Consumer medicine information

Actikerall

Fluorouracil; Salicylic acid

BRAND INFORMATION

Brand name

Actikerall

Active ingredient

Fluorouracil; Salicylic acid

Schedule

What is in this leaflet

This leaflet answers some common questions about ACTIKERALL.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

Keep this leaflet with the medicine. You may need to read it again.

What ACTIKERALL is used for

ACTIKERALL is used to treat mild to moderate solar keratosis lesions, also known as actinic keratosis lesions or sunspots.

Solar keratoses are rough, red, scaly or crusty spots on the skin that are caused by too much exposure to sunlight. They are more common on sun-exposed areas, such as the face, nose, ears, chest, forearms and back of the hands.

Solar keratoses are usually harmless, but there is a risk that they may turn into skin cancer.

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

This medicine is available only with a doctor's prescription.

How it works

ACTIKERALL contains two active substances, fluorouracil and salicylic acid.

Fluorouracil belongs to a group of medicines known as antimetabolites which inhibit the growth of cells (cytostatic agent).

Salicylic acid is a hard skin softening substance.

Before you use ACTIKERALL

When you must not use it

Do not use ACTIKERALL if you have an allergy to:

any medicine containing fluorouracil, salicylic acid or acetylsalicylic acid (aspirin)
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not use this medicine if you have dihydropyrimidine dehydrogenase (DPD) enzyme deficiency or are taking medicines that could lower your DPD levels. This enzyme plays an important role in the breakdown of fluorouracil. As a result, fluorouracil might accumulate in your body. It may be necessary to have your DPD levels checked before starting treatment with ACTIKERALL.

Do not use ACTIKERALL if you have kidney problems.

Do not use this medicine if you are pregnant or there is a possibility you may be pregnant. It may affect your developing baby if you use it during pregnancy.

Do not breast-feed if you are using this medicine. It is unknown whether the active ingredient fluorouracil passes into breast milk. Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

Your doctor can discuss with you the risks and benefits involved.

Do not use this medicine after the expiry date (EXP) printed on the pack, if the packaging is torn, shows signs of tampering, or 3 months has passed after first opening the bottle. If it has expired or is damaged, return it to your pharmacist for disposal.

Once opened, the solution can only be used for 3 months. Discard 3 months after first opening the bottle.

If you are not sure whether you should start using ACTIKERALL, talk to your doctor or pharmacist first.

Before you use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

ACTIKERALL contains the ingredient dimethyl sulfoxide which may be an irritant to the skin.

Tell your doctor if you have or have had any inflammatory skin conditions, bleeding skin lesions or any other skin condition.

You must tell your doctor if you are using any other dermatological products to treat solar keratoses.

Tell your doctor if you have or have had DPD (dihydropyrimidine dehydrogenase) enzyme deficiency.

Tell your doctor if you suffer from a reduced ability to sense touch, pain and temperature. If you have diabetes you may experience these symptoms. In this case, your treatment areas will be closely monitored by your doctor.

Tell your doctor if you work outside for long periods of time during the day. ACTIKERALL is not recommended for people who work outdoors for long periods of time.

If you have not told your doctor about any of the above, tell them before you start using ACTIKERALL.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and ACTIKERALL may interfere with each other. These include:

medicines used to treat viruses such as chicken pox or shingles
phenytoin, a medicine used to treat epilepsy
methotrexate, a medicine used to treat cancer and autoimmune diseases
medicines used to treat diabetes e.g. sulphonylureas.

These medicines may be affected by ACTIKERALL or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use ACTIKERALL

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the carton/bottle, ask your doctor or pharmacist for help.

When to use it

ACTIKERALL should be applied once daily unless your doctor has told you otherwise.

If you have a solar keratosis in an area of thin skin e.g. around the eyes and temple, your doctor may tell you to apply ACTIKERALL less frequently. If severe side effects occur, your doctor may reduce the frequency of drug application to three times per week until the side effects improve.

It may also be necessary for your doctor to monitor your treatment more often.

How long to use it for

ACTIKERALL is applied to the treatment area once daily until the lesions have completely cleared or for up to a maximum of 12 weeks.

Improvement of solar keratosis can be seen as early as 4 weeks after starting treatment and the improvement increases over time up to 12 weeks.

The clearance of solar keratoses may continue for up to 8 weeks after you have stopped using ACTIKERALL.
If you feel that the product is not working as described, talk to your doctor or pharmacist.

How to use it

For the first application to the skin (topical use):

To open the bottle, press the lid down and turn.

Remove excess solution from the brush by wiping it on the neck of the bottle.

Dab the solution on the solar keratosis and a small area of healthy skin surrounding it once daily. This rim of healthy skin should be no more than 0.5 cm wide. Do not apply on a total area greater than 25 square centimetres (cm²) at any one time.

Multiple solar keratoses (up to 10 lesions) can be treated simultaneously, but do not use ACTIKERALL on large areas of skin. The total area of skin being treated with ACTIKERALL at any one time should not exceed 25 cm². As a guide, the rectangle outline drawn on the side of the medicine carton, where your pharmacist may attach a dispensing label, represents a total area of 25 cm². Examples of acceptable treatment areas are below:

When treating individual solar keratosis lesions, ensure the solution only comes into contact with the lesion and a maximum rim of 0.5 cm of healthy skin around the lesion.
If your doctor has advised you to use ACTIKERALL as field treatment, multiple lesions as well as the surrounding skin can be treated at the same time within the treatment area of up to 25 cm².
Let the solution dry to form a film.
Do not cover with a dressing.

Close the bottle properly.

Subsequent applications:

Remove the white film on your skin from the previous day’s application by simply peeling it off. Warm water may help to remove the film.
Follow the instructions as described for the first application.

Further instructions

ACTIKERALL must not be allowed to come into contact with the eyes, the inside of the mouth or nose or the genitals (mucous membranes).

ACTIKERALL should not be applied to hairy skin as the hair becomes stuck together.

Hair removal such as shaving should be considered prior to applying ACTIKERALL.

ACTIKERALL may permanently stain clothing, fabric or acrylics (such as acrylic bathtubs), so avoid contact with them.

ACTIKERALL is flammable: keep away from fire or flames.

Close the bottle tightly to prevent it from drying out. If ACTIKERALL dries out, it must not be used any longer.

Do not use ACTIKERALL if you notice any crystals.

Do not use ACTIKERALL 3 months after first opening the bottle.

If you forget to use it

Do not apply more than once daily. You will be more likely to experience skin reactions and they will be more severe if used more than recommended.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to use your medicine, ask your pharmacist for some suggestions.

If you use too much (overdose) or swallow the solution

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else has used too much ACTIKERALL or in the case of accidental swallowing. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using ACTIKERALL

Your appearance may look worse and you may feel uncomfortable symptoms on the treated area while treatment is in progress. Sometimes it can take several weeks after treatment with ACTIKERALL has stopped before you see any improvement in your condition.

Things you must do

Limit your exposure to the sun during treatment with ACTIKERALL. This will help reduce any side effects of the medication.

If you are about to start any new medicine, remind your doctor and pharmacist that you are using ACTIKERALL.

Tell any other doctors, dentists, and pharmacists who treat you that you are using this medicine.

If you become pregnant while using this medicine, tell your doctor immediately.

Things you must not do

Do not use ACTIKERALL to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop using your medicine without checking with your doctor.

Do not let ACTIKERALL come into contact with the eyes, the inside of the mouth or nose or the genitals (mucous membranes).

Things to be careful of

While treatment is in progress, it is important to consider the following:

Wherever possible, the skin area treated with ACTIKERALL should be protected against direct sunlight and other forms of ultraviolet radiation using hats and clothing. The treated skin should not be covered with dressings or bandages.
Before going outdoors, apply a broad-spectrum sunscreen (SPF 30 or higher) over the dried film of ACTIKERALL on the lesion if the skin surface is unbroken (not eroded, scabby, bleeding or exfoliated). Reapply the sunscreen several times during the day.
ACTIKERALL should not be used on bleeding lesions.
ACTIKERALL should not be used around the eyes, nose or mouth unless directed by your doctor.
Avoid cosmetics and other dermatological preparations on the treatment area, unless otherwise instructed by your doctor. Once you stop using ACTKERALL, talk to your doctor or pharmacist before applying cosmetics or other dermatological products on the affected skin.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using ACTIKERALL.

This medicine helps most people with solar keratoses, but it can have unwanted side effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

The most common side effects of ACTIKERALL are reactions at the application site and include:

redness
inflammation
irritation
itching
burning
pain
crusting
whitish discolouration and scaling of the skin
rash
scarring
bleeding in the treatment area

Tell your doctor if you experience any of the above side effects and they worry you. These reactions are common and are signs that the medicine is working.

The salicylic acid in ACTIKERALL may cause slight irritation, such as skin inflammation (dermatitis) and contact allergic reactions. Symptoms of contact allergic reactions may include itching, reddening and small blisters even outside the area of application.

Tell your doctor if you experience an allergic reaction that sounds like this.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

swelling and soreness of the mouth and tongue.
fever and chills

These are serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above such as headache may also occur in some people.

After using ACTIKERALL

Storage

Keep this medicine in a cool, dry place where the temperature stays below 25°C. Do not refrigerate. Do not freeze. Keep the bottle tightly closed.

Do not store ACTIKERALL or any other medicine in the bathroom or near a sink. Do not leave it on a windowsill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Do not use ACTIKERALL after the expiry date which is stated on the label and on the carton.

Disposal

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

ACTIKERALL is a clear, colourless to slightly orange–white solution. It is packed in a 25 mL brown glass bottle with a child-resistant closure.

Ingredients

The active substances of ACTIKERALL are fluorouracil and salicylic acid.

One gram of solution contains:

5 mg of fluorouracil, and
100 mg of salicylic acid.

It also contains the following inactive excipients:

dimethyl sulfoxide
ethanol absolute
ethyl acetate
pyroxylin
butyl methacrylate/ methyl methacrylate copolymer (3:1)

This medicine does not contain lactose, sucrose, gluten, tartazine or any other azo dyes.

Sponsor

ACTIKERALL is distributed by:

Mayne Pharma International Pty Ltd
1538 Main North Road
Salisbury South, SA 5106
Under licence from Almirall

® = Registered Trademark

Australian Registration Number:
AUST R 287446

This leaflet was prepared in March 2023.

For the most up to date version of this leaflet go to actikerall.com.au

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Actikerall

Active ingredient

Fluorouracil; Salicylic acid

Schedule

1 Name of Medicine

Fluorouracil, salicylic acid.

2 Qualitative and Quantitative Composition

1 g of solution contains 5 mg of fluorouracil and 100 mg of salicylic acid as the active ingredients.

Excipient with known effect.

Contains 19% v/v alcohol (as ethanol absolute).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Actikerall is a clear, colourless to slightly orange-white solution for topical application only.

4 Clinical Particulars

4.1 Therapeutic Indications

Actikerall is indicated for the topical treatment of solar (actinic) keratosis.

4.2 Dose and Method of Administration

Actikerall is for topical use only.
Actikerall is not for oral, ophthalmic, intranasal, intravaginal, intra-auditory canal or intra-anal use.

Recommended dosing.

Actikerall should be applied to solar keratosis lesions or used as a field treatment, on an area of up to 25 cm² once daily until the lesions have completely cleared or for up to a maximum of 12 weeks. Larger areas should be treated a section (not exceeding 25 cm²) at a time.
When Actikerall is applied to the skin, local skin reactions such as erythema, inflammation, irritation (including burning), pain, pruritus, bleeding and erosion can occur.
This is a sign that the medication is working. A response can be seen as early as 4 weeks. Response increases over time and data are available for treatment up to 12 weeks. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to eight weeks after treatment cessation.
If severe side effects occur, reduce the frequency of drug application to three times per week until the side effects improve.
If areas of skin with a thin epidermis are treated (e.g. around the eyes and temples), Actikerall should be applied less frequently and the course of the therapy monitored more often.

Method of administration.

When used to treat individual solar keratosis lesions, Actikerall should be applied to the lesions and should only come into contact with the lesion and a rim of a maximum of 0.5 cm of healthy skin surrounding the lesion.
There is experience in treating up to ten lesions at the same time. If field treatment is preferred, multiple solar keratosis lesions and surrounding skin can be treated simultaneously. The total field area of skin being treated with Actikerall at any one time should not exceed 25 cm² (5 cm x 5 cm). If the required treatment area exceeds 25 cm², treat the clinically most relevant area first for the prescribed period. After this, another area can be treated.
Actikerall is applied to the treatment area by using the brush applicator connected to the closure cap. To avoid overloading the brush with solution, the brush should be wiped off on the neck of the bottle before application.
The treated area should not be covered after application and the solution should be left to dry to form a film over the applied area. The film appears white after the solvent has evaporated. This produces an occlusive effect which promotes penetration of the active substances into the epidermis, where solar keratoses are located. Each time Actikerall is reapplied any existing film coating should be removed just beforehand by simply peeling it off. Warm water may help to remove the film.
Wherever possible, the treated area should be protected against direct sunlight and other forms of ultraviolet radiation with barriers (i.e. hats and clothing). If the treated skin surface is unbroken, a broad spectrum sunscreen (SPF 30 or higher) should be applied every day before going outdoors, and regularly reapplied during the day.

Instructions during use.

The bottle should be closed tightly after use or Actikerall will dry up quickly and can no longer be used.
Actikerall should not be used if crystals form in the bottle or on the brush.
Actikerall should not come into contact with textiles or acrylics (e.g. acrylic bathtubs) as the solution may cause permanent stains.
Actikerall should not be applied to hairy skin as the hair becomes stuck together. When applied to hairy skin, shaving or other suitable methods of hair removal should be considered prior to any application of Actikerall.
Keep Actikerall away from fire or flames.

4.3 Contraindications

Hypersensitivity to the fluorouracil, salicylic acid, acetylsalicylic acid (aspirin) or to any of the excipients.
Must not be used during lactation, an existing pregnancy or by women for whom pregnancy cannot be excluded with certainty.
Must not be used to treat patients with renal insufficiency.
Must not be used in conjunction with potent inhibitors of the fluorouracil-degrading enzyme dihydropyrimidine dehydrogenase (DPD).
Must not be used in patients with a known DPD deficiency.
Actikerall must not be allowed to come into contact with the eyes or mucous membranes.

4.4 Special Warnings and Precautions for Use

Skin.

Use only on a total area no greater than 25 cm² (5 cm x 5 cm) at any one time.
Use only on actinic keratosis of mild to moderate severity (Grade I and II according to Olsen 1991).
Use only on the face, forehead or bald scalp (excluding eyelids, lips and mucosa).
Local skin responses such as erythema, inflammation, irritation (including burning), pain, pruritus, bleeding and erosion can occur after topical application of Actikerall. Local skin responses are common and the majority are mild to moderate. However, local skin responses of severe intensity have been experienced by patients (see Section 4.8 Adverse Effects (Undesirable Effects)). The treatment effect may not be adequately assessed until resolution of local skin response.
Application of the product on areas of skin with a thin epidermis may potentially result in an increased risk of systemic absorption of topical drugs. An increase in the incidence and frequency of adverse reactions associated with the administration of the active components (fluorouracil and salicylic acid) may also be noted when applied to skin with a thin epidermis. If areas of skin with a thin epidermis are treated, Actikerall should be applied less frequently and the course of the therapy monitored more often.
Actikerall should not be used on bleeding lesions.
Solar keratosis is due to chronic UV damage and any local irritation where Actikerall has been applied may be made worse by sun exposure. Patients should be counselled to protect the skin against further excessive or cumulative UV exposure, especially in the area being actively treated with Actikerall.
There is no experience in treating solar keratosis with Actikerall in an area that is also affected by another skin disease and the clinician should take into account that the outcome of treatment may differ.
Concurrent use of Actikerall with dermatological products with drying, peeling, desquamating, or abrasive effects may cause a cumulative irritant or drying effect, resulting in excessive irritation of the skin. Such agents can include: abrasive or medicated cleansers; benzoyl peroxide; resorcinol; sulfur; tretinoin; topical alcohol-containing preparations; isotretinoin; or other cosmetics (medicated or non-medicated) with a strong drying effect.
There is currently no data available on Actikerall treatment of other body areas apart from the face, forehead and bald scalp.
The safety and efficacy of treating recurrent lesions with Actikerall has not been evaluated in clinical trials.
Actikerall contains dimethyl sulfoxide which may be an irritant to the skin.
Actikerall contains the cytostatic agent, fluorouracil.

Patients with DPD deficiency.

The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role in the breakdown of fluorouracil. Inhibition, deficiency or decreased activity of this enzyme can result in accumulation of fluorouracil.
If applicable, the determination of DPD enzyme activity should be checked before starting treatment with fluorouracil and other fluoropyrimidines.

Other.

Patients who take phenytoin concomitantly with fluorouracil should be regularly tested for elevated plasma levels of phenytoin.
In patients with sensory disturbances (e.g. those with diabetes mellitus), close medical monitoring of the treatment area is required.
No experience exists for the treatment of basal cell carcinoma and Bowen's disease, which should therefore not be treated with the product.

Use in the elderly.

The usual adult dose may be used.

Paediatric use.

Solar keratosis is not a disease of a paediatric population. Therefore, the safety and efficacy of Actikerall in this population has not been established.

Effects on laboratory tests.

Not applicable.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role in the breakdown of fluorouracil. Potent DPD inhibitors such as some nucleoside analogues may lead to a drastic increase in plasma concentrations of fluorouracil or other fluoropyrimidines and thus an associated increase in toxicity. For this reason, an interval of at least 4 weeks between the use of fluorouracil and nucleoside analogues should be observed.
In case of accidental administration of nucleoside analogues to patients who are being treated with fluorouracil, effective measures for reducing fluorouracil toxicity should be taken. Admission to a hospital may be indicated. All necessary measures for protection from systemic infections and dehydration should be introduced.
Elevated plasma levels of phenytoin leading to symptoms of phenytoin intoxication have been reported with the concomitant administration of systemic fluorouracil and phenytoin.
There is no evidence for relevant systemic absorption of salicylic acid; however, absorbed salicylic acid may interact with methotrexate and sulphonylureas.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies with systemic fluorouracil resulted in transient male infertility and in reduction of pregnancy rates in female rodents. However, this is unlikely to be of relevance in humans due to the very limited absorption of active compounds after topical administration of Actikerall.
No studies on the effect on fertility have been conducted with the fluorouracil/salicylic acid combination.
(Category D)
There are no data from the use of topical fluorouracil in pregnant women. A teratogenic effect of systemically administered fluorouracil has been observed in animals. Several studies following systemic administration of fluorouracil indicate potential high dose teratogenic or embryotoxic effects but less or no effects on fertility or general reproductive performance. Salicylic acid can adversely influence the outcome of pregnancy in rodents and is not known to have any teratogenic effects.
The potential risk for humans is unknown, hence Actikerall is contraindicated in pregnancy or where pregnancy cannot be excluded (see Section 4.3 Contraindications).
No studies on the effect on embryofetal development have been conducted with the fluorouracil/salicylic acid combination.
It is unknown whether fluorouracil or its metabolites are excreted in human milk after topical application. Hence, Actikerall is contraindicated in breastfeeding women (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Actikerall has no influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

The most frequently reported adverse drug reactions are often related to an extension of the pharmacological activity of Actikerall. When used for focal application to solar keratosis on a total area up to 25 cm² (study no. 98605101-0702) these were within the system organ class of general disorder and administration site conditions (93%), and skin and subcutaneous tissue disorders (12.8%). MedDRA system version 11.1 was used to record adverse drug reactions.
Adverse events reported when used by field directed application (study no. 98605101 1401) were recorded using the MedDRA system version 17.1 and direct comparison with focal use may not be robust. In the field directed study, the adverse events within the system organ class of general disorder and administration site conditions occurred in 99.1% of subjects treated with Actikerall. Skin and subcutaneous tissue disorders occurred in 8.1%. Premature discontinuation was more common in the field directed study.
In a Phase II comparator controlled study (study no. H 1005 6002-1007) adverse reactions were recorded using MedDRA version 14.1. The most common local skin reactions were erythema, scab/crusting and burning, mainly of mild to moderate intensity.
The most frequent adverse drug reactions recorded in the focal application study (study no. 98605101-0702) under the system organ class of administration site conditions were application site irritation (including burning) (86.1%), application site inflammation (73.3%), application site pruritus (44.9%), application site pain (25.1%) and application site erythema (11.2%).
Although local treatment emergent adverse events (TEAEs) in the system organ class of administration site conditions were mainly mild to moderate in intensity, some patients receiving Actikerall experienced local TEAEs of severe intensity. These included irritation (21.4%), inflammation (15.5%), pruritus (4.8%), pain (4.3%), erythema (1.6%), erosion (1.1%) and ulcer (1.1%).
No serious drug-related adverse events were reported in patients who received Actikerall.
The majority of Actikerall subjects experienced inflammation (70.3%) and burning (81.3%) within the first 6 weeks of treatment and diminished in frequency by end of treatment.

Clinical trial (study no. 98605101-0702) - focal application.

The data described below reflect exposure to Actikerall compared to placebo, and to 3% diclofenac gel in 470 patients in a randomized, placebo-controlled, double-blind, three armed, parallel group, multi-centre trial. Patients were instructed to apply Actikerall, placebo or 3% diclofenac gel to the face, forehead or bald scalp on a total skin area of 25 cm² daily for up to 12 weeks. Patients were not tested for DPD deficiency and patients with known DPD deficiency were excluded from the trial.
Drug-related treatment-emergent adverse events occurring at a frequency ≥ 1% were mainly comprised of application site disorders and skin disorders (see Table 1).

The adverse events reported in the Phase III field directed study (no. 98605101-1401) are consistent with those described above. In the Phase II comparator controlled study (no. H 1005 6002-1007), the most common local skin reactions were erythema, scab/crusting and burning, mainly of mild to moderate intensity.

Description of selected adverse reactions.

Adverse reactions are listed according to MedDRA (version 11.1) system organ class and in decreasing frequencies defined as very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data).
Application site reactions are frequently reported with Actikerall treatment and are expected to occur, because these are related to the pharmacological activity of the active substances fluorouracil and salicylic acid on the skin. Severe application site reactions can be managed by dose reduction (see Section 4.2 Dose and Method of Administration). In case of bleeding, stop treatment until adverse reaction improves (see Section 4.4 Special Warnings and Precautions for Use). When surface of contiguous application increases (field up to 25 cm²), administration site adverse reactions frequency may increase. In particular frequency of dermatitis, scab, erosion, bleeding, oedema may be very common, while frequency of ulcer may be common.

Other adverse reactions include.

General disorders and administration site conditions.

Uncommon - exfoliation, dermatitis, ulcer, eczema, oedema at application site.

Skin and subcutaneous tissue disorders.

Uncommon - skin erosion, skin plaque, pruritus.

Infections and infestations.

Uncommon - gastroenteritis, influenza.

Eye disorders.

Uncommon - dry eye, eye pruritus, lacrimation increased.

Post-marketing experience.

Isolated cases of allergic reaction, contact dermatitis, application site scar and rash have been reported. The frequency cannot be determined due to spontaneous reporting of cases.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Significantly more applications than recommended result in increased frequency and severity of reactions at the application site.
In case of accidental oral ingestion of Actikerall, signs of fluorouracil toxicity may include nausea, vomiting, diarrhoea, stomatitis, oesophago-pharyngitis, gastrointestinal ulceration and bleeding, or haemorrhage from any site. Clinical signs and symptoms of salicylate poisoning include tinnitus, hyperventilation, tachycardia, and metabolic acidosis.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacodynamic studies have not been conducted on the combination of fluorouracil and salicylic acid for topical use.

Mechanism of action.

Fluorouracil (5-FU).

The active substance fluorouracil is a cytostatic agent that has an antimetabolite effect. Due to its structural similarity with the thymine (5-methyluracil) occurring in nucleic acids, fluorouracil prevents its formation and utilisation and in this way inhibits both DNA and RNA synthesis. The result is growth inhibition of those cells in particular which, as in the case of solar keratoses, are at a stage of accelerated growth and therefore absorb fluorouracil in increased quantities. As a consequence, the growth of viruses, which can be involved in solar keratosis development, is also inhibited. See Figure 1.

Salicylic acid.

Salicylic acid is considered to be a phenolic aromatic acid and is lipid soluble. Its mechanism of action as a keratolytic and corneolytic agent is thought to be related to its interference with corneocyte adhesion, its solubilising effect on intercellular cement, and its loosening and detachment of corneocytes. By acting as an organic solvent, salicylic acid may remove intercellular lipids covalently linked to the cornified envelope surrounding cornified cells.
Topical salicylic acid has anti-inflammatory and anti-exudative properties, which may partly be due to an inhibition of prostaglandin synthesis, and partly due to a vasoconstrictive effect. This could possibly explain the anti-pruritic and antihidrotic effects of salicylic acid.
Salicylic acid has been added to Actikerall for its keratolytic properties in order to improve penetration of the active substance, which is particularly difficult in the case of hyperkeratotic solar keratoses. The same effect is achieved by the excipient dimethyl sulfoxide, which acts as a solubiliser for the active ingredient fluorouracil.

Clinical trials.

The efficacy of Actikerall is supported by two pivotal Phase III trials and one open label, comparative Phase II trial:

Study number H 1005 6002-0702.

In a randomised, placebo-controlled, double-blind, three-armed, parallel group, multi-centre pivotal Phase III trial, 470 patients with solar keratosis grade I to II (see Table 2) were randomised in a 2:2:1 ratio to be treated topically with either Actikerall once daily, Solaraze (diclofenac gel 3%) twice daily or placebo solution once daily.

Patients had 4 -10 clinically confirmed solar keratosis lesions on the face, forehead, and/or bald scalp. The total treatment area was up to a maximum of 25 cm². Patients were treated for a maximum of 12 weeks or until the lesions had completely cleared or ulceration of the lesions had occurred.
The primary objective of the study was to show superiority of Actikerall to placebo and non-inferiority to the comparator Solaraze, measured by histological clearance of 1 predefined representative target solar keratosis lesion 8 weeks post-treatment.
Secondary objectives were the improvement of treated lesions evaluated by standard clinical scores, physician's assessment of tolerability and safety (physician's global assessment (PGA), physician's tolerability scores (PGT)) and patient's assessment of tolerability and efficacy.
At the post-treatment assessment at 8 weeks after the end of treatment, solar keratosis could no longer be detected in the biopsy in 70.1% of the patients in the Actikerall group, in 54.1% of the patients in the Solaraze group, and in 42.7% of the patients in the placebo group (FAS).
At the post-treatment visit, 74.5% of the lesions were cleared in the Actikerall group compared to 54.6% in the Solaraze group and 36.5% in the placebo group. The number of patients with complete response (all lesions cleared) was again highest in the Actikerall group (55.4%, p < 0.001 for Actikerall versus both placebo and Solaraze) compared to 32.0% in the Solaraze group (p = 0.0013 compared to placebo) and 15.1% in the placebo group.
The decrease in mean number of lesions for each treatment group over the treatment and post-treatment period is shown on Figure 2. The changes from baseline to EOT for Actikerall (p = 0.00062) and Solaraze (p = 0.00869) were statistically superior to placebo.

Data for overall lesion response at weeks 2, 6, the end of the trial (week 12) and at the posttreatment assessment shown on Figure 3.

By EOT, the investigators rated the global outcome (PGA) as very good or good in 82.3% of the patients in the Actikerall group (144 patients), in 74.3% of patients in the Solaraze group (130 patients) and 65.6% of patients in the placebo group (61 patients).
Following the post-treatment visit, patients with remaining lesions were treated with conventional therapy (primarily cryotherapy, laser therapy and/or diclofenac gel). Follow-up visits were conducted to assess recurring and new lesions at 6 and 12 months after EOT.
Maintenance of cleared lesions at 6 and 12 months after EOT was higher with Actikerall (91.6% and 85.8% respectively) compared with Solaraze (82.8% and 81.0%) and with placebo (86.2% and 79.8%).
Complete clinical clearance of lesions continued to be higher in Actikerall patients (42.0%) than in Solaraze (28.8%) or placebo patients (18.9%) at 6 months after EOT. By 12 months after EOT, the proportion of patients with complete clinical clearance was similar in the Actikerall (36.4%) and the Solaraze groups (36.8%) and higher than in the placebo group (25.0%).

Study number 98605101-1401.

This pivotal Phase III trial was a multicentre, randomised, parallel, double-blind, vehicle controlled study to investigate the efficacy of Actikerall in comparison with a vehicle solution in the field-directed treatment of patients with solar keratosis grade I or II (intensity graded as per Table 2).
The primary objective was to determine the efficacy of Actikerall as measured by complete clinical clearance of solar keratosis lesions in the field treatment area, 8 weeks after end of treatment (EOT). The field treatment area was a contiguous area of 25 cm² covering 4 to 10 solar keratosis lesions located on the patient's face, forehead, and/or bald scalp.
Overall, 143 patients (83.8% in the Actikerall group and 90.9% in the vehicle group) completed the study as planned.
At the post-treatment assessment at 8 weeks after end of treatment (EOT), complete clinical clearance (CCC) of solar keratosis lesions for the ITT population was observed in 49.5% of patients in the Actikerall group and 18.2% of patients in the vehicle group (odds ratio: 3.9, 95% CI: 1.7, 8.7, p = 0.0006).
Secondary efficacy endpoints, such as total lesion count, lesion grade severity, physician's global assessment (PGA), and patient's overall assessment of efficacy confirmed the results of the primary endpoint.
During the treatment period, no significant differences in lesion count were observed between the treatment and control arms. However, at 8 weeks following EOT, the mean reduction in overall lesion count from baseline was larger in the Actikerall treatment group (78.4%) than the control group (47.4%) (ITT population).
Eight weeks after EOT, 81.7% of the lesions in the Actikerall group transitioned from Grade I or II to Grade 0, with 14.6% remaining as Grade I and 3.7% as Grade II. In contrast, only 51.0% of Grade I or II lesions in the vehicle group had transitioned to Grade 0, with 35.8% remaining as Grade I and 13.2% as Grade II.
With respect to PGA of efficacy, detailed comparison of treatments revealed that there were no significant differences between Actikerall and vehicle during the treatment period (Week 2 to Week 12), whereas eight weeks after EOT, the treatment difference was statistically significant, favouring the Actikerall group (p < 0.0001).
Although there are no robust data due to the small sample size of a substudy on the treatment of sub-clinical solar keratosis lesions detected using reflectance confocal microscopy, results showed greater efficacy in the Actikerall group compared with the vehicle group.

Study number 1005-6002-1007.

Study -1005-6002-1007 was a randomised, prospective, open-label, comparator-controlled, 2-arm, parallel group, multi-centre trial to investigate the efficacy of Actikerall in comparison with cryotherapy in patients with solar keratosis grade II to III (see Table 2).
Patients were randomised 1:1 to either apply Actikerall once daily for a period of up to 6 weeks, or alternately receive cryotherapy on Days 1 and 21 (only if necessary) in the selected test areas on the face, forehead or bald scalp where the total test area did not exceed 25 cm². Patients returned to the investigational sites on Days 21, 42 (end of treatment), 98 (8 weeks after EOT) and for a 6-month follow-up.
The primary efficacy endpoint was histological clearance rate of solar keratosis lesions at 8 weeks after EOT with Actikerall or at 14 weeks after first cryotherapy. Secondary endpoints were lesion clearance rate (complete and partial clinical clearance), lesion count (clinical evaluation), lesion recurrences during 6-month follow-up, lesion area, physician's global assessment scores (PGA, PGT), patient's global assessment of efficacy and tolerability, assessment of cosmetic outcome and adverse events/serious adverse events.
Table 3 summarises the efficacy outcome measures at post-treatment visit on Day 98 (8 weeks after EOT).

From study initiation to 6-month-post-treatment follow-up, recurrence of cleared solar keratosis lesions (no clinically visible lesions in the treatment area on Day 98) was reported in 39.4% (13/33) of patients receiving Actikerall and 84.8% (28/33) of patients receiving cryotherapy (see Figure 4).

In patients with complete clinical clearance at 14 weeks post-treatment, 27.3% (3/11) of patients receiving Actikerall and 50.0% (4/8) of patients receiving cryotherapy reported recurrent lesions at 6-month post-treatment follow-up.
The mean change from baseline to week 14 was similar for both treatments (-5.2 and 5.7 lesions per patient in the Actikerall and cryotherapy groups respectively). At Day 98, 33.3% (11/33) of patients in the Actikerall group had complete clearance of all lesions compared with 25.0% (8/32) in the cryotherapy group. Partial clearance (> 75% reduction) at Day 98 occurred in 51.5% (17/33) and 62.5% (20/32) for Actikerall and cryotherapy respectively.
At 6 months' follow-up, the proportion of patients with a 'very good/good' outcome according to the physician's global assessment scores was 84.9% (28/33) in the Actikerall group and 83.9% (26/33) in the cryotherapy group. A total of 13/33 (39.4%) patients in the Actikerall group and 7/33 (21.2%) of patients in the cryotherapy group had a physician's global assessment of 'very good', defined as lesion clearance with no signs of solar keratosis. Patients' assessment of clinical improvement was rated as 'very good/good' by 81.8% of patients receiving Actikerall and 78.2% of patients receiving cryotherapy.
At week 14, the proportion of patients who assessed themselves as having a 'good/very good' cosmetic outcome was 84.9% (28/33) for Actikerall vs. 81.3% (26/31) for cryotherapy. At the 6-month follow-up visit, the proportion of patients with a 'good/very good' cosmetic outcome was 87.8% (29/33; 'very good' rating, 24.2%) for Actikerall and 80.7% (25/31; 'very good' rating, 9.7%) for cryotherapy.

5.2 Pharmacokinetic Properties

Fluorouracil.

Absorption.

In a human pharmacokinetic study analysing the absorption rate of fluorouracil after application of up to 1 g of fluorouracil-salicylic acid solution (the same formulation as Actikerall) in the treatment of warts there was a median percutaneous absorption of fluorouracil of 0.0085% after a single application. With repeated (three times daily) doses, median percutaneous absorption was 0.035%.
Measurements of the amount of fluorouracil excreted in the urine of patients after application of 5% fluorouracil showed that < 3% of the amount applied is absorbed through intact skin, while substantially more may be absorbed from diseased skin (up to 61% in one case treating a large area of squamous cell carcinoma).

Distribution.

Once absorbed into the systemic circulation, fluorouracil is distributed throughout body tissues, including the brain, entering cells by passive diffusion.

Metabolism.

Information on the metabolism of 5-FU is based on studies from intravenous (i.v.) administration of 5-FU. Fluorouracil is metabolised primarily in the liver via the same biochemical pathways as uracil. It is converted into several active metabolites: 5-fluorodeoxyuridine monophosphate, fluorodeoxyuridine triphosphate; and fluorouridine triphosphate. A key enzyme in the metabolic pathway is dehydropyrimidine dehydrogenase which converts fluorouracil to dehydrofluorouracil.

Excretion.

Fluorouracil is partly excreted as CO₂. The elimination half-life from plasma is approximately 10 minutes following intravenous administration.