Metvix: Indications, Dosage, Precautions, Adverse Effects
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Metvix - Product Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Actinic Keratosis, Basal Cell Carcinoma, Skin Cancer
Class: Antibiotics/antineoplastics, Antineoplastics
Form: Cream
Ingredients: methyl aminolevulinate hydrochloride, glyceryl monostearate, cetostearyl alcohol, polyoxyl stearate, cholesterol, oleyl alcohol, glycerol, white soft paraffin, isopropyl myristate, arachis (peanut) oil, refined almond oil, edetate disodium, methylparaben, propylparaben, purified water.

Summary Product Information

Route of Administration Dosage Form ⁄ Strength Clinically Relevant Nonmedicinal Ingredients
Topical Cream/168 mg/g methyl aminolevulinate (as methyl aminolevulinate hydrochloride) Arachis (peanut) oil, refined almond oil
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

Metvix cream in combination with 630 nm wavelength red light illumination using the Aktilite CL 128 lamp is indicated 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.
  • treatment of primary superficial basal cell carcinoma outside the H-zone of the face (e.g. ears, nose) when other therapies are considered less appropriate. The lesions should have been confirmed previously by biopsy.

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 (see Warnings and Precautions).

Geriatrics (≥ 65 Years of Age)

No overall differences in safety and efficacy were observed between patients aged 65 years and older and those who were younger.

Pediatrics

It is not recommended that Metvix cream be used in pediatric patients (see Warnings and Precautions).

Contradications

  • Patients who are hypersensitive to this drug or aminolevulinic acid or to any ingredient in the formulation (including peanut and almond oil) or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section.
  • Patients with cutaneous photosensitivity/porphyria, or known allergies to porphyrins.
  • Patients with morpheaform basal cell carcinoma.

Warning and Precautions

Serious Warnings and Precautions

  • Metvix cream is intended for topical use. Do not apply to the eyes or to mucous membranes.
  • This product should be administered by trained physicians only.
  • Care should be taken by the physician when applying Metvix cream to avoid inadvertent skin contact (see Sensitivity/Resistance section below).
  • Patients with sBCC treated with Metvix–PDT must have regular follow–up of the treatment site since the efficacy is generally less than with surgery.
  • The long–term efficacy of Metvix–PDT with Aktilite CL128 for the treatment of sBCC has not been established. Data from studies performed with a different lamp showed that the sBCC lesion CR at 12 months was similar to that observed with the Aktilite CL128 lamp, but decreased to 29–60% at 60 months post–treatment.

General

Metvix Cream Application

During the time period between the application of Metvix cream and exposure to red light illumination, the treatment site will become photosensitive. After Metvix 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, protective clothing, or similar 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 Metvix cream and photodynamic therapy light treatment.

After illumination of Metvix 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, Metvix cream should be applied by a trained physician to the skin lesion 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.

Photosensitivity and Device Precautions

The patient, operator and other persons present during red light treatment should wear protective goggles that sufficiently screen out red light with wavelengths from 570 to 670 nm.

If for any reason the patient cannot have the red light treatment after application of Metvix 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 Metvix cream should be avoided.

Carcinogenesis and Mutagenesis

Please see Toxicology section. Long-term studies to evaluate the carcinogenic potential of Metvix cream have not been performed.

Hematologic

Metvix cream has not been tested on patients with inherited or acquired coagulation defects.

Hepatic/Biliary/Pancreatic

The results of repeated-dose toxicity studies indicated that the liver was the target organ for high intravenous doses of methyl aminolevulinate in rats, but examination of liver function tests from phase I trials in humans did not reveal any changes that were inconsistent with random variation.

Immune

A study conducted in immunocompromised organ transplant recipients did not identify any safety concern in this population, adverse events being similar to those reported in trials in immunocompetent patients. However, the efficacy of Metvix in immunocompromised patients has not been well established.

Ophthalmologic

Application of Metvix cream to the eyes or to mucous membranes should be avoided.

Sensitivity/Resistance

Contact sensitization (allergenicity) has been observed in 14-52% of subjects previously exposed to Metvix on at least 4 occasions (See Toxicology). Care should be taken by the physician applying Metvix 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.

The excipients cetostearyl alcohol and peanut oil may elicit local skin reactions such as contact eczema in rare cases, while methylparaben and propylparaben may sometimes cause allergic reactions.

Sexual Function/Reproduction

The effect of Metvix-PDT on sexual function and reproduction has not been investigated.

Skin

The safety and efficacy of Metvix cream has not been established in patients with porphyria or pigmented or highly infiltrating lesions. Thick (hyperkeratotic) actinic keratosis should not be treated with Metvix cream.

Please see "General" above for precautions regarding photosensitivity reactions.

Special Populations

Pregnant Women

Intravenous methyl aminolevulinate was teratogenic in rabbits at a high dose (see Toxicology). It is not known whether Metvix cream can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Treatment with Metvix cream is not recommended during pregnancy. Metvix cream should be given to pregnant women only if the benefit risk ratio is favourable.

Nursing Women

The amount of methyl aminolevulinate secreted into human breast milk following topical administration of Metvix cream is not known. In the absence of clinical studies and because many drugs are excreted in human milk, caution should be exercised when Metvix is administered to a nursing woman.

Pediatrics

Actinic keratosis and basal cell carcinoma are seldom observed under the age of 18 and therefore, there is no experience with the use of Metvix-PDT in this population.
Metvix cream is not recommended for use in pediatric patients.

Adverse Reactions

Adverse Drug Reaction Overview

Adverse drug reactions are categorized as appearing at the treatment site or non-treatment site. The common adverse drug reactions reported in all studies of Metvix-PDT were local phototoxic reactions.

Clinical Trial Adverse Drug Reactions

Actinic Keratosis Studies

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 Metvix Cream 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 1-1 shows the incidence and severity of adverse drug reactions in these two trials.

Table 1-1: Incidence of Adverse Drug Reactions in ≥1% of Subjects with actinic keratoses in Studies 1 and 2 (Safety Population)
Metvix and Aktilite PDT
n = 126
Vehicle and Aktilite PDT
n = 105
Any Treatment Site Adverse Drug Reaction All Events* Severe All Events* Severe
113 (90%) 28 (22%) 48 (48%) 0 (0%)
Skin burning/pain/discomfort 109(86%) 25 (20%) 38 (36%) 0 (0%)
Erythema 80 (63%) 7(6%) 11 (10%) 0 (0%)
Scabbing/crusting/blister/erosions 36 (29%) 2 (2%) 1 (1%) 0 (0%)
Pruritus 28 (22%) 0 (0%) 8 (8%) 0 (0%)
Skin or eyelid edema 23 (18%) 2 (2%) 1 (1%) 0 (0%)
Skin exfoliation 17 (14%) 4 (3%) 3 (3%) 0 (0%)
Skin warm 5 (4%) 0 (0%) 2 (2%) 0 (0%)
Application site discharge 3 (2%) 0 (0%) 0 (0%) 0 (0%)
Skin hemorrhage 2 (2%) 0 (0%) 0 (0%) 0 (0%)
Skin tightness 2 (2%) 0 (0%) 0 (0%) 0 (0%)
Skin hyperpigmentation 2 (2%) 0 (0%) 0 (0%) 0 (0%)
Non Treatment Site Adverse Drug Reaction 13 (10%) 2 (2%) 0 (0%) 0 (0%)
Headache 3 (2%) 1 (1%) 0 (0%) 0 (0%)

*Mild, Moderate, or Severe

The most common adverse drug reactions were attributable to phototoxicity reactions at the treatment site.

Less Common Clinical Trial Adverse Drug Reactions in Actinic Keratoses Studies (<1%)

Eye disorders: eye pain, lacrimation increased
Gastrointestinal disorders: nausea
General disorders and administration site conditions: chills
Injury, poisoning and procedural complications: contusion
Nervous system disorders: dizziness
Skin and subcutaneous tissue disorders: hyperhidrosis

Superficial Basal Cell Carcinoma Study

A total of 234 subjects were screened and 196 subjects enrolled in the pivotal superficial basal cell carcinoma study. Regarding drug adverse events, there were more events and more subjects in Metvix-PDT group than in surgery group (37% subjects with 65 related adverse events versus 14.6% subjects with 21 related adverse events). Most related adverse events were dermatologic and more frequent in Metvix-PDT group (34% subjects with 61 related dermatologic adverse events versus 7.3% subjects with 8 adverse events). These adverse events are summarised in Table 1-2.

Table 1-2: Incidence of Adverse Drug Reactions in ≥1% of Subjects in Superficial Basal Cell Carcinoma Study (Safety Population)
Metvix (N=100) Surgery (N=96)
Mild< Moderate Mild Moderate Severe
Any Adverse Events 26 (26%) 11 (11%) 10 (10.4%) 3 (3.1%) 1 (1.0%)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Pain 1 (1%) 1 (1%) 1 (1.0%)
INFECTIONS AND INFESTATIONS All
Application site infection
Wound infection
1 (1%)
1 (1%)


3 (3.1%)

3 (3.1%)
1 (1.0%)

1 (1.0%)
1 (1.0%)

1 (1.0%)
NEOPLASM BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) Basal cell carcinoma 1 (1%)
NERVOUS SYSTEM DISORDERS Headache 1 (1%)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS All
Milia
Photosensitivity reaction
Skin Hyperpigmentation
Erythema
Keloid scar
Pain of skin
Pruritus
Scar
24 (24%)
2 (2%)
22 (22%)





9 (9%)

9 (9%)
1 (1%)




5 (5.2%)



3 (3.1%)
1 (1.0%)

1 (1.0%)
1 (1.0%)
1 (1.0%)





1 (1.0%)









INJUIRY, POISONING AND PROCEDURAL COMPLICATIONS All
Postprocedural pain
Wound Dehiscence




4 (4.2%)
2 (2.1%)
2 (2.1%)




MUSCULOSCELETAL AND CONNECTIVE TISSUE DISORDERS Shoulder pain 1 (1.0%)
SURGICAL AND MEDICAL PROCEDURES All
Slin lesion excision
Suture insertion




2 (2.1%)
1 (1.0%)
1 (1.0%)




Related = possibly, probably or definitely related.

The most commonly reported related adverse events were expected: photosensitivity reaction for Metvix-PDT (31% subjects with 57 adverse events), and wound infection for surgery procedure (5.2% subjects with 5 adverse events). Among these subjects, there was 1 subject (1.7%) in surgery group who reported related adverse events of severe intensity. In the Metvix–PDT group, the majority of related adverse events were of mild severity.

Abnormal Hematologic and Clinical Chemistry Findings

No abnormalities attributable to treatment with Metvix-PDT have been observed. The results ofrepeated-dose toxicity studies indicated that the liver was the target organ for high intravenous doses of methyl aminolevulinate in rats, but examination of liver function tests from phase I trials in humans did not reveal any changes that were inconsistent with random variation.

Adverse Drug Reactions From Other Clinical Trials

In addition, there were reports of parathesia, and, urticaria, rash, skin hypopigmentation, heat rash, and fatigue in Phase III studies in which the illumination was performed with a different lamp (CureLight 01). There were also isolated reports of scar in a dose ranging study performed with CureLight where a relationship to treatment was uncertain.

Post-Market Adverse Drug Reactions

Application site eczema, allergic contact dermatitis and urticaria have been described in post-marketing reports. Most cases were localized to the treatment area and were not severe; some cases of erythema and swelling have been more extensive.

Drug Interactions

Overview

There have been no studies of the interaction of Metvix with other drugs, including local anesthetics. It is possible that concomitant use of other known photosensitizing agents might increase photosensitivity reactions when treated with Metvix cream.

The demographic of the treated population is largely elderly patients receiving a variety of concomitant systemic medications, and there is no suggestion of any interaction between Metvix–PDT and these medications.

Drug-Drug Interactions

Interactions with other drugs have not been established.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

This product is not intended for application by patients or unqualified medical personnel; therefore, this product is only dispensed to physicians.

Recommended Dose and Dosage Adjustment

Actinic Keratosis

For treatment of thin or non-hyperkeratotic and non-pigmented actinic keratosis lesions on the face and scalp, one treatment session with Metvix-PDT should be performed followed by a second treatment session 7 days later. The treated lesions should be evaluated after 3 months, and up to two additional treatment sessions can be performed if needed. Multiple lesions can be treated in one session. Metvix-PDT is not recommended for treatment of Grade III hyperkeratotic lesions. A maximum of 2 g of Metvix cream per treatment session should be applied.

Superficial Basal Cell Carcinoma (outside the H-zone of the face)

One treatment session with Metvix-PDT should be performed with a second treatment session 7 days later. The treated lesions should be evaluated after 3 months, and if needed, two additional treatment sessions 7 days apart should be performed. A maximum of 2 g of Metvix cream per treatment session should be applied.

Missed Dose

If the patient for any reason cannot have the red light treatment within the 3 hour prescribed period after application, the cream should be rinsed off. The patient should be instructed to protect the exposed area from sunlight, and prolonged or intense light for two days.

Administration

One Metvix–PDT session consists of:

  1. Lesion debriding

    Before applying Metvix cream, the surface of the lesions should be prepared with a small dermal curette to remove scales and crusts and to roughen the surface of the lesion (Fig.1 and Fig.2). This is to facilitate access of the cream and light to all parts of the lesion.

  2. Application of Metvix cream

    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.

    Using a spatula, apply a layer of Metvix cream about 1 mm thick to the lesion and the surrounding 5 mm of normal skin. Multiple lesions may be treated during the same treatment session. Each treatment field should be limited to the size of the light field of the lamp.

  3. Cover the lesion(s)

    The area to which the cream has been applied should then be covered with an occlusive, non-absorbent dressing (Fig. 3). After cream application, patients should avoid exposure of the treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) prior to red light treatment. Exposure to other light sources 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, protective clothing or similar 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 Metvix cream outside the treatment site to the eyes or surrounding skin. The treated site should be protected from extreme cold with adequate clothing or by remaining indoors between the application of Metvix cream and the PDT light treatment.

    Figure 3

  4. Wait for 3 hours (at least 2.5 hours, but no more than 4 hours) (see Warnings and Precautions)

    Metvix cream should not be applied for longer than the recommended time. If PDT cannot be performed on the patient after the application of Metvix cream, the cream should be rinsed off with saline and gauze and treated areas should be protected from sunlight and prolonged and intense light for 2 days.

  5. Removal of Dressing and Rinse Off Excess Cream

    Following removal of the occlusive dressing, clean the area with saline and gauze (Fig. 4). Nitrile gloves should be worn.

    Figure 4

  6. Illumination of Metvix Treated Lesion (see Warnings and Precautions)

    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 precautions provided with the lamp. The patient and operator should wear protective goggles during illumination. The lamp should be carefully positioned so that dosing is accurate and immediately thereafter the lesion should be exposed to red light at 630 nm and a total light dose of 37 J/cm2 (Fig. 5).

    Figure 5

    Patients should be advised that transient stinging and/or burning at the target lesion sites may occur during the period of light exposure. It is not necessary to protect healthy skin surrounding the lesions during exposure.

    If red light treatment is interrupted or stopped for any reason, it may be restarted. Metvix cream is not intended for use with any device other than the approved lamp: Aktilite CL 128. Use of Metvix cream without subsequent red light illumination is not recommended.

Overdosage

Metvix Cream

Metvix cream overdose has not been reported in clinical trials or in post-marketing experience and is not likely to occur in clinical practice due to the nature of the treatment being administered directly by a physician.

No incidences of oral ingestion of Metvix cream have been reported. In the unlikely event that the drug is ingested, monitoring and supportive care is recommended. Methyl aminolevulinate has a low order of single-dose oral and intravenous toxicity in mice and rats; the minimally lethal oral acute dose was more than 2000 mg/kg.

Red Light

There is no information on overdose of red light following Metvix cream application. If red light overexposure and a skin burn occurs, the patient should be treated according to standard practice for the treatment of cutaneous burns.

Action and Clinical Pharmacology

Mechanism of Action

Photosensitization occurs through the metabolic conversion of methyl aminolevulinate (prodrug) to photoactive porphyrins (PAP), which accumulates 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. The absorption of light causes an excited state of the 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 lesions using Metvix cream, plus illumination with Aktilite CL 128 (630 nm wavelength red light) at 37 J/cm2, is the basis for Metvix photodynamic therapy (PDT).

Pharmacodynamics

See Mechanism of Action above.

Pharmacokinetics

Absorption

In vitro dermal absorption of radiolabelled methyl aminolevulinate applied to human cadaver skin has been studied. After 24 hours, the mean cumulative absorption through human skin was 0.26% of the administered dose. A skin depot containing 4.9% of the dose was formed. No corresponding studies in compromised human skin (damage similar to actinic keratosis, BCC, roughened surfaces or without stratum corneum) were performed.

There is no information on the pharmacokinetics of methyl aminolevulinate in human serum due to the instability of the drug in serum.

Metabolism, Distribution and Elimination

The metabolic pathway in humans by which photoactive porphyrins are produced from methyl aminolevulinate is not fully elucidated.

In humans, the levels of photoactive porphyrins in the skin were indirectly determined through a semi-quantitative method measuring the skin fluorescence following methyl aminolevulinate application. A higher degree of accumulation of photoactive porphyrins in lesions compared to normal skin has been demonstrated after topical application of methyl aminolevulinate.

After application of methyl aminolevulinate to the skin of human subjects for 3 hours, a subsequent illumination with a narrow red light spectrum at 630 nm wavelength and a total light dose of 37 J/cm2 reduced the fluorescence of skin lesions near pre-treatment levels immediately after illumination, but it did not result in complete photobleaching. Thereafter, an increase in fluorescence 2 hours following the illumination was observed. Complete photobleaching was observed 24 hours following the illumination.

Special Populations and Conditions

The pharmacokinetics of methyl aminolevulinate has not been investigated in conditions such as hepatic insufficiency, or renal insufficiency. Any systemic effects are considered to be negligible due to selective accumulation of the compound in lesions compared to normal skin and since systemic absorption is usually minimal after topical administration (see Adverse Reactions).

Storage and Stability

Store refrigerated, 2-8 °C.

Shelf-life: 18 months.

Use contents within one week after opening. The product should not be used after 24 hours without refrigeration.

Special Handling Instructions

Contact sensitization (allergenicity) has been observed with the use of Metvix cream (See Adverse Reactions and Clinical Trials). Care should be taken by individuals handling Metvix 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 from this product.

Dosage Forms, Composition and Packaging

Metvix cream is an oil-in-water emulsion. Metvix cream contains methyl aminolevulinate hydrochloride equivalent to 168 mg/g of methyl aminolevulinate.

It 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.

Metvix cream is packaged in a 2 gram aluminum tube sealed with an aluminum membrane and a screw cap.