Consumer medicine information

Tolak 4% Once Daily Cream

Fluorouracil

BRAND INFORMATION

Brand name

Tolak 4% Once Daily

Active ingredient

Fluorouracil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tolak 4% Once Daily Cream.

SUMMARY CMI

TOLAK® 4% ONCE DAILY cream

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.

1. Why am I using TOLAK 4% ONCE DAILY?

TOLAK 4% ONCE DAILY contains the active ingredient fluorouracil. TOLAK 4% ONCE DAILY is used to treat a skin condition called actinic keratosis, also known as solar keratoses or sunspots. Fluorouracil belongs to a group of medicines known as antimetabolites that inhibit the growth of cells (cytostatic agent).

For more information, see Section 1. Why am I using TOLAK 4% ONCE DAILY? in the full CMI.

2. What should I know before I use TOLAK 4% ONCE DAILY?

Do not use if you have ever had an allergic reaction to fluorouracil 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 TOLAK 4% ONCE DAILY? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TOLAK 4% ONCE DAILY 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 TOLAK 4% ONCE DAILY?

TOLAK 4% ONCE DAILY is usually used for 4 weeks. Apply the cream once daily to cover the areas of your skin to be treated.

More instructions can be found in Section 4. How do I use TOLAK 4% ONCE DAILY? in the full CMI.

5. What should I know while using TOLAK 4% ONCE DAILY?

Things you should doIt is likely that the area of the skin treated will become red, probably followed by inflammation/swelling, possibly some discomfort, skin erosion and eventually, healing. This is the expected normal response to treatment and it shows that TOLAK 4% ONCE DAILY is working. Talk to your doctor if your skin becomes much worse, you experience pain or if you are worried. Your doctor may prescribe you another cream to relieve any discomfort.
Things you should not do
  • Avoid exposure to UV-radiation (e.g. sun, tanning salon) during and immediately following treatment with TOLAK 4% ONCE DAILY. Your skin can become more sensitive to sunlight.
  • Do not apply TOLAK 4% ONCE DAILY directly into eyes, nose, mouth, or other mucous membranes because irritation, local inflammation and ulceration can occur.
  • Do not apply TOLAK 4% ONCE DAILY on open wounds or damaged skin
  • Do not apply TOLAK 4% ONCE DAILY under bandages or dressing as this may increase inflammatory reactions of the skin.
Driving or using machinesIt is unlikely that treatment with TOLAK 4% ONCE DAILY will have any effect on the ability to drive and use machines.
Drinking alcoholIt is unlikely that alcohol will have any effect on you while you are using TOLAK 4% ONCE DAILY
Looking after your medicineStore it in a cool dry place – where the temperature stays below 25°C – away from moisture, heat or sunlight

For more information, see Section 5. What should I know while using TOLAK 4% ONCE DAILY? in the full CMI.

6. Are there any side effects?

The most common side effects are skin reactions on the site of application (irritation, pain, reaction, redness, itching, inflammation, oedema, (swelling).

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.



FULL CMI

TOLAK® 4% ONCE DAILY cream

Active ingredient(s): Fluorouracil

Consumer Medicine Information (CMI)

This leaflet provides important information about using TOLAK 4% ONCE DAILY. 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 TOLAK 4% ONCE DAILY.

Where to find information in this leaflet:

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

1. Why am I using TOLAK 4% ONCE DAILY?

TOLAK 4% ONCE DAILY contains the active ingredient fluorouracil. Fluorouracil belongs to a group of medicines known as antimetabolites that inhibit the growth of cells (cytostatic agent).

TOLAK 4% ONCE DAILY is used to treat a skin condition called actinic keratosis, also known as solar keratoses 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 eventually turn into skin cancer.

What should I know before I use TOLAK 4% ONCE DAILY?

2. What should I know before I use TOLAK 4% ONCE DAILY?

Warnings

Do not use TOLAK 4% ONCE DAILY if:

  • you are allergic to fluorouracil, 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 are allergic to peanuts or soya
  • you are taking medicines known as antiviral nucleosides which are used to treat chickenpox or shingles (eg brivudine, sorivudine)
  • Do not use this medicine if you have a dihydropyrimidine dehydrogenase (DPD) enzyme deficiency

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

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition
  • have an inflammatory skin conditions such as darkening of skin during pregnancy (chloasma) or a chronic rash (rosacea).
  • you work outside for long periods of time during the day. TOLAK 4% ONCE DAILY is not recommended for people who work outdoors for long periods of time.

TOLAK 4% ONCE DAILY also contains stearyl alcohol, which may cause skin irritation.

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

Do not use this medicine if you are pregnant or intend to become pregnant.

TOLAK 4% ONCE DAILY must not be used during pregnancy. Women who are able to become pregnant should use an effective method of birth control during treatment with TOLAK 4% ONCE DAILY and for one month after the last application. Talk to your doctor if you need advice on contraception. If you become pregnant during treatment inform your doctor immediately and make use of genetic counselling.

Do not use this medicine if you are breastfeeding or intend to breastfeed.

It is not known if TOLAK 4% ONCE DAILY passes into your breast milk. If use of TOLAK 4% ONCE DAILY is absolutely necessary, breastfeeding must be discontinued.

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.

Medicines that may increase the effect of TOLAK 4% ONCE DAILY include:

  • medicines to treat chickenpox or shingles (brivudine and sorivudine). These medicines may increase the possibility of side effects with TOLAK 4% ONCE DAILY. Therefore these medicines must not be used with; or within 4 weeks prior to starting TOLAK 4% ONCE DAILY.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TOLAK 4% ONCE DAILY.

4. How do I use TOLAK 4% ONCE DAILY?

How much to use

Apply the cream once daily to cover the areas of your skin to be treated as follows:

  • Wash, rinse, and pat dry gently the skin areas to be treated.
  • Apply a thin film of cream to the areas to be treated.
  • Massage gently the cream evenly into your skin.
  • Avoid contact with other areas of your body, and transfer of the cream from your body to other people.
  • Wash your hands well after you have applied TOLAK 4% ONCE DAILY.

When you use TOLAK 4% ONCE DAILY it is likely that the area of the skin that you are treating will become red.

TOLAK 4% ONCE DAILY destroys cancerous and pre-cancerous cells of the skin, while having less effect on normal cells.

TOLAK 4% ONCE DAILY will also treat abnormalities of the skin that were previously not visible to the naked eye, and these abnormalities may become red and inflamed.

This will probably be followed by inflammation/swelling, possibly some discomfort, skin erosion and, eventually, healing. This is the expected normal response to treatment and shows that TOLAK 4% ONCE DAILY is working.

Sometimes the response is more severe (see Side Effects). If your skin becomes much worse, you experience pain or if you are worried, talk to your doctor. Your doctor may prescribe another cream to relieve any discomfort.

The skin reactions are transient and resolve within 2-4 weeks after the end of treatment. Therefore, after stopping treatment, you may find that your skin takes approximately 4 weeks to heal.

Wash the skin to be treated using lukewarm water. Avoid soap or other cleansing products which may sting or irritate your skin, especially as treatment progresses.

Be very careful not to allow TOLAK 4% ONCE DAILY to come into contact with mucous membranes, such as eyes, eyelids, nostrils and lips.

Do not apply TOLAK 4% ONCE DAILY under bandages or dressing as this may increase inflammatory reactions of the skin.

Follow the instructions provided and use TOLAK 4% ONCE DAILY until your doctor tells you to stop.

TOLAK 4% ONCE DAILY should only be used by adults 18 years of age and older.

When to use TOLAK 4% ONCE DAILY

TOLAK 4% ONCE DAILY should be used once daily 1.5 – 2 hours before bedtime to enable complete absorption.

TOLAK 4% ONCE DAILY should be used for 4 weeks unless your Doctor has given you a different instruction.

If you forget to use TOLAK 4% ONCE DAILY

TOLAK 4% ONCE DAILY should be used regularly at the same time each day. If you have forgotten to use the cream at the usual time, apply TOLAK 4% ONCE DAILY as soon as you remember.

If it is almost time for your next application, skip the one you missed and apply TOLAK 4% ONCE DAILY when you are next meant to.

Do not apply twice as much to make up for the application you missed.

If you use too much TOLAK 4% ONCE DAILY

If you apply TOLAK 4% ONCE DAILY more often than once daily, you will be more likely to experience skin reactions and they may be more severe.

If you think that you or anyone else may have swallowed TOLAK 4% ONCE DAILY by mistake, 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 TOLAK 4% ONCE DAILY?

Things you should do

It is likely that the area of the skin treated will become red, probably followed by inflammation/swelling, possibly some discomfort, skin erosion and eventually, healing. This is the expected normal response to treatment and it shows that TOLAK 4% ONCE DAILY is working. Talk to your doctor if your skin becomes much worse, you experience pain or if you are worried. Your doctor may prescribe you another cream to relieve any discomfort.

Limit your exposure to sun during and immediately following treatment with TOLAK 4% ONCE DAILY.

This will help reduce the likelihood and severity of unwanted side effects.

Apply a broad spectrum sunscreen (SPF 30 or higher) every day before going outdoors, and regularly reapply during the day, except directly on the treatment area.

TOLAK 4% ONCE DAILY can make you more sensitive to sunlight. In addition to sunscreen, wear a wide-brimmed hat, long sleeves and trousers (or a long skirt) to protect your skin.

Remind any doctor, dentist or pharmacist you visit that you are using TOLAK 4% ONCE DAILY.

Keep all of your doctor's appointments so that your progress can be checked. Always discuss with your doctor any problems or difficulties experienced during or after using TOLAK 4% ONCE DAILY.

Things you should not do

  • Avoid exposure to UV-radiation (e.g. sun, tanning salon) during and immediately following treatment with TOLAK 4% ONCE DAILY. Your skin can become more sensitive to sunlight.
  • Do not apply directly or let TOLAK 4% ONCE DAILY come into contact with eyes, eyelids, nostrils, mouth, or other mucous membranes because irritation, local inflammation and ulceration can occur.
  • Do not apply TOLAK 4% ONCE DAILY on open wounds or damaged skin

Things to be careful of

While treatment is in progress follow these personal care tips:

  • Avoid using cosmetics or other topical medications, directly on the treatment area, unless directed by your doctor.
  • Your treated skin is expected to become irritated and uncomfortable whilst using TOLAK 4% ONCE DAILY. Applying other products directly on the treatment area may make your discomfort worse.
  • You may continue to shave whilst using TOLAK 4% ONCE DAILY, but take care not to cut your skin in the treatment area.
  • As facial skin becomes inflamed during TOLAK 4% ONCE DAILY treatment shaving with a conventional razor may become unpleasant. You may prefer instead to lightly shave with an electric razor or clip the facial hair.

Driving or using machines

It is unlikely that treatment with TOLAK 4% ONCE DAILY will have any effect on the ability to drive and use machines.

Drinking alcohol

It is unlikely that alcohol will have any effect on you while you are using TOLAK 4% ONCE DAILY

Looking after your medicine

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

Store it in a cool dry place - where the temperature stays below 25°C - 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 window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Once you have opened the tube of TOLAK 4% ONCE DAILY, it should be discarded after 4 weeks.

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
Common (may affect up to 1 in 10)
  • Skin reactions on the site of application: irritation, pain, reaction, redness, itching, inflammation, oedema (swelling)
  • Eye irritation

Uncommon (may affect up to 1 in 100)

  • Impetigo (bacterial infection of the skin)
  • Sore throat (pharyngitis)
  • Insomnia
  • Nasal discomfort
  • Lip blister
  • Nausea
  • Swelling around the eyes (oedema)
  • Increased watery eyes (lacrimation)
  • Redness
  • Skin reactions on the site of application: bleeding, erosion, eczema, discomfort, dryness, burning/tingling, photosensitivity reaction (increase in the reactivity of the skin to sunlight)
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • mouth ulceration (mucositis)
  • stomach-area (abdominal) pain
  • bloody diarrhea
  • vomiting
  • fever
  • 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.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here 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 TOLAK 4% ONCE DAILY contains

Active ingredient
(main ingredient)		Fluorouracil
Other ingredients
(inactive ingredients)		Stearoyl macrogolglycerides
Butylated hydroxytoluene
Cetyl alcohol
Citric acid
Glycerol
Isopropyl myristate
Methyl gluceth-10
Methyl hydroxybenzoate
Propyl hydroxybenzoate
Purified water
Arachis oil (peanut oil)
Sodium hydroxide
Stearic acid
Stearyl alcohol

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

What TOLAK 4% ONCE DAILY looks like

TOLAK 4% ONCE DAILY is a white to off-white cream.

AUST R: 328512

Sponsor

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065 Australia
Phone: +61 2 8436 8300
Web: www.aspenpharma.com.au

® = Registered Trademark

This leaflet was updated in November 2024

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Tolak 4% Once Daily

Active ingredient

Fluorouracil

Schedule

S4

 

1 Name of Medicine

Fluorouracil.

2 Qualitative and Quantitative Composition

Tolak 4% Once Daily cream contains fluorouracil (5-FU) 4% w/w (equivalent to 40 mg/g).

Excipients with known effect.

Methyl hydroxybenzoate, propyl hydroxybenzoate, and, arachis oil (peanut oil).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cream, white to off-white in appearance.

4 Clinical Particulars

4.1 Therapeutic Indications

Tolak 4% Once Daily is indicated for the topical treatment of actinic keratosis (AK) of the face, ears, and/or scalp in adults.

4.2 Dose and Method of Administration

Tolak 4% Once Daily should be applied once daily in an amount sufficient to cover the whole area of the face and/or ears and/or scalp where AK lesions have been identified with a thin film, using the fingertips to gently massage the medication uniformly into the skin.

Duration of treatment.

Apply Tolak 4% Once Daily for a period of 4 weeks as tolerated.
The development of an inflammatory response is associated with the pharmacological action of 5-FU on dysplastic AK cells. This is characterised by local skin reactions that peaks at 4 weeks of treatment and resolves within 2-4 weeks after the end of treatment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects) for normal pattern of response).
In case of severe discomfort during treatment or where skin reactions last more than 4 weeks, symptomatic treatment (such as emollients or topical corticosteroids) should be offered.
The number of retreatments with Tolak 4% Once Daily is the decision of the treating physician. When assessing options to treat recurrent lesions, the physician should consider that repeated treatment with Tolak 4% Once Daily in case of recurrence has not been formally assessed. The duration between initial treatment and retreatment with Tolak 4% Once Daily in clinical studies ranged between 7 and 13 months (mean: 9.4 months). The number of retreatments with Tolak 4% Once Daily is the decision of the treating physician (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Evaluation of the therapeutic effect can be assessed approximately 4 weeks after end of treatment.

Method of administration.

Treatment areas should be washed, rinsed and dried prior to applying Tolak 4% Once Daily.
Thoroughly wash hands after applying Tolak 4% Once Daily (see Section 4.4 Special Warnings and Precautions for Use).

Special populations.

Paediatric population.

No data are available in the paediatric population since children do not have actinic keratosis.

Elderly population.

No dedicated studies in elderly patients have been conducted. No dose adjustment is required for elderly patients (65 years and older) based on the results of the clinical studies (see Section 5.1 Pharmacodynamic Properties).

Hepatic and renal impairment.

No dosage adjustment is required for patients with hepatic or renal impairment.

4.3 Contraindications

Tolak 4% Once Daily is contraindicated:
In patients with known hypersensitivity to the active substance or to any of the excipients, see Section 6.1 List of Excipients.
In patients with allergy to peanut or soya (see Section 6.1 List of Excipients).
During pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).
During breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).
In coadministration with brivudine, sorivudine and analogues as they may lead to a substantial increase in plasma levels of 5-FU and associated toxicity. The antiviral nucleoside drugs brivudine and sorivudine are potent inhibitors of dihydropyrimidine dehydrogenase (DPD), a 5-FU metabolising enzyme (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In patients with dihydropyrimidine dehydrogenase (DPD) deficiency (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Do not apply Tolak 4% Once Daily directly into eyes, nose, mouth, or other mucous membranes because irritation, local inflammation and ulceration can occur. Patients should wash hands well after applying Tolak 4% Once Daily.
Tolak 4% Once Daily should not be applied to open wounds or damaged skin where the skin barrier is compromised.
The normal pattern of response includes: an early inflammatory phase (typically characterised by erythema, which may become intense and blotchy); an apoptotic phase (characterised by skin erosion); and finally healing (when epithelialisation occurs).
The clinical manifestation of response usually occurs in the second week of treatment. However, these effects can sometimes be more severe (see Section 4.8 Adverse Effects (Undesirable Effects)). In case of severe discomfort during treatment or for skin reactions lasting more than 4 weeks, symptomatic treatment (such as emollients or topical corticosteroids) should be offered (see Section 4.2 Dose and Method of Administration).
Occlusive dressings may increase inflammatory skin reactions.

Ophthalmic adverse reactions.

Corneal and conjunctival disorders have occurred with topical 5-FU. Avoid applying to the periocular area. To avoid transfer of the drug into the eyes and/or contact lenses and to the periocular area during and after application, patients should wash hands well after applying Tolak 4% Once Daily. If accidental exposure occurs, patients should flush eye(s) with large amounts of water.

Hypersensitivity reactions.

Allergic contact dermatitis (delayed type hypersensitivity reaction) has been observed with topical 5-FU preparations. Delayed type hypersensitivity should be suspected in the event of severe pruritus or eczema at the application site or at a distant site.
Although the potential for a delayed hypersensitivity reaction to 5-FU exists, patch testing to confirm hypersensitivity may be inconclusive.
Tolak 4% Once Daily contains peanut oil. The peanut oil used in Tolak 4% Once Daily is tested for residual protein through amino acid analysis; the acceptance criterion for total protein is no more than 0.5 parts per million. Physicians should use caution in prescribing Tolak 4% Once Daily for peanut-sensitive individuals (see Section 4.3 Contraindications).
Tolak 4% Once Daily contains:
Methyl hydroxybenzoate and propyl hydroxybenzoate which may cause allergic reactions (possibly delayed).
Butylated hydroxytoluene which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.
Cetyl alcohol and stearyl alcohol which may cause local skin reactions (e.g. contact dermatitis).

Photosensitivity.

Topical 5-FU is associated with photosensitivity reactions. Exposure to ultraviolet rays including sunlight, sun lamps, and tanning beds should be avoided during treatment with Tolak 4% Once Daily.

Dihydropyrimidine dehydrogenase (DPD) deficiency.

Tolak 4% Once Daily must not be used on patients with DPD deficiency (see Section 4.3 Contraindications). Life-threatening systemic toxicity has been reported with the topical use of fluorouracil in a patient with DPD deficiency. Symptoms of serious side effects included severe stomach-area abdominal pain, bloody diarrhea, vomiting, fever, and chills. Physical examination revealed stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, and inflammation of the esophagus, stomach and small bowel.
A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency may result in increased availability of fluorouracil to the anabolic pathway, which may lead to increased interference with DNA and RNA synthesis and increased cytotoxic activity and potential toxicities. Therefore, Tolak 4% Once Daily is contraindicated in patients with DPD deficiency.
Patients should discontinue Tolak 4% Once Daily if symptoms of 5-FU systemic toxicity develop (see Section 4.9 Overdose).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Systemic concentrations of fluorouracil after topical dermal administration of Tolak 4% Once Daily appear to be low and as such are considered unlikely under normal circumstances to significantly influence the pharmacokinetics of other concomitantly administered systemic drugs (see Section 5.2 Pharmacokinetic Properties). Because life-threatening systemic toxicity has been reported with the topical use of fluorouracil in a patient with DPD deficiency (see Section 4.4 Special Warnings and Precautions for Use), concomitant use of substances that decrease the activity of DPD (such as capecitabine, brivudine, sorivudine, and interferon-α) could result in a pronounced increase in systemic fluorouracil concentrations and associated toxicity and is therefore not advised (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
The concomitant use of brivudine and sorivudine with Tolak 4% Once Daily is contraindicated (See Section 4.3 Contraindications). Treatment with the antiviral nucleoside analogues brivudine or sorivudine and topical application of Tolak 4% Once Daily should be separated by an interval of at least four weeks.
Systemic administration of fluorouracil or its prodrugs has led to signs of increased activity and adverse effects of CYP2C9 substrates such as warfarin and phenytoin. Bleeding complications have been observed upon concomitant administration with warfarin, and symptoms of phenytoin intoxication have been observed upon concomitant administration with phenytoin. The possibility of drug interactions between Tolak 4% Once Daily and CYP2C9 substrates, particularly those with a narrow therapeutic index, should be considered.
Systemic interactions between Tolak 4% Once Daily and other concomitantly administered systemic drugs may be more pronounced in patients with DPD deficiency. When DPD deficiency is suspected, the possibility of drug interactions between systemically absorbed fluorouracil and the concomitant medicines should be considered. The possibility of DPD deficiency when drug interactions are suspected should also be considered.
Concomitant administration of leucovorin may enhance both the activity and toxicity of fluorouracil by increasing the inhibition by fluorouracil of the enzyme thymidylate synthase. The relevance of this activity to the topical dermal use of Tolak 4% Once Daily in the treatment of actinic keratosis lesions is likely to be minimal due to the low systemic absorption of fluorouracil after topical dermal administration as Tolak 4% Once Daily.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No clinical data in humans are available on the effects of topical 5-FU on fertility. Fertility studies with systemic 5-FU resulted in impairment of male fertility and in a reduction of pregnancy rates in female rodents. The use of topical 5-FU may impair female and male fertility. Topical 5-FU is not recommended in women and men attempting to have a child.
(Category D)
There are no adequate data from the use of topical 5-FU in pregnant women. Systemic administration of high doses of 5-FU have teratogenic and/or embryotoxic effects in mice, rats, hamsters and monkeys.
Cases of miscarriage and birth defects (including cleft lip and cleft palate) have been reported when pregnant women were exposed to a topical or parenteral fluorouracil product. In addition, ventricular septal defect and cases of miscarriage occurred when pregnant women applied a topical fluorouracil product to mucous membranes (Tolak 4% Once Daily is not indicated for use on the mucous membrane).
The potential risk for humans is unknown, hence Tolak 4% Once Daily must not be used during pregnancy (see Section 4.3 Contraindications).
Women of childbearing potential should not become pregnant during topical 5-FU therapy and should use effective method of contraception during treatment with 5-FU therapy. If a pregnancy occurs during treatment the patient should be advised about the risk for the child of adverse effects associated with the treatment and genetic counselling is recommended.
 No information is available on the excretion of 5-FU into breast milk. As risk to nursing infants cannot be excluded, Tolak 4% Once Daily must not be used in nursing mothers (see Section 4.3 Contraindications). If use of Tolak 4% Once Daily is absolutely necessary, breastfeeding must be discontinued.

4.7 Effects on Ability to Drive and Use Machines

It is unlikely that treatment with Tolak 4% Once Daily will have any effect on the ability to drive and use machines when used according to the dosage instructions.

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The most frequently reported events in subjects treated with Tolak 4% Once Daily in the primary clinical studies were application site reactions. Tolerability at the application site was evaluated in the primary clinical studies. Local reactions related to tolerability, associated with the pharmacological action of 5-FU included erythema, scaling/dryness, oedema, crusting, erosions, stinging/burning, and pruritus with an incidence of 62% to 99% by symptom. Most of these local reactions were reported as mild (17% to 37% by symptom) or moderate (22% to 44% by symptom); severe reactions were less frequent (6% to 38% by symptom, with overall lower occurrence of severe reactions compared to active comparator (5% 5-FU cream). They were transient with a peak at 4 weeks of treatment and resolved within 2-4 weeks after the end of treatment (also see Section 4.4 Special Warnings and Precautions for Use for normal pattern of response). Application site reactions are presented in Table 1.
All other adverse effects (including insomnia, nasal discomfort, pharyngitis, nausea, periorbital oedema, impetigo, rash, and lip blister) were reported at a frequency below 1%.
Table 2 lists the adverse reactions reported in AK patients treated with Tolak 4% Once Daily for 4 weeks during the primary clinical studies.
Their frequency is defined using the following convention: 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).

Description of selected adverse reactions.

Photosensitivity.

Topical 5-FU is associated with photosensitivity reactions including severe sunburn. Photosensitivity reaction was reported in one subject (0.3%) in the primary clinical studies of Tolak 4% Once Daily. It should be noted that photosensitivity reaction was also reported by a subject in the vehicle group.

Post-marketing experience.

Hypersensitivity reactions.

Although no case has been reported in the primary clinical trials of Tolak 4% Once Daily, allergic contact dermatitis (delayed type hypersensitivity reaction) has been reported with topical 5-FU drugs and with Tolak 4% Once Daily since first marketing approval.

Reporting suspected adverse effects.

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

4.9 Overdose

When applied to the skin as recommended, systemic intoxication with 5-FU is unlikely. Application of significantly higher doses than recommended may result in an increase in the frequency and severity of reactions at the application site.
There is no known clinical case of accidental ingestion of Tolak 4% Once Daily, however if this occurs signs of 5-FU overdosage may include nausea, vomiting, diarrhea and stomatitis.
Blood dyscrasias may occur in severe cases. Daily white cell counts should be performed, and appropriate measures should be taken accordingly for the prevention of systemic infection.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: pyrimidine analogues. ATC code: L01BC02.

Mechanism of action.

The active substance fluorouracil (5-FU) is a cytostatic agent that has an antimetabolite effect. Due to its structural similarity with the thymine (5-methyluracil) occurring in nucleic acids, 5-FU prevents its formation and utilisation and, in this way, inhibits both DNA and RNA synthesis which results in growth inhibition.

Clinical trials.

The safety and the efficacy of Tolak 4% Once Daily were evaluated in two primary, multi-centre, randomised, controlled studies (Trial 1 and Trial 2) in subjects with at least 5 visible actinic keratosis lesions on the face, scalp, and/or ear (not exceeding 1 cm). Trial 1 compared Tolak 4% Once Daily to an active comparator (5-FU 5%) (twice daily) and a negative placebo control (vehicle). Trial 2 was a placebo-controlled study. Application of the medication, once daily for 4 weeks, involved field treatment of the whole area of the face and/or ears and/or scalp where actinic keratosis lesions were identified at baseline. A high proportion of patients in these studies applied Tolak 4% Once Daily cream on a large area of skin between 240 cm2 and 961 cm2. All efficacy endpoints were evaluated at 4 weeks post-treatment. Subjects were all Caucasian with a mean age of approximately 68 years (33-89 years). The mean number of actinic keratosis lesions was 14.4 and 16.2 (Trial 1) and 19.2 and 23.2 (Trial 2), in the Tolak 4% Once Daily group and the placebo group, respectively.
As shown in Table 3, in both trials, superiority of Tolak 4% Once Daily was demonstrated versus vehicle. In Trial 1, the difference in "100% complete clearance rate" of Tolak (5-FU 4%; cream once daily) (54.4%) minus active comparator (5-FU 5% cream; twice daily) (57.9%) was 3.5% with a lower 97.5% confidence limit of -11.11%. The difference in "75% complete clearance rate" of Tolak (80.5%) minus active comparator (80.2%) was 0.3% with a lower 97.5% confidence limit of -5.94% in the intention-to-treat population (with similar results in the per-protocol population).
The safety of 4-week treatment Tolak 4% Once Daily was assessed up to 4 weeks post-treatment. The majority of the reported adverse reactions and local skin responses were mild to moderate in intensity and resolved without sequelae.

Long term efficacy - lesion recurrence.

After completing the two primary clinical studies, patients treated with Tolak 4% Once Daily were followed up for 12 months for lesion recurrence. Of the 184 patients included in the analysis of recurrence, 83 (45.1%) patients remained clear 12 months after treatment and 101 (54.9%) patients had a recurrence within 12 months.
The duration between initial treatment and retreatment with Tolak 4% Once Daily in clinical studies ranged between 7 and 13 months (mean: 9.4 months). There was no formal assessment of repeated treatment with Tolak 4% Once Daily in case of recurrence.

Paediatric population.

No data are available in paediatric patients.

Elderly population.

Of the 403 subjects treated with Tolak 4% Once Daily in the phase III clinical trials, 204 subjects were 68 years and older while 199 subjects were below 68 years of age. No overall differences in efficacy were observed between the two groups.

5.2 Pharmacokinetic Properties

5-FU shows low absorption following topical application. In a systemic absorption study of topically applied Tolak 4% Once Daily, 8 of 21 patients had undetectable (1 nanogram/mL) levels of 5-FU. Among patients with detectable plasma 5-FU levels, the highest level of plasma 5-FU was generally observed at 1-hour post-dose and the observed maximum concentration ranged between 1.1 - 7.4 nanogram/mL.
5-FU may be metabolised by catabolic or anabolic routes which are similar to those of endogenous uracil. The rate-limiting step in the metabolism of 5-FU is conversion to 5-6- dihydrofluorouracil by the enzyme DPD.

5.3 Preclinical Safety Data

Genotoxicity.

5-FU has no potential to induce point mutations in bacteria. 5-FU induced chromosome aberrations and/or micronuclei in vitro in several cell lines and was clastogenic after IP or oral administrations in mice and rats and after dermal application to mice.

Carcinogenicity.

No evidence of carcinogenicity was found in several studies in rats or mice after intravenous or oral administration.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tolak 4% Once Daily cream is for topical use only and contains fluorouracil (5-FU) 4% w/w (equivalent to 40 mg/g). The cream also contains the excipients: stearoyl macrogolglycerides, butylated hydroxytoluene, cetyl alcohol, citric acid, glycerol, isopropyl myristate, methyl gluceth-10, methyl hydroxybenzoate, propyl hydroxybenzoate, purified water, arachis oil (peanut oil), sodium hydroxide, stearic acid and stearyl alcohol.

6.2 Incompatibilities

Not applicable.

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.
Shelf-life after first opening the immediate packaging: 4 weeks.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Aluminium tube with membrane, internally coated with an epoxyphenolic lacquer, with a polypropylene piercing screw cap.
Pack sizes: 20 g and 40 g.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

Chemical Abstracts Service (CAS) registry number: 51-21-8.
Chemical name: 5-Fluoropyrimidine-2,4(1H,3H)-dione.
Molecular formula: C4H3FN2O2. Relative molecular weight: 130.1.
5-FU is a white or almost white, crystalline powder. It is sparingly soluble in water, slightly soluble in alcohol, practically insoluble in chloroform. Its dissociation constants (pKa) are 8.0 and 13.0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes