`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`Metvixia safely and effectively. See full prescribing information
`
`for Metvixia.
`
`
`METVIXIA (methyl aminolevulinate) Cream, 16.8%
`
`For Topical Use Only
`Initial U.S. Approval: 2004
`
`
`--------------------------INDICATIONS AND USAGE-------------------------
`
` Metvixia Cream, a porphyrin precursor, in combination with the Aktilite
` CL128 lamp, a narrowband, red light illumination source, is indicated for
`
`
`
` treatment of thin and moderately thick, non-hyperkeratotic, non-pigmented
`actinic keratoses of the face and scalp in immunocompetent patients when
`used in conjunction with lesion preparation in the physician’s office when
`
`
`other therapies are considered medically less appropriate (1)
`
`
`
`--------------------- DOSAGE AND ADMINISTRATION ---------------------
`Photodynamic therapy with Metvixia Cream is a multi-stage process
`
`
`comprised of:
`
`lesion preparation
`•
`
`application of Metvixia Cream
`
`•
`
`occlusion for 3 hours
`
`•
`
`removal of excess cream with saline
`•
`
`illumination with the Aktilite CL128 lamp emitting a narrow
`
`•
`output spectrum red light with a peak at 630 nm and a spectral
`
`half-width of approximately 20 nm at a light dose of 37 J/cm2
`
`
`using the Aktilite CL128 lamp.
`
`Two treatment sessions should be administered one week apart. Multiple
`
`lesions may be treated during the same treatment session using a total of not
`
`more than 1 grams (half tube) of Metvixia Cream. Wear nitrile gloves at all
`times during this procedure. (2)
`
`Metvixia Cream is not for ophthalmic, oral or intravaginal use. (2)
`
`
`-----------------DOSAGE FORMS AND STRENGTHS----------------------
`Metvixia Cream, 16.8% (3)
`
`
`
`
`
`
`
`
`
`
`---------------------------- CONTRAINDICATIONS ---------------------------
`Metvixia Cream is contraindicated in patients with (4):
`
`
`cutaneous photosensitivity
`
`•
`
`known allergies to porphyrins
`•
`
`known sensitivities to any of the components of Metvixia Cream,
`
`
`•
`which includes peanut and almond oil
`
`
`
`
`
`
`----------------------WARNINGS AND PRECAUTIONS---------------------
`Metvixia Cream is intended for topical use in the physician’s office by
`physicians only . The recurrence rate of treated lesions is unknown. (5.1)
`
`
`
`
`
`
`•
`
`Patients and providers should wear protective eyewear before
`operating the Aktilite lamp. Patients should be cautioned with
`
`
`regard to protective clothing after exposure to Metvixia (5.2).
`
`• Do not apply to the eyes or to mucous membranes. Metvixia
`
`Cream has demonstrated a high rate of contact sensitization
`
`(allergenicity) (5.3) .
`
`
`
`
`-----------------------------ADVERSE REACTIONS ---------------------------
`Most common related adverse reactions (incidence greater than 10% and
`greater than placebo) are erythema; pain, burning and discomfort; pruritus;
`
`scabbing, crusting and erosions; edema and exfoliation of the skin (6)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact XXXX at 1-
`
`8XX-XXXX or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`----------------------USE IN SPECIFIC POPULATIONS --------------------
`
`No overall differences in safety and efficacy were observed between patients
`
`
`aged 65 years and older and those who were younger (8.5)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved labeling
`
`
`
`
`Revised: 6/2008
`
`001
`
`

`

`1
`2
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Lesion preparation
`
`2.2 Application of Metvixia Cream
`
`
`2.3 Application of Occlusive Dressing
`
`
`
`2.4 Occlusion for 3 hours
`
`
`2.5 Removal of excess cream with saline
`
`
`2.6
`Illumination with red light (Aktilite CL128 lamp)
`
`
`
`[SEE ALSO OPERATORS MANUAL FOR AKTILITE CL128]
`
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 General
`
`
`Photosensitivity
`5.2
`5.3 Hypersensitivity
`5.4 Coagulation Defects
`5.5 Device
`
`ADVERSE REACTIONS
`
`6.1 Dermal Safety Studies
`
`6.2 Clinical Studies Experience
`
`
`
`6.3
`Postmarketing Experience
`
`
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`
`
`
`6
`
`
`
`
`7
`8
`
`
`
`
`Pediatric Use
`8.4
`
`
`
`8.5 Geriatric Use
`
`10 OVERDOSAGE
`
`
`10.1 Metvixia Cream Overdose
`
`
`
`
`10.2 Aktilite Red Light Overdose
`
`11
`DESCRIPTION
`12
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`13
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
` 13.3 Reproductive Toxicology
`
`14
`CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing
`
`information are not listed.
`
`
`
`002
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`INDICATIONS AND USAGE
`1
`Metvixia Cream in combination with Aktilite CL128 lamp red light illumination is
`indicated for treatment of thin and moderately thick, non-hyperkeratotic, non-pigmented
`actinic keratoses of the face and scalp in immunocompetent patients. This photodynamic
`therapy should be used in conjunction with appropriate lesion preparation in the physician’s
`office when other therapies are considered medically less appropriate [See Dosage and
`Administration (2)].
`
`The safety and efficacy have not been established for the treatment of cutaneous
`malignancies or for skin lesions other than non-hyperkeratotic face and scalp actinic
`keratoses using PDT with Metvixia Cream. The safety and efficacy of Metvixia Cream
`have not been established in patients with immunosuppression, porphyria or pigmented
`actinic keratoses.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`Photodynamic therapy (PDT) for non-hyperkeratotic actinic keratoses with Metvixia Cream
`
`is a multi-stage process as described below: Two treatment sessions one week apart should
`be administered. Not more than one gram (half tube) of Metvixia Cream should be applied
`per treatment session. Multiple lesions may be treated during the same treatment session
`using a total of one gram of Metvixia Cream. Lesion response should be assessed 3 months
`after the last treatment session. Nitrile gloves should be worn when applying and removing
`the cream.
`
`The Aktilite CL128 lamp, which is equipped with light emitting diodes (LEDs), emits red
`light with a narrow spectrum at approximately 630 nm, and a half-width of approximately
`20 nm. The light dose to be used is 37 J/cm2, and the lamp should be placed 50 to 80 mm
`from the skin. The area of skin that can be illuminated is 80 x 180 mm. Calibration by the
`operator is not needed, and the illumination time is calculated automatically. The LED
`panel window should be cleaned daily with a slightly moist clean cloth.
`
`If Aktilite 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 at least 48
`hours.
`
`Use of Metvixia Cream without subsequent red light illumination is not recommended.
`
`This product is to be used only by physicians in the physician’s office. Metvixia Cream is
`not for ophthalmic, oral, or intravaginal use. Physicians should be knowledgeable about
`photodynamic therapy and familiar with the Aktilite Operators Manual prior to use of
`
`Metvixia Cream.
`
`
`
`
`One Metvixia-PDT session consists of:
`
`• Lesion preparation [See Dosage and Administration (2.1)]
`
`
`
`
`003
`
`

`

`
`• Application of Metvixia Cream [See Dosage and Administration (2.2)]
`
`
`
`• Application of occlusive dressing [See Dosage and Administration (2.3)]
`
`
`• Occlusion for 3 hours [See Dosage and Administration (2.4)]
`
`
`• Removal of excess cream with saline [See Dosage and Administration (2.5)]
`
`
`• Positioning Aktilite CL128 lamp [See Dosage and Administration (2.6)]
`
`
`Illumination with red light (Aktilite CL128 lamp) [See Dosage and Administration (2.7)]
`
`•
`
`
` 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
`
`004
`
`

`

`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
`
`
`
`
`
`
`
`005
`
`

`

`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 to3.2
`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
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`16.8% cream in 2 g tubes
`
`
`
`
`CONTRAINDICATIONS
`4
`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 and Precautions
`
`(5)].
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`5.1 General
`Metvixia Cream is intended for topical use in the physician’s office by physicians.
`
`
`
`
`
`
`006
`
`

`

`
`
`
`
`Metvixia Cream has not been studied for more than one course which consists of two
`treatment sessions one week apart. There is no information available regarding the
`recurrence rate for lesions treated with this therapy. 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 (6.1)]. 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 refined peanut and almond oil.
`
`Metvixia Cream has not been tested in patients who are allergic to peanuts.
`
`
`5.4 Coagulation defects
`Metvixia Cream has not been tested on patients with inherited or acquired coagulation
`defects.
`
`
`007
`
`

`

`5.5 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.
`
`
`
`ADVERSE REACTIONS
`6
`6.1 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 an 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.
`
`6.2 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.
`
`
`008
`
`

`

`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 studies, 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.
`
`Incidence of Treatment Site Adverse Reactions in ≥1% of Subjects in Studies 1 and 2
`Table 1:
`(Safety Population)
`
`Vehicle & Aktilite PDT
`n = 105
`All Grades*
`Severe
`48 (46%)
`0 (0%)
`38 (36%)
`0 (0%)
`0 (0%)
`11 (10%)
`
`0 (0%)
`1 (1%)
`0 (0%)
`8 (8%)
`
`0 (0%)
`1 (1%)
`
`0 (0%)
`3 (3%)
`
`0 (0%)
`2 (2%)
`
`0 (0%)
`0 (0%)
`
`0 (0%)
`0 (0%)
`
`0 (0%)
`0 (0%)
`0 (0%)
`0 (0%)
`
`
`
`
`
`Metvixia & Aktilite PDT
`
`n = 126
`All Grades*
`Severe
`
`Any Treatment Site Adverse
`113 (90%)
`28 (22%)
`Reaction
`Skin burning/pain/discomfort
`109 (86%)
`25 (20%)
`Erythema
`80 (63%)
`7 (6%)
`
`Scabbing/crusting/blister/erosions 36 (29%)
`2 (2%)
`Pruritus
`28 (22%)
`0 (0%)
`Skin or eyelid edema
`23 (18%)
`2 (2%)
`Skin exfoliation
`17 (14%)
`4 (3%)
`Skin warm
`5 (4%)
`0 (0%)
`Application site discharge
`3 (2%)
`0 (0%)
`Skin hemorrhage
`2 (2%)
`0 (0%)
`
`Skin tightness
`2 (2%)
`0 (0%)
`Skin hyperpigmentation
`2 (2%)
`0 (0%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`*Mild, Moderate, or Severe
`
` 6.3 Postmarketing Experience
`
`The following adverse reactions have been identified during post approval use of Metvixia
`Cream outside of the United States. 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.
`
`
`Reports of serious adverse reactions at or near the application site include pain, erythema,
`edema, pustules, scab, crusting, and hyperpigmentation. 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
`edema, eyelid swelling, macular edema, vitreous detachment and keratitis.
`
`
`
`
`DRUG INTERACTIONS
`7
`There have been no studies of the interaction of Metvixia Cream with other drugs,
`including local anesthetics. It is possible that concomitant use of other known
`photosensitizing agents might increase the photosensitivity reaction of actinic keratoses
`
`009
`
`

`

`
`
`
`
`treated with Metvixia Cream.
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Teratogenic effects: Pregnancy Category C:
`There are no adequate and well-controlled studies with Metvixia Cream in pregnant
`women. Intravenous methyl aminolevulinate hydrochloride (HCl) 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 Section 13.3)
`
`
`Nursing Mothers
`8.3
`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.
`
`
`Pediatric Use
`8.4
`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.
`
`010
`
`

`

`
`
`
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`OVERDOSAGE
`10
`10.1 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 with saline and water, and the patient should protect the
`exposed area from sunlight, prolonged or intense light for two days.
`
`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
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`burn, the patient should be treated in accordance with standard practice for treatment of
`cutaneous burns.
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`DESCRIPTION
`11
`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:
`
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` Metvixia Cream, for topical use only, is cream to pale yellow in color, contains glyceryl
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`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.
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`12
`CLINICAL PHARMACOLOGY
`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
`
`O
`
`Cl -
`
`O
`
`OCH3
`
`
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`+
`NH3
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`Pharmacokinetics
`
`actinic (solar) ketatosis lesions is the combination of photosensitization by topical
`application of Metvixia cream to the lesions and subsequent illumination with red light of
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` narrow spectrum using a light dose of 37 J/cm2 delivered by the Aktilite CL128 lamp.
`
`12.2
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`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.
`
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` NONCLINICAL TOXICOLOGY
`13
`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.
`
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`13.3 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%).
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`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%).
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`CLINICAL STUDIES
`14
`Metvixia Cream 16.8 % for photodynamic therapy (PDT) by illumination using the Aktilite
`CL128 lamp was studied in 211 randomized subjects with a total of 1555 non-
`hyperkeratotic actinic keratoses in two multicenter, randomized, double-blind vehicle-
`controlled clini