light treatment.

2.5 Removal of Excess Cream with Saline

• Following removal of the occlusive dressing, clean the area with saline and gauze. Wear nitrile gloves.

Figure 4: Cream removal

2.6 Positioning Aktilite CL128 Lamp

• See Aktilite CL128 Operators Manual for specific warnings, cautions and instructions. If necessary adjust the dose to 37 J/cm2 . Calibration by the operator is not required. Position the lamp over the area to be illuminated by the use of guide light. The distance between the LED panel and the lesion surface should be 50 to 80 mm (2 to 3.2 in). Do not stare into the beam. The patient and operator should wear appropriate eye protection during illumination. Patient protective goggles or eye shields are dark or of metal to block visible light.

Figure 5: Positioning Aktilite CL128

2.7 Illumination with Aktilite CL128 Lamp Red Light

• The required illumination time (7-10 minutes) is calculated automatically, and remaining time will be displayed at the control panel. The illumination stops automatically. The illumination may be paused and started again. Patients should be advised that transient pain, burning or stinging at the target lesion sites may occur during the period of light exposure.

Figure 6: Illumination

5.1 General

METVIXIA Cream is intended for topical use in the physician’s office by physicians. METVIXIA Cream has not been studied for more than one course which consists of two treatment sessions one week apart.

Clinical studies did not follow patients beyond 3 months, and the recurrence rate of treated lesions is unknown.

5.2 Photosensitivity

During the time period between the application of METVIXIA Cream and exposure to Aktilite red light illumination, the treatment site will become photosensitive.

If for any reason the patient cannot have the Aktilite 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.

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 Cream and Aktilite red 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.

5.3 Hypersensitivity

METVIXIA Cream has demonstrated a high rate of contact sensitization (allergenicity) [See Adverse Reactions (6.2)]. 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 is formulated with peanut oil and refined almond oil.

METVIXIA Cream has not been tested in patients who are allergic to peanuts.

5.4 Aktilite Lamp

Before operating the Aktilite CL128 lamp, personnel should refer to the Operators Manual for specific warnings, cautions and instructions. Care should be exercised when positioning and operating the lamp. During the red light illumination period, the patient, operator and other persons present should wear protective goggles that sufficiently screen out the appropriate spectrum of red light. The protective goggles or eye shields provided for the patient are dark or of metal to block visible light. The green professional protective glasses provided for the operator screen out the relevant spectrum of red light and the room will still appear bright for the operator to see. Do not stare into the beam. For lamp assembly, maintenance, service and technical data the personnel should refer to the Operators Manual.

6.1 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 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 trials, out of 126 subjects treated with METVIXIA Cream, six METVIXIA 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 PDT subjects paused illumination due to pain, burning or stinging but did subsequently complete treatment.

* Mild, Moderate, or Severe

6.2 Dermal Safety Studies

Studies in healthy volunteer subjects and subjects with actinic keratoses previously treated with METVIXIA-PDT on at least 4 previous occasions have demonstrated that METVIXIA Cream has the potential to cause irritancy and sensitization. A cumulative irritancy and sensitization (allergenicity) study of METVIXIA Cream with a cross-sensitization challenge with aminolevulinic acid (ALA) was performed in 156 subjects. METVIXIA 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 aluminum Finn Chamber. After the 3-week continuous treatment period and a 2-week interval without further applications, subjects were challenged with METVIXIA Cream, METVIXIA 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 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-PDT on at least 4 previous occasions. METVIXIA 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.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of METVIXIA Cream. 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.

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 macular edema, vitreous detachment and keratitis. There have been reports of angioedema, facial edema and application site infections.

8.1 Pregnancy

Teratogenic effects: Pregnancy Category C:

There are no adequate and well-controlled studies with METVIXIA Cream in pregnant women. Intravenous methyl aminolevulinate hydrochloride (HCI) was teratogenic in rabbits at a high dose. METVIXIA Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

A Maximum Topical Human Dose (MTHD) of 2 g of METVIXIA Cream 16.8% containing 420 mg methyl aminolevulinate hydrochloride corresponding to 7 mg/kg or 259 mg/m2 for a 60 kg patient and an estimated maximum systemic uptake of 1% was used for the animal multiple of human systemic exposure calculations presented in this labeling.

In development toxicity studies, pregnant rabbits received intravenous doses of methyl aminolevulinate hydrochloride up to 926 times the MTHD on Days 6 to 18 of gestation. Slightly lower fetal body weights and increased incidences of fetuses with jugals connected/fused to maxilla, supernumerary ribs, incompletely ossified cranial bones and other ossification irregularities were noted in the high dose (926 times the MTHD) group, compared to the control group. The embryo-fetal effects in the high dose group were associated with maternal toxicity. These effects did not occur at 463 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%. Developmental toxicity studies in rats were negative at daily exposure levels up to 1622 times the MTHD on a mg/m2 basis.

In the prenatal and postnatal development toxicity study, pregnant rats received intravenous doses of methyl aminolevulinate hydrochloride up to 1160 x the MTHD from Day 6 of gestation to Day 24 of lactation. There were no treatment-related effects on litter size, pup mortality, pup weights, or post weaning performance in the pups (including development and reproduction). A slightly longer duration of gestation and a slight delay in pup physical development were noted in the 580-1160 x the MTHD groups [See Nonclinical Toxicology (13.2)].

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when METVIXIA Cream is administered to a nursing woman.

8.4 Pediatric Use

Actinic keratosis is not a condition generally seen within the pediatric population. The safety and effectiveness in pediatric patients below the age of 18 have not been established.

8.5 Geriatric Use

Of the 211 subjects in the clinical studies with METVIXIA-PDT, 136 subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

10.1 METVIXIA Cream Overdose

METVIXIA Cream overdose has not been reported.

10.2 Aktilite Red Light Overdose

Red light overdose (excess illumination time) using Aktilite CL128 following METVIXIA Cream application has not been reported. If red light overexposure were to result in a burn, the patient should be treated in accordance with standard practice for treatment of cutaneous burns.

12.1 Mechanism of Action

Photosensitization following application of METVIXIA Cream occurs through the metabolic conversion of methyl aminolevulinate (prodrug) to photoactive porphyrins (PAPs), which accumulate 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. METVIXIA photodynamic therapy (PDT) of actinic (solar) keratosis lesions is the combination of photosensitization by topical application of METVIXIA Cream to the lesions and subsequent illumination with red light of narrow spectrum using a light dose of 37 J/cm2 delivered by the Aktilite CL128 lamp.

12.3 Pharmacokinetics

The time-course of Protoporphyrin IX in actinic keratosis lesions and surrounding skin after application of METVIXIA Cream has been monitored by means of fluorescence. The optimum concentration of methyl aminolevulinate cream (16.8 %) and duration of application (3 h) were derived from such studies of pharmacokinetics in skin using a range of concentrations (1.6%, 8% and 16.8%) and cream application times (up to 28 h). Three hours after the application of METVIXIA Cream 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. In a fluorescence study of 8 patients with actinic keratoses using METVIXIA Cream 16.8% applied for 3 h and illumination with the Aktilite CL128 lamp, 88% photodegradation of Protoporphyrin IX was observed immediately after illumination, followed by a transient small secondary increase in fluorescence 2 hours after illumination. At 24 and 48 hours, 94% and 96% degradation of Protoporphyrin IX, respectively from baseline, was observed.

13.1 Carcinogenesis, Mutagenesis and Impairment of 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.

A fertility study was performed in male and female rats with intravenous doses of methyl aminolevulinate hydrochloride up to 500 mg/kg/day (3000 mg/m2, 1158 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%). Males were treated for 4 weeks prior to mating and for 5 additional weeks after mating. The females were treated for 2 weeks prior to mating and then until Day 6 of gestation. There were no treatment-related effects on fertility and mating performance seen in this study.

13.2 Reproductive Toxicology

Development toxicity studies have been performed in pregnant rats with intravenous doses of methyl aminolevulinate hydrochloride up to 700 mg/kg/day on Days 6 to 16 of gestation. There were no treatment-related effects on fetal body weight, sex ratio, external malformations and variations, and skeletal abnormalities and ossification extent. Only a slight non-significant increase in early embryonic death was noted in the 700 mg/kg/day group, compared to the control group. The fetal NOAEL (No Adverse Effect Level) was 350 mg/kg/day methyl aminolevulinate hydrochloride in pregnant rats (2100 mg/m2, 811 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%).

Development toxicity studies have also been performed in pregnant rabbits with intravenous doses of methyl aminolevulinate hydrochloride up to 200 mg/kg/day on Days 6 to 18 of gestation. Slightly lower fetal body weights and increased incidences of fetuses with jugals connected/fused to maxilla, supernumerary ribs, incompletely ossified cranial bones and other ossification irregularities were noted in the high dose (200 mg/kg/day) group, compared to the control group. The fetal NOAEL was 100 mg/kg/day methyl aminolevulinate hydrochloride in pregnant rabbits (1200 mg/m2, 463 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%).

In the prenatal and postnatal development toxicity study in rats treated with intravenous doses of methyl aminolevulinate hydrochloride up to 500 mg/kg/day from Day 6 of gestation to Day 24 of lactation, there were no treatment-related effects on litter size, pup mortality, pup weights, and post weaning performance of the F1 animals including development and reproductive capacity. Only a slightly longer duration of gestation and a slight delay in pup physical development were noted in the 250 and 500 mg/kg/day groups. The NOAEL was 125 mg/kg/day methyl aminolevulinate hydrochloride (750 mg/m2, 290 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%).