Consumer medicine information

Actikerall

Fluorouracil; Salicylic acid

BRAND INFORMATION

Brand name

Actikerall

Active ingredient

Fluorouracil; Salicylic acid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Actikerall.

SUMMARY CMI

ACTIKERALL®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using ACTIKERALL?

ACTIKERALL contains the active ingredients fluorouracil and salicylic acid. ACTIKERALL is used to treat mild to moderate solar keratosis lesions, also known as actinic keratosis lesions or sunspots.

For more information, see Section 1. Why am I using ACTIKERALL? in the full CMI.

2. What should I know before I use ACTIKERALL?

Do not use if you have ever had an allergic reaction to fluorouracil, salicylic acid or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ACTIKERALL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ACTIKERALL and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ACTIKERALL?

Follow all directions given to you by your doctor or pharmacist. ACTIKERALL should be applied once daily unless your doctor has provided you with other instructions.

More instructions can be found in Section 4. How do I use ACTIKERALL? in the full CMI.

5. What should I know while using ACTIKERALL?

Things you should do
  • Limit your exposure to the sun during treatment with ACTIKERALL.
  • Call your doctor straight away if you become pregnant while using this medicine.
  • Remind any doctor, dentist or pharmacist you visit that you are using ACTIKERALL.
Things you should not do
  • Do not use ACTIKERALL to treat any other conditions 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 mucous membranes.
Driving or using machinesACTIKERALL has no influence on the ability to drive and use machines.
Drinking alcoholTell your doctor if you drink alcohol.
Looking after your medicineStore below 25°C. Do not refrigerate. Do not freeze. Keep the bottle tightly closed.

For more information, see Section 5. What should I know while using ACTIKERALL? in the full CMI.

6. Are there any side effects?

Common side effects include redness, inflammation, irritation, itching, burning, pain, crusting, whitish discolouration/scaling of the skin, rash, scarring and bleeding in the treatment area. Serious side effects include swelling/soreness of the mouth/tongue and fever/chills. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring in Australia. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

WARNING: ACTIKERALL® is intended for use only on mild and moderate solar keratosis. ACTIKERALL should only be used on a total area no greater than 25 cm2 at a time. Use ACTIKERALL only on the face, forehead or bald scalp. Do not use ACTIKERALL on eyelids, lips or mucous membranes.



FULL CMI

ACTIKERALL®

Active ingredients: fluorouracil and salicylic acid

Consumer Medicine Information (CMI)

This leaflet provides important information about using ACTIKERALL. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ACTIKERALL.

Where to find information in this leaflet:

1. Why am I using ACTIKERALL?
2. What should I know before I use ACTIKERALL?
3. What if I am taking other medicines?
4. How do I use ACTIKERALL?
5. What should I know while using ACTIKERALL?
6. Are there any side effects?
7. Product details

1. Why am I using ACTIKERALL?

ACTIKERALL contains the active ingredients 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.

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.

2. What should I know before I use ACTIKERALL?

Warnings

Do not use ACTIKERALL if:

  • you are allergic to fluorouracil, salicylic acid, acetylsalicylic acid (aspirin) or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • 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.
  • you have kidney problems.
  • you are pregnant or there is a possibility you may be pregnant.

Check with your doctor if you:

  • have any other medical conditions.
  • take any medicines for any other condition
  • have allergies to any other medicines, foods, preservatives or dyes.
  • have or have had any inflammatory skin conditions, bleeding skin lesions or any other skin condition. ACTIKERALL contains the ingredient dimethyl sulfoxide which may be an irritant to the skin.
  • are using any other dermatological products to treat solar keratoses.
  • have or have had DPD (dihydropyrimidine dehydrogenase) enzyme deficiency.
  • 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.
  • you work outside for long periods of time during the day. Protect your skin from the sun to limit further UV exposure, especially in the area being actively treated with ACTIKERALL. See Section 5. What should I know while using ACTIKERALL?

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

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

Before you start using ACTIKERALL, talk to your doctor if you are breastfeeding or intend to breastfeed.

You must not breastfeed if you are using this medicine. It is unknown whether the active ingredient fluorouracil passes into breastmilk.

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

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements 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 for immunosuppression, or used to treat cancer or 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.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ACTIKERALL.

4. How do I use ACTIKERALL?

How much to use

Follow the instructions provided and use ACTIKERALL until your doctor tells you to stop.

For the first application to the skin:

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

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

  1. 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. 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 represents a total area of 25 cm2. Examples of acceptable treatment areas are below:

Let the solution dry to form a film.
Do not cover with a dressing.
  1. Close the bottle properly.

Subsequent applications:

  1. 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.
  2. Follow the instructions as described for the first application.

When to use ACTIKERALL

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.

Further instructions

ACTIKERALL must not be allowed to come into contact with the eyes, the inside of the mouth or nose or the 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 ACTIKERALL

Do not apply more than once daily.

You will be more likely to experience skin reactions and they will be more severe if you use 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 ACTIKERALL or swallow the solution

If you think that you have used too much ACTIKERALL, or in the case of accidental swallowing, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while 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 should 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.

Call your doctor straight away if you:

  • become pregnant while using this medicine.

Remind any doctor, dentist or pharmacist you visit that you are using ACTIKERALL.

Things you should not do:

  • Do not use ACTIKERALL to treat any other conditions 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 mucous membranes.

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 ACTIKERALL, talk to your doctor or pharmacist before applying cosmetics or other dermatological products on the affected skin.

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Store below 25°C.
  • Do not refrigerate.
  • Do not freeze.
  • Keep the bottle tightly closed.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

When to discard your medicine (as relevant)

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

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • redness
  • inflammation
  • irritation
  • itching
  • burning
  • pain
  • crusting
  • whitish discolouration and scaling of the skin
  • rash
  • scarring
  • bleeding in the treatment area
Speak to your doctor if you have any of these less serious 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.

Serious side effects

Serious side effectsWhat to do
  • swelling and soreness of the mouth and tongue
  • fever and chills
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these 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 else that may be making you feel unwell.

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What ACTIKERALL contains

Active ingredient
(main ingredient)		One gram of solution contains:
  • 5 mg of fluorouracil, and
  • 100 mg of salicylic acid
Other ingredients
(inactive ingredients)
  • dimethyl sulfoxide
  • ethanol absolute
  • ethyl acetate
  • pyroxylin
  • butyl methacrylate/ methyl methacrylate copolymer (3:1)
Potential allergensThis medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes

Do not use this medicine if you are allergic to any of these ingredients.

What ACTIKERALL 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 (Aust R 287446).

Who distributes ACTIKERALL?

Australia

Mayne Pharma International Pty Ltd
1538 Main North Road
Salisbury South, SA 5106

Under licence from Almirall

® = Registered Trademark

This leaflet was prepared in February 2025.

For the most up to date version of the Consumer Medicines Information go to actikerall.com.au

Published by MIMS May 2025

BRAND INFORMATION

Brand name

Actikerall

Active ingredient

Fluorouracil; Salicylic acid

Schedule

S4

 

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.

Salicylic acid.

Absorption.

Experiments in animals and human pharmacokinetic trials have shown that salicylic acid penetrates the skin surface rapidly, depending on the substrate and other factors influencing penetration, such as the condition of the skin.
Skin damage dramatically increases the penetration of salicylic acid through the skin. In patients with eczema, penetration was increased by 100% compared to healthy patients.
The systemic exposure (AUC) of a 30% salicylic acid solution, applied for 5 minutes to the full face, was 50 times lower than that from an oral dose of 650 mg acetylsalicylic acid. This result was in the range of that observed with a 2% concentration of salicylic acid applied as a leave-on product to the same body surface area. Systemic exposure (AUC) to salicylic acid was ~15% compared with oral administration of 81 mg of acetylsalicylic acid.

Distribution.

After absorption, salicylate is distributed throughout most body tissues and transcellular fluids. In humans 80-90% is bound to plasma proteins, especially albumin.

Metabolism.

Biotransformation of salicylates occurs mainly in the endoplasmic reticulum and mitochondria of the liver cells. The main metabolites are salicyluric acid, the phenolic glucuronide and the acyl glucuronide.

Excretion.

Excretion of salicylates occurs mainly via the kidney through a combination of glomerular filtration and tubular excretion, in the form of free salicylic acid, salicyluric acid, salicylic phenolic acid, acyl glucuronides and gentisic acid. Salicylic acid appears in the urine 15-30 minutes following topical application.

Topical administration of fluorouracil/salicylic acid combination.

Absorption.

The potential augmentation in systemic absorption of fluorouracil by the keratolytic properties of salicylic acid was investigated in a substudy of the H 1005 6002-0702 Phase III trial (n = 30). No levels above the limit of quantitation (LOQ, 0.05 microgram/mL) were measured after treatment with Actikerall solution.
Plasma concentrations of salicylic acid in the substudy were mostly reported below the 1.0 microgram/mL LOQ. Slightly higher levels were found in a small number of patients (n = 3), most probably from oral acetylsalicylic acid taken concomitantly. Nevertheless, the plasma levels were well below 300 microgram/mL at which toxicity may occur.

5.3 Preclinical Safety Data

Genotoxicity.

Fluorouracil was an in vitro mutagen in some test strains.
Fluorouracil has been shown to be mutagenic and clastogenic in a number of other studies. Oncogenic transformation of fibroblasts from mouse embryo has been induced in vitro by fluorouracil, but the relationship between oncogenicity and mutagenicity is not clear. A positive effect was observed in the micronucleus test on bone marrow cells of the mouse following fluorouracil injections, and fluorouracil at very high concentrations produced chromosomal breaks in hamster fibroblasts in vitro.
Salicylic acid is not known to have any mutagenic or genotoxic effects.
No genotoxicity studies have been conducted with the fluorouracil/salicylic acid combination.

Carcinogenicity.

A number of studies investigated carcinogenicity of fluorouracil in rodents and showed no effect. However, in a single study there is evidence of carcinogenicity of fluorouracil in mice following intraperitoneal administration.
Salicylic acid is not known to have any carcinogenic effects.
No carcinogenicity studies have been conducted with the fluorouracil/salicylic acid combination.

6 Pharmaceutical Particulars

6.1 List of Excipients

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

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration, Instructions during use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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.
Do not use content after 3 months of first opening the bottle.

6.4 Special Precautions for Storage

Store below 25°C. Do not freeze. Do not refrigerate. Keep the bottle tightly closed.

6.5 Nature and Contents of Container

Actikerall is available as a 25 mL solution in a brown glass bottle with a child-resistant closure of white polypropylene and enclosed in a cardboard carton. The closure of the bottle is connected to a brush to apply the solution. The brush applicator consists of polyethylene (HDPE and LDPE 1:1) with brush hairs of nylon secured in shaft with stainless steel.

6.6 Special Precautions for Disposal

Any unused product or waste material should be disposed of safely. Patients/carers should be encouraged to return any unused product to the pharmacy, where it should be disposed of in accordance with national and local requirements.

6.7 Physicochemical Properties

Chemical structure.

Fluorouracil.


Molecular formula: C4H3FN2O2.
Relative molecular mass: 130.08.

Salicylic acid.


Molecular formula: C7H6O3.
Relative molecular mass: 138.10.

CAS number.

Fluorouracil: 51-21-8.
Salicylic acid: 69-72-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes