Consumer medicine information

Metvix Cream

Methyl aminolevulinate

BRAND INFORMATION

Brand name

Metvix

Active ingredient

Methyl aminolevulinate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Metvix Cream.

What is in this leaflet

This leaflet answers some common questions about METVIX. It does not contain all the available information.

It does not take the place of talking to your doctor or nurse.

All medicines have risks and benefits. Your doctor has weighed the risks of you using METVIX against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or nurse.

Keep this leaflet. You may need to read it again.

What METVIX is used for

METVIX contains the active ingredient methyl aminolevulinate (as hydrochloride) that belongs to a group of medicines called antineoplastic agents or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

METVIX is used for treating spots on the face and scalp that are thin and not dark-coloured, that are at risk of turning into skin cancer (pre-cancerous lesions called actinic keratosis, or AK). It is used when other treatments are considered unacceptable. METVIX is also used to treat some shallow basal cell carcinomas (BCCs) (a form of skin cancer) as well as Bowen’s disease, when surgery is not a suitable option. Bowen’s disease is a persistent, flat, red-brown scaly or crusted area on the skin which is due to a tumour inside the upper layer of the skin. If untreated it may spread or eventually invade deeper structures of the skin.

METVIX works by killing cancer or pre-cancer cells by preventing them from growing or multiplying. Treatment consists of application of Metvix cream followed by light exposure (Photodynamic Therapy or PDT) using either a red LED lamp (for AK, BCCs and Bowen’s disease) or daylight (for AK only). The affected areas absorb methyl aminolevulinate from the cream. By light exposure, the cancerous cells are destroyed. Normal skin will not be affected.

Ask your doctor if you have any questions about why METVIX has been prescribed for you. Your doctor may have prescribed it for another reason.

METVIX is not addictive.

METVIX is available only with a doctor’s prescription.

Before you use METVIX

When you must not use it

Do not use METVIX:

  • For children under 18 years of age
  • If you have porphyria (a rare blood pigment disorder)
  • If you have a type of Basal Cell Carcinoma (BCC) called morpheaform.
  • If you have a type of skin cancer called invasive squamous cell carcinoma
  • If you have an allergy to any medicine containing methyl aminolevulinate
  • If you have an allergy to arachis (peanut) oil
  • If you have an allergy to any of the ingredients listed at the end of this leaflet

Symptoms of an allergic reaction, which can lead to angioedema, may include:

  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives of the skin, especially on the areas of the skin where the cream was applied.

Tell immediately your Doctor if you have a history of allergies; they may give you a small test dose to see how you react to METVIX.

Do not use METVIX after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your doctor or nurse for disposal.

Before you start to use it

METVIX should only be used on thin and non-pigmented actinic keratosis (pre-cancerous lesions or AK). The performance of Metvix on thicker, deeper or darker skin cancers is unknown.

METVIX should only be used on the first presentation of any Basal Cell Carcinomas (BCCs). The performance of METVIX on recurring BCCs is unknown.

METVIX should only be used on non-pigmented, small (<40 mm diameter) and non- genital Bowen’s disease lesions. The performance of Metvix on larger, deeper, darker or genital skin cancers is unknown.

Before you start treatment with METVIX, any UV-treatment on your skin should be ceased.

METVIX treatment with red LED lamp should only be administered in the presence of a doctor, a nurse, or other health care professional trained to apply Photodynamic Therapy (PDT).

Tell your doctor if you are pregnant or plan to become pregnant. Like most antineoplastic medicines, METVIX is not recommended for use during pregnancy. It is unknown whether METVIX may affect your developing baby if you use it during pregnancy. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breast-feeding. A risk to the new-borns/infants cannot be excluded. To avoid the possibility that the baby may be affected by METVIX, you should cease breast-feeding while using METVIX and for 2 days after treatment.

Tell your doctor if you have a history of high blood pressure. Your doctor may decide to measure your blood pressure if you experience severe pain during illumination with the red LED lamp. If your blood pressure is high, your doctor may then decide to stop the procedure.

If you have not told your doctor about any of the above, tell him/her before treatment with METVIX.

Taking other medicines

Tell your Doctor or Nurse if you are using any other medicines, creams or ointments, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and METVIX may interfere with each other. Your Doctor and Nurse may have more information on medicines to be careful with while using METVIX.

How to use METVIX

Health care professionals will perform all of the steps in your treatment:

The treatment session begins with preparation of the cancerous or pre-cancerous skin by removing scales and crusts and roughening of the skin surface. Some Basal Cell Carcinomas (BCCs) are often covered by an intact layer of skin which should be removed. This helps METVIX cream and light treatment to reach affected skin.

METVIX cream is then applied by spatula in a layer to the lesion and a small area of the surrounding skin.

Avoid getting the METVIX cream into your eyes. METVIX cream should not be applied to eyelids and mucous membranes.

PDT with a red LED lamp

If your Doctor prescribes photodynamic therapy (PDT) treatment with a red LED lamp source with your Metvix, your lesions are prepared as described above. After Metvix cream is applied, the area will be covered with a dressing, and this should remain in place for 3 hours. The dressing and the cream are then gently removed with saline water, and finally the treated area will immediately be exposed to PDT via a red LED lamp source. Eyes should be protected from intense LED light, so you will be given goggles to wear during this treatment.

As a general precaution, sun exposure of the treated area and surrounding skin should be avoided for about 2 days following treatment.

Daylight PDT

Your Doctor will only prescribe daylight PDT if you have actinic keratosis on the face and scalp, and the weather is suitable to stay comfortably outdoors for 2 hours. If the weather is rainy, or is likely to become so, Metvix daylight treatment should not be used. An appropriate sunscreen should be applied to all exposed areas. The sunscreen used must offer adequate protection (Sun Protection Factor (SPF) 30 or higher). Only sunscreens with chemical filters should be used with daylight PDT. The sunscreens should not include physical filters (such as titanium dioxide, zinc oxide or iron oxide) as these filters interrupt the effectiveness of the daylight PDT treatment.

If your Doctor prescribes daylight PDT treatment, your lesions are prepared as described above 15 minutes after sunscreen application. After Metvix cream is applied, no occlusion is necessary before daylight exposure. Treatment with daylight should begin within 30 minutes of Metvix cream application, and should continue for 2 hours. During this time, you should remain outside and carry out usual daily activities. On sunny days, if you feel uncomfortable in direct sunlight, you may take shelter in the shade. Following the 2 hours exposure period, the cream will be removed with saline water. As a general precaution, sun exposure of the treated area and surrounding skin should be avoided for about 2 days following treatment.

Follow up treatment sessions

Only 1 treatment session of PDT (either with red LED light or daylight) is required for AK. Multiple skin lesions may be treated during the same treatment session. Your Doctor will assess the response after 3 months. Treatment may be repeated once only after this period, if necessary. This repeat treatment will also be a single session.

Treatment for BCC and Bowen’s disease will consist of 2 sessions of PDT with red LED light, 1 week apart. Multiple skin lesions may be treated during the same treatment session. Your doctor will assess the response after three months. Treatment may be repeated once only after this period, if necessary. This repeat treatment will also consist of two sessions, one week apart. The sites of successfully treated lesions should be reviewed at 6-12 monthly intervals to detect recurrence.

Tell your Doctor if you notice that any of the areas of skin treated with Metvix have changed or appear worse

What if I am given too much METVIX

If the application time or the light dose is increased, a more severe local reaction might result. You should contact your doctor or nurse if you have any concerns.

What if treatment is stopped

If the treatment is stopped before the full light dose has been given with the red LED light, or before the end of the 2 hour daylight exposure, the success of the treatment might be compromised.

Whilst you are using METVIX

Things you must do

Tell all doctors and nurses who are treating you that you are using METVIX.

If you feel that METVIX is not helping your condition, tell your doctor or nurse.

Tell your doctor if you become pregnant while using METVIX.

Things you must not do

After undergoing METVIX treatment, ensure the treated area and surrounding skin are protected from sunshine for 2 days after treatment.

Side effects

Tell your doctor or nurse as soon possible if you do not feel well whilst you are using METVIX.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or nurse to answer any questions you may have.

Tell your Doctor or Nurse if you notice any of the following and they worry you:

  • Local discomfort at the treatment site during and after light exposure including skin burning, warm sensation, pricking and tingling skin or stinging sensation, swelling, pain, itching of skin and redness
  • Crusting, ulceration, weeping or discharge, blistering, peeling, bleeding skin, skin infection and changes to the colour of the skin
  • Headache

These are more common side effects of METVIX, particularly with red LED light Photo Dynamic Therapy (PDT).

The most frequent of these symptoms is a painful and burning skin sensation, typically beginning during or soon after red light exposure, lasting for a few minutes to hours and resolving on the day of treatment. Severity of these symptoms is usually mild or moderate, but rarely, it may require early termination of illumination.

Treatment with daylight PDT is associated with similar type of side effects but significantly less pain, and substantially less local discomfort than with red LED light PDT.

Tell your Doctor or nurse if you notice any of the following:

  • nettle rash (urticaria)
  • skin rash
  • allergic reaction which can lead to angioedema with the following symptoms: swelling of the face, the tongue or the throat, or difficulty in breathing
  • eczema or thinning of skin
  • dizziness
  • Memory loss or confusion state or disorientation
  • eye pain and eye irritation
  • swollen eyes, eyelids, face
  • nausea
  • fatigue
  • skin irritation
  • wound haemorrhage

Increase of blood pressure may be induced by pain associated with the use of red light.

These are uncommon side effects of METVIX or their frequency is unknown.

Other side effects not listed above may occur in some patients. Do tell your Doctor or Nurse if you notice any side effects not mentioned in this leaflet.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using METVIX

Storage

METVIX should be stored in a refrigerator, below 8°C. An opened tube should be used within 1 week.

Keep out of the reach and sight of children.

Product description

What it looks like

METVIX contains 160 mg/g of methyl aminolevulinate (as hydrochloride) and is cream to pale brown in colour.

It is supplied in a tube containing 2 g cream.

Ingredients

Each gram of METVIX contains 160mg of methyl aminolevulinate as the active ingredient.

It also contains the inactive ingredients:

  • glyceryl monostearate (self-emulsifying)
  • cetostearyl alcohol
  • PEG-40 stearate
  • methyl hydroxybenzoate (E 218)
  • propyl hydroxybenzoate (E 216)
  • disodium edetate
  • glycerol
  • white soft paraffin
  • cholesterol
  • isopropyl myristate
  • arachis oil (peanut oil)
  • almond oil (refined)
  • oleyl alcohol
  • purified water

Sponsor / distributor

Galderma Australia Pty Ltd
Suite 4, 13B Narabang Way
Belrose NSW 2085
Ph 1800 800 765

In New Zealand by:

Healthcare Logistics’
58 Richard Pearce Drive
Airport Oaks
Auckland
Telephone 0800 174 104

Made in the United Kingdom and/or France

Australia Registration Number:
AUST R 93838

® Registered Trademark

This leaflet was prepared in June 2022

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Metvix

Active ingredient

Methyl aminolevulinate

Schedule

S4

 

1 Name of Medicine

Methyl aminolevulinate (as hydrochloride).

2 Qualitative and Quantitative Composition

Metvix cream contains 160 mg/g of methyl aminolevulinate (as hydrochloride).

List of excipients with known effect.

Contains peanut products, tree nut products and hydroxybenzoates.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cream to pale brown cream.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of thin or nonhyperkeratotic and nonpigmented actinic keratoses on the face and scalp when other registered therapies are unacceptable.
Primary treatment of superficial and/or nodular basal cell carcinoma where surgery is considered inappropriate.
Treatment of biopsy proven squamous cell carcinoma in situ (Bowen's disease), where surgery is considered inappropriate.
Metvix is indicated in adults above 18 years of age.

4.2 Dose and Method of Administration

Adults (including the elderly).

For treatment of actinic keratoses (AK), one session of photodynamic therapy (PDT) should be administered with either red LED light via a suitable lamp (c-PDT) or exposure to natural daylight (DL-PDT). Treated lesions should be assessed after three months and those with non-complete response should be retreated, as per the initial treatment method.
For treatment of basal cell carcinoma (BCC) and squamous cell carcinoma in situ (Bowen's disease) two sessions of c-PDT should be administered with an interval of one week between sessions.
Treated lesions should be assessed after three months and those with non-complete response should be retreated, as per the initial treatment method. In clinical trials in BCC, approximately 25-30% of patients required retreatment at 3 months. In the clinical trial in Bowen's disease, approximately 20% of patients required retreatment at 3 months.

Procedure for AK, BCC and Bowen's disease using red LED light.

Before applying Metvix, the surface of the lesions should be prepared by removing scales and crusts and roughening the surface of the lesion. Nodular BCC lesions are often covered by an intact epidermal keratin layer which should be removed. Exposed tumour material should be removed gently without any attempt to excise beyond the tumour margins.
Apply a layer of Metvix (about 1 mm thick, using a spatula) to the lesion and the surrounding 5-10 mm of normal skin. Cover the treated area with an occlusive dressing for 3 hours.
Remove the dressing and clean the area with saline and immediately expose the lesion to red light with a continuous spectrum of 570-670 nanometre and a total light dose of 75 J/cm2 or an LED light source with an average wavelength of 630 nanometre and a light dosage of 37 J/cm2 giving the same activation of accumulated porphyrins may be used at the lesion surface. The light intensity at the lesion surface should not exceed 200 mW/cm2.
Only lamps listed in the Australian Register of Therapeutic Goods should be used, equipped with necessary filters and/or reflecting mirrors to minimize exposure to heat, blue light and UV radiation. It is important to ensure that the correct light dose is administered. The light dose is determined by factors such as the size of the light field, the distance between lamp and skin surface, and illumination time. These factors vary with lamp type and the lamp should be used according to the user manual. The light dose delivered should be monitored if a suitable detector is available.
Patient and operator should adhere to safety instructions provided with the light source. During illumination patient and operator should wear protective goggles which correspond to the lamp light spectrum.
Healthy untreated skin surrounding the lesion does not need to be protected during illumination.
Multiple lesions may be treated during the same treatment session.
Close long term clinical monitoring of BCC and Bowen's disease is recommended, with histology if necessary.

Procedure for AK using daylight.

If deemed appropriate, patients with AK may be treated with Metvix activated by daylight (DL-PDT), instead of using red LED light (c-PDT). Metvix DL-PDT treatment is exclusively for patients with face and scalp AK, and results in significantly lower pain scores than with c-PDT treatment.
Metvix DL-PDT treatment can be used if the weather is suitable to stay comfortably outdoors for 2 hours. If the weather is rainy, or is likely to become so, Metvix daylight treatment should not be used. An appropriate sunscreen should be applied to all exposed areas. The sunscreen used must offer adequate protection (SPF 30 or higher) and not include physical filters (e.g. titanium dioxide, zinc oxide, iron oxide) as these inhibit absorption of visible light which may impact efficacy. Only sunscreens with chemical filters should be used with daylight procedure.
Sunscreen should be applied 15 minutes prior to lesion preparation. The surface and surrounding area of the AK lesions should be prepared by removing scales and crusts and roughening the surface of the lesions. Metvix cream should then be applied however no occlusion is necessary.
Daylight exposure should begin within 30 minutes and continue for 2 hours. During this time, patients should remain outside and carry out usual daily activities. On sunny days, should the patient feel uncomfortable in direct sunlight, shelter in the shade may be taken. Following the 2 hour exposure period, Metvix cream should be removed with saline water.
Treated lesions should be evaluated after 3 months and, if necessary, a second treatment session should be repeated.

Instruction for use/ handling.

Metvix should not be mixed with other drugs or preparations.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients including arachis oil (peanut oil); morpheaform basal cell carcinoma; invasive squamous cell carcinoma of the skin; porphyria.

4.4 Special Warnings and Precautions for Use

General.

Direct eye contact should be avoided. Metvix cream should not be applied to the eyelids and mucous membranes.
Methyl aminolevulinate may cause sensitization by skin contact resulting in angioedema, application site eczema or allergic contact dermatitis.
The excipients cetostearyl alcohol and arachis oil may rarely cause local skin reactions (e.g. contact dermatitis), methyl and propylhydroxybenzoate may cause allergic reactions (possibly delayed).
Any UV therapy should be discontinued before treatment. As a general precaution, sun exposure on the treated lesion sites and surrounding skin has to be avoided for a couple of days following treatment.
In patients with a history of hypertension, pain during illumination may induce increased blood pressure. It is thus recommended to measure blood pressure in these patients who experience severe pain, and interrupt illumination (in addition to taking specific measures when needed) if these patients also present severe hypertension.
Metvix with red LED light should only be administered in the presence of a physician, a nurse or other healthcare professionals trained in the use of photodynamic therapy with Metvix.
Minimum effective dose is not defined.
Conventional photodynamic therapy (PDT) with a red-light lamp may be a precipitating factor for transient global amnesia in very rare instances. Although the exact mechanism is not known, stress and pain associated with illumination with the lamp may increase the risk to develop transient amnesia. If signs of confusion or disorientation are observed, PDT must be discontinued immediately.

Actinic keratosis.

There is no histological confirmation on clearance of lesions nor data on patients previously treated with 5FU or tretinoin.
There is no experience of treating pigmented or highly infiltrating lesions with Metvix. Thick (hyperkeratotic) actinic keratoses should not be treated with Metvix.
There is limited experience from post-authorisation exposure in treating actinic keratoses in transplant patients on immunosuppressive therapy. A close monitoring of these patients, with re-treatment if necessary is recommended in this population.

Basal cell carcinoma.

The efficacy of Metvix in treating basal cell carcinomas that have recurred following previous treatment has not been determined. Therefore, Metvix should only be used in the treatment of primary lesions.
There is no experience in treating basal cell carcinomas associated with xeroderma pigmentosum, Gorlin's syndrome or immunosuppressive therapy.
The sites of successfully treated lesions should be reviewed at 6-12 monthly intervals to detect recurrence.

Squamous cell carcinoma in situ (Bowen's disease).

There is no experience of treating lesions which are pigmented, highly infiltrating or located on the genitalia with Metvix cream. There is no experience of treating Bowen's disease lesions larger than 40 mm in diameter.
The sites of successfully treated lesions should be reviewed at 6-12 monthly intervals to detect recurrence.
The efficacy of Metvix in treating Bowen's disease lesions that have recurred following previous treatment has not been determined. Therefore, Metvix should only be used in the treatment of primary lesions.
There is limited experience from post-authorisation exposure in treating Bowen's disease in transplant patients on immunosuppressive therapy. A close monitoring of these patients, with re-treatment if necessary is recommended in this population.

Use in hepatic impairment.

No information is available on the use of Metvix in this population.

Use in renal impairment.

No information is available on the use of Metvix in this population.

Use in the elderly.

No dosage adjustment required.

Paediatric use.

There is no experience of treating patients below the age of 18 years. Metvix is not recommended for use in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No specific interaction studies have been performed with Metvix.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies on the reproductive toxicity of methyl aminolevulinate have not been performed.
(Category B2)
No clinical data on exposed pregnancies are available for methyl aminolevulinate. No reproductive studies in animals have been performed. The potential risk is unknown. Methyl aminolevulinate is not recommended during pregnancy.
There are no human data on the excretion of methyl aminolevulinate in human breast milk or on the safety of methyl aminolevulinate exposure in newborns/ infants following topical application of Metvix. A risk to the newborns/ infants cannot be excluded. Therefore, breastfeeding should be discontinued for 48 h after application of Metvix.

4.7 Effects on Ability to Drive and Use Machines

No effects on ability to drive and use machines have been observed.

4.8 Adverse Effects (Undesirable Effects)

Between 60% and 80% of patients in clinical trials using conventional photodynamic therapy (c-PDT) experienced reactions localised to the treatment site that are attributable to the toxic effects of the photodynamic therapy (phototoxicity) or to the preparation of the lesion. The most frequent symptoms are painful and burning skin sensation typically beginning during illumination or soon after and lasting for a few hours with resolution on the day of treatment. The severity is usually mild or moderate, but rarely, it may require early termination of illumination. The most frequent signs of phototoxicity are erythema and oedema which may persist for 1 to 2 weeks or occasionally for longer. In two cases they persisted for more than one year. See Table 1.
The following non-local adverse events were reported in clinical trials (c-PDT).

Nervous system disorders.

Uncommon: headache, dizziness.

Eye disorders.

Uncommon: eye pain, eye irritation, eye swelling.

Vascular disorders.

Uncommon: wound haemorrhage.

Gastrointestinal disorders.

Uncommon: nausea.

General disorders and administration site conditions.

Uncommon: fatigue.
There were also isolated reports of scar where a relationship to treatment was uncertain.
Repeated use did not increase the frequency or intensity of the local phototoxic reactions.
In the Australian study comparing DL-PDT to c-PDT, 39% of patients treated with daylight (versus 59% for patients treated with c-PDT) reported at least one treatment related adverse effect, the most frequent (≥ 4.0%) being skin reaction, scab, photosensitivity reaction and skin pain.

Adverse reactions - postmarketing (c-PDT).

Application site eczema and allergic contact dermatitis have been described in postmarketing reports. Most cases were localised to the treatment area and were not severe. Erythema and swelling have been more extensive on rare occasions. Eyelid oedema, face oedema (swelling face), angioedema, hypertension and transient global amnesia (including confusional state and disorientation) have also been described in postmarketing reports.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

The severity of local phototoxic reactions such as erythema, pain and burning sensation may increase in case of prolonged application time or very high red LED light intensity.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Methyl aminolevulinate is an antineoplastic agent. After topical application of methyl aminolevulinate, during the 3 hours under occlusion, porphyrins will accumulate intracellulary in the treated skin lesions. The intracellular porphyrins (including PpIX) are photoactive, fluorescing compounds and, upon light activation in the presence of oxygen, singlet oxygen is formed which causes damage to cellular compartments, in particular the mitochondria. Light activation of accumulated porphyrins leads to a photochemical reaction and thereby phototoxicity to the light exposed target cells.
Metvix in combination with light activation is referred to as Metvix photodynamic therapy (Metvix-PDT).
When methyl aminolevulinate is used with natural daylight, the procedure consists of continuous light exposure. PpIX is continuously being produced and activated within the target cells creating a constant microphototoxic effect without the PpIX accumulation associated with conventional photodynamic therapy (c-PDT).

Clinical trials.

Actinic keratosis (AK).

Treatment with red LED light.

The clinical trial programme to establish the efficacy and safety of Metvix for the treatment of AK comprises a total of 831 patients who participated in controlled studies of which 568 patients with 1829 lesions were treated with Metvix. A further 423 patients with 1470 AK lesions were treated in the compassionate use programme.
Controlled studies included the two pivotal placebo controlled studies of Metvix-PDT for the treatment of lesions on the face and scalp (see Table 2), one placebo controlled study (PC T302/99) and one active controlled study of Metvix-PDT versus cryotherapy (PC T301/99), both of which involved treatment of AK lesions at any site on the body.
Two randomised, double blind placebo controlled studies have been conducted in Australia and USA. Patients who were included had previously untreated facial and scalp actinic keratoses (AKs) that were slightly palpable (better felt than seen) to moderately thick (easily felt and seen). Hyperkeratotic actinic keratosis lesions were excluded. Metvix 160 mg/g cream or placebo cream was applied for 3 hours before illumination with a light dose of 75 J/cm2 (wavelength 570 to 670 nanometre). Two treatment sessions were given 7 days apart. A "cleared" AK lesion was defined as being not visible and not palpable when 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 100% of the lesions were cleared are shown in Table 2.
The Australian study PC T305/99 included a third arm consisting of treatment with one freeze thaw cycle with liquid nitrogen spray. The results of the PP population are presented in Table 3.
An open, noninferiority, randomized study, PC T311 was conducted in Sweden to compare two treatment regimens of Metvix-PDT in patients with up to 10 clinically confirmed mild to moderate AK lesions on the face or scalp. A total of 211 patients with 413 lesions were included in the study. Metvix 160 mg/g cream was applied for 3 hours before illumination with an LED light source with an average wavelength of 630 nanometre and a light dosage of 37 J/cm2.
Regimen I: Patients were treated once with Metvix-PDT. Lesions with noncomplete response were given one further treatment at the 3 month visit.
Regimen II: Treatment with Metvix-PDT consisted of two treatment sessions one week apart.
All patients were clinically assessed three months after their final Metvix treatment. Patient complete response rates (i.e. the proportion of patients where all lesions had shown a complete clinical response) and lesion complete response rates for each treatment group in the PP population are shown in Table 4.
The efficacy of a single initial treatment of Metvix-PDT was not inferior to two treatments administered 7 days apart when the difference between regimen I and regimen II was calculated to be less than 15% (one sided, upper limit, CI 97.5%).
Another study with conventional photodynamic therapy (c-PDT) showed that over 50% of patients with a complete response after 3 months had no recurrence after 1 year follow-up.

Treatment with daylight.

The efficacy and safety of Metvix daylight photodynamic therapy (DL-PDT) was compared to Metvix conventional photodynamic therapy (c-PDT) in a 24-week randomised, investigator blinded, intraindividual study conducted across 7 Australian centres. One hundred patients aged over 18 years with mild AK and with or without moderate AK were treated on one side of the face or scalp with Metvix DL-PDT and on the contralateral side with Metvix c-PDT. The c-PDT treatment procedure consisted of gentle curettage of lesions, then Metvix cream application, followed by area occlusion, then dressing removal, and finally 7-10 minutes photodynamic treatment with red LED light via a suitable lamp. The DL-PDT procedure consisted of gentle curettage of lesions, Metvix application without occlusion and, after 30 minutes, a 2 h exposure to daylight.
Both the efficacy and safety of Metvix DL-PDT were addressed with two coprimary endpoints. The coprimary efficacy endpoint was the percentage change from baseline in the total number of treated mild lesions per side at week 12 (noninferiority of Metvix DL-PDT compared to Metvix c-PDT). The coprimary safety endpoint was subject assessment of maximal pain per side at the baseline treatment session (superiority of Metvix-DL-PDT compared to Metvix c-PDT). The study results demonstrated that DL-PDT is as effective as c-PDT for treating AK lesions (percentage change from baseline in the total number of treated mild lesions per side after 12 weeks), but with significantly reduced subject pain. Metvix DL-PDT treatment benefit was similar (noninferior) to Metvix c-PDT (89.2% vs 92.8%, per protocol population) at week 12 after one session and the maintenance of lesion response rate remained noninferior for patients presenting at week 24 (96% for DL-PDT and 96.6% for c-PDT).
All subjects received an effective light dose on the DL-PDT treated side (22.8 ± 12.4 J/cm2). No correlation was found between light dose received by subjects and efficacy or safety variables.
The safety results of this AK study with DL-PDT compared to c-PDT showed that both treatment arms were well tolerated. Pain was assessed on an 11 point scale ranging from 0 (no pain at all) to 10 (extreme pain). DL-PDT was associated with significantly less pain compared to c-PDT (0.8 vs 5.7, p < 0.001); 81.6% subjects reported no pain with DL-PDT vs 2% with c-PDT (see Section 4.8 Adverse Effects (Undesirable Effects)).
Superficial and/or nodular basal cell carcinoma (BCC). The clinical trial program to establish the efficacy and safety of Metvix for the treatment of superficial and/or nodular BCC comprised a total of 480 patients, of which 341 patients with 498 lesions were treated with Metvix-PDT.
The American pivotal double blind placebo controlled study PC T307/00 showed that PDT with Metvix is superior to PDT with placebo cream in nodular BCC. Active controlled studies included the European studies PC T303/99 which compared Metvix-PDT to surgery in nodular BCC and PC T304/99 which compared Metvix-PDT to cryotherapy in superficial BCC. The superficial lesions were initially treated with one PDT session, whereas nodular lesions were given two PDT sessions one week apart. The results of these studies are presented in Tables 5 and 6.
Lesion recurrence was assessed at 24 months for all lesions that were disease free 3 and 12 months after the last treatment. The lesion recurrence rates at 24 months are given in Table 7.
Long-term outcomes beyond 24 months are unknown.
Squamous cell carcinoma in situ (Bowen's disease). A clinical trial to establish the efficacy and safety of Metvix for the treatment of squamous cell carcinoma in situ (Bowen's disease) comprised a total of 225 patients, 96 of whom were treated with Metvix-PDT. This study, PC T309/00, was a prospective, randomised placebo controlled multicentre European study in which patients were treated with either Metvix-PDT; placebo PDT; cryotherapy or 5-fluorouracil 5% cream (5-FU). Randomisation was to either PDT or standard therapy. Standard therapy was either cryotherapy or fluorouacil at the physician's choice. Within the PDT group, patients were further randomized in the ratio 5:1 to either Metvix-PDT or placebo PDT. The comparison with placebo PDT was double blinded; however, the comparison with the other treatments was unblinded. Responses to treatment were based on clinical, not histological, assessment.
There were 275 lesions in the 225 patients. The distribution of lesions was similar in all groups: 65% of lesions were located on the extremities, 23% on the face and scalp and 12% on the neck or trunk. Patients with large lesions (> 40 mm in diameter), strongly pigmented lesions or genital lesions were excluded.
Metvix cream was applied 3 hours prior to illumination in two sessions one week apart. Light dose was 75 J/cm2 (wavelength 570-670 nanometre). Partial responders received a second cycle of treatment 3 months later. Metvix-PDT (n = 96) was significantly superior to placebo-PDT (n = 17) in complete response rate at 3 months after one cycle 73% vs 24%, p < 0.001 in the intent to treat analysis.
Metvix-PDT was noninferior to cryotherapy and fluorouracil in complete response rate 3 months after 1-2 cycles of treatment based on the upper bound of the 97.5% confidence interval of the difference being less than 15%. See Table 8.

5.2 Pharmacokinetic Properties

In vitro dermal absorption of radiolabelled methyl aminolevulinate applied to human 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.
In humans, the selective accumulation of porphyrins in lesions compared to normal skin has been demonstrated with Metvix. With conventional PDT, after application of the cream for 3 hours and subsequent illumination with noncoherent light of 570-670 nanometre wavelength and a total light dose of 75 J/cm2 or an LED light source with an average wavelength of 630 nanometre and a light dosage of 37 J/cm2, complete photobleaching occurs with levels of porphyrins returning to pretreatment values.

5.3 Preclinical Safety Data

Genotoxicity.

There was no consistent evidence for genotoxic activity of methyl aminolevulinate and its metabolites in an in vitro assay of gene mutation or a chromosomal damage assay in vitro in the presence or absence of photoactivation, or in a chromosomal damage assay in vivo in the absence of photoactivation.

Carcinogenicity.

Studies on the carcinogenic potential of methyl aminolevulinate have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Other excipients are self-emulsifying glyceryl monostearate, cetostearyl alcohol, PEG-40 stearate, methyl hydroxybenzoate, propyl hydroxybenzoate, disodium edetate, glycerol, white soft paraffin, cholesterol, isopropyl myristate, arachis oil (peanut oil), almond oil (refined), oleyl alcohol and purified water.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Shelf life of unopened container: 15 months.
Shelf life of opened container: 1 week after first opening.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 8°C. Refrigerate.

6.5 Nature and Contents of Container

Metvix is supplied in epoxy coated aluminum tubes containing 2 g cream.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

79416-27-6.

7 Medicine Schedule (Poisons Standard)

Prescription Medicine (S4).

Summary Table of Changes