EFUDIX CREAM 5%

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS

REGULATIONS (PREPARATIONS 1986)

This medicine will be dispensed with a physician's prescription only

Efudix

Cream 5%

COMPOSITION:

Active Ingredient:

Each gram of cream contains - Fluorouracil 50 mg

Read this package insert in its entirety before using this medicine. This insert

includes concise information regarding this medicine. If you have any additional

questions, please refer to your doctor or pharmacist.

This medicine was prescribed for the treatment of your ailment. Do not give it to

others. It may cause them harm even if they seem to have a similar disease.

1. WHAT EFUDIX IS AND WHAT IS IT USED FOR?

Efudix cream is used for the treatment of skin problems, such as keratosis

and basal cell carcinoma (BCC). The active ingredient Fluorouracil belongs to

a group of anti-cancerous drugs.

This medicine is not intended for children and adolescents under the age of

Important Information About How Efudix Works

Efudix destroys cancerous and pre-cancerous cells, while having little effect

on normal cells.

When you use Efudix it is likely that the area of the skin that you are treating

will become red. 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 Efudix is working.

Sometimes the response is more severe (see section 4 “Possible Side

Effects”). If your skin becomes much worse, you experience pain or if you are

worried, talk to your doctor. Your doctor may prescribe you another cream to

relieve any discomfort.

After stopping treatment you may find that your skin takes one to two months

to heal completely.

Efudix will also treat abnormalities of the skin that were previously not visible

to the naked eye, and these abnormalities may become red and inflamed.

2. BEFORE YOU USE EFUDIX CREAM:

Special warnings related to the use of this drug:

Avoid contact of this medicine with your eyes or mouth, be especially careful

when this medicine is intended for the area of your eye lids, nose or lips (see

section 3, “How to use Efudix Cream”).

Do not apply this medicine to open wounds. This may cause a large amount

of this drug to be absorbed in your blood, which very rarely, can cause side

effects.

Before starting treatment with Efudix, tell your doctor if you are suffering from

reduced activity or deficiency of the enzyme DPD (dihydropyrimidine

dehydrogenase).

Avoid exposure to direct sun light, lamps and tanning beds as much as

possible during treatment with Efudix, these will increase the effects of Efudix

and may increase skin reactions.

Exposure to UV-radiation (e.g) natural sunlight, tanning salon) should be

avoided.

Closing bandages or dressing may increase inflammatory reactions of the

skin.

Children and adolescents

Efudix Cream is not for use in anyone under 18 years of age.

Inform your doctor or pharmacist if you are taking or have recently

taken any other medicines, including medicines obtained without a

prescription and food supplements. It is particularly important to inform your

doctor or pharmacist if you are taking:

Anti-viral medications for the treatment of diseases such as chickenpox or

shingles

(brivudine, sorivudine). It is also important to inform your doctor or

pharmacist if these medicines were taken in the past four weeks. These drugs

may increase the activity of Efudix and by this increase the risk of side effects

)see below)

Do not use Efudix cream if:

You are sensitive (allergic) to the active ingredient Fluorouracil or to any of the

other components of this drug (listed in section 6).

You are pregnant, think you may be pregnant or breast feeding

if you are using any medicines known as antiviral nucleosides (e.g.

brivudine, sorivudine). These medicines are usually used to treat chickenpox

or shingles.

You are taking anti viral medications for the treatment of

conditions such as chickenpox or shingles

Pregnancy , breast-feeding and fertility

Do not use Efudix cream if you are pregnant, think you may be pregnant.

effective method of contraception must be used dur- ing treatment with Efudix

Cream.

If you become pregnant during treatment inform your doctor immediately and

make use of genetic counselling.

Do not use Efudix Cream and tell your doctor if you are breast-feeding. If use

during breastfeeding is absolutely necessary, breast-feeding must be

discontinued.

The use of Efudix Cream may impair female and male fertility. Efudix Cream

is not recommended in men attempting to father a child.

Driving and using machines

It is unlikely that the treatment will have any effect on your ability to drive or

use machines.

Important information about some of the medicine’s ingredients

Efudix Cream contains some ingredients that can cause side effects. These

are:

stearyl alcohol and propylene glycol, which can cause local skin

irritations(e.g. contact dermatitis, which is an inflammation of the skin).

E218 (methyl parahydroxybenzoate) and E216

(propylparahydroxybenzoate), which can cause allergic reactions.

Do not use Efudix if you are allergic to any of its ingredients.

3. HOW TO USE EFUDIX?

Always use according to physician`s instructions.

Check with your doctor or

pharmacist if you are not sure about the dosage and how to apply the cream.

If you think the activity of this medicine is too strong or too week, inform your

doctor and do not change the dose without consulting your physician.

If you accidentally swallowed from Efudix cream, refer immediately to a

doctor, pharmacist or a hospital`s emergency room and bring the package of

this medicine with you.

If the cream has accidentally entered your eyes, mouth, nose or another

person has accidentally used it, wash the cream off using water then contact

your doctor, pharmacist or go to your nearest hospital straight away and bring

the package of this medicine with you.

How to apply Efudix

For external use only

Only use Efudix Cream on the skin and avoid contact with the eyes and

mouth.

Apply a thin layer of the cream to the affected area as instructed by

your doctor.

It is very important that you do not use too much cream and do not

apply the cream on open cuts. This may lead to some cream being

absorbed into the blood and, very rarely, this can cause side effects.

The dosage and treatment will be determined by the doctor only. The

usual dosage is: apply a thin layer of Efudix cream on the affected

area, -2 times a day for at least 3-4 weeks.

Wash your hands thoroughly after using this cream (except when the

hands are the treated area).

Your doctor will tell you if you need to apply a dressing to the treated

skin.

Never treat an area of skin larger than 23 x 23 cm (approximately the

size of a dinner plate) at any one time. Larger areas will be treated in

separate parts each time

If you forget to use Efudix Cream, apply the cream as soon as possible. However, if

it is nearly time for your next dose, skip the missed dose and carry on as before. Do

not apply a double dose to make up for a forgotten dose.

Do not take medicines in the dark! Check the label each time you take a medicine.

Wear eye glasses if you need them.

If you have additional questions regarding the use of this medicine, consult your

doctor or pharmacist.

4. SIDE EFFECTS:

Like all medicines, Efudix may cause side effects in some patients. Do not be

alarmed by the list of side effects; you may not experience any of them. The

usual response to treatment with Efudix is described in Section 1, under “How

Efudix works”.

You must tell your doctor IMMEDIATELY if you experience any of these

side effects:

Stomach problems such as pain, cramps, diarrhoea and vomiting

* Swelling and soreness of the mouth and tongue

* Fever or feeling generally unwell.

These side effects may occur if you use too much cream or if you apply the

cream to open cuts.

Additional side effects:

Very rare (may affect up to 1 in 10,000 people)

Relating to the skin and subcutaneous tissue: itching, redness, burning

sensation, severe peeling, intense swelling or inflammation, ulceration,

blistering, irritation, pain, hives and rash. These are generally a severe

response to treatment and usually occur in the areas of the skin where

the cream has been applied. Exposure to sunlight may increase the

intensity of the reaction.

* Rash on areas other than where the cream was applied

* Hair loss

Not known (frequency cannot be estimated from the available data)

* Painful and/or watering eyes

* Taste disturbance

* Headache, dizziness, nausea

Consult your physician if you get any side effects, if one of the side effects

becomes worse or if you suffer from side effects that have not been

mentioned in this leaflet.

Reporting side effects:

Side effects can be reported to the Ministry of Health through a link "report of

side effects due to medicine treatment" located in the home page of the

Ministry of Health website (www.health.gov.il) refers to online form for

reporting side effects or be entering the following link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=Adv

ersEffectMedic@moh. gov.il

5. HOW TO STORE EFUDIX CREAM?

Avoid poisoning! This medicine and all other medicines must be stored in

a safe place out of the reach and sight of children and/ or infants. This will

help avoid poisoning. Do not induce vomiting without being explicitly

instructed to do so by your physician

Do not use this medicine after the expiry date (exp. date) which appears

on the package and tube. The expiry date refers to the last day of that

month

Store at a temperature below 30°C

Use within three months after opening

6. FURTHER INFORMATION:

Each tube contains: 20g of 5% w/w fluorouracil.

In addition to the active ingredient Fluorouracil, this medicine also

contains: White soft paraffin, Stearyl alcohol, Propylene glycol,

Polysorbate 60, Methyl parahydroxybenzoate, Propyl

parahydroxybenzoate, Purified water

What does Efudix look like and what is the content of the package: Efudix

is a white opaque cream. Marketed in a package of 20 gram

Registration Holder and Address: MegaPharm Ltd, P.O. Box 519 Hod

Ha`Sharon 45105

Name of Manufacturer and Address:

ICN POLFA RZESZOW S.A., POLAND

2 PRZEMYSLOWA ST., 35-959 RZESZOW, POLAND

רובע

MEDA PHARMA GmbH & CO.KG, GERMANY

BENZSTRASS. 1, 61352 BAD HOMBURG, GERMANY

This leaflet was checked and approved by the Ministry of Health in

December 2011 and was updated according to guideline of Ministry of

Health in August 2018.

Registration number in the Ministry of Health`s national book of drugs:

062 40 21478

Summary of Product Characteristics

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1. NAME OF THE MEDICINAL PRODUCT

Efudix Cream 5%

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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Efudix cream contains 5% w/w fluorouracil.

For the full list of excipients, see section 6.1.

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3. PHARMACEUTICAL FORM

White, opaque cream.

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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Antineoplastic agent to treat actinic keratosis multiple and superfacial

basal cell carcinoma.

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4.2 Posology and method of administration

Efudix cream is for topical application.

Pre-malignant conditions

The cream should be applied thinly to the affected area once or twice

daily; an occlusive dressing is not essential.

Malignant conditions

The cream should be applied once or twice daily under an occlusive

dressing where this is practicable.

The cream should not harm healthy skin. Treatment should be continued

until there is marked inflammatory response from the treated area,

preferably with some erosion in the case of pre-malignant conditions.

Severe discomfort may be alleviated by the use of topical steroid cream.

The usual duration of treatment for an initial course of therapy is three to

four weeks, but this may be prolonged. Lesions on the face usually

respond more quickly than those on the trunk or lower limbs whilst lesions

on the hands and forearms respond more slowly. Healing may not be

complete until one or two months after therapy is stopped.

Elderly

Many of the conditions for which Efudix is indicated are common in the

elderly. No special precautions are necessary.

Children

In view of the lack of clinical data available, Efudix is not recommended for

use in children.

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4.3 Contraindications

Efudix is contraindicated in patients with known hypersensitivity to

fluorouracil or any of the excipients listed in section 6.1.

Coadministration of Efudix with antiviral nucleoside drugs (e.g. brivudine

and analogues) may lead to a substantial increase in plasma levels of

fluorouracil and associated toxicity and is contraindicated. Brivudine and

analogues are potent inhibitors of DPD, a fluorouracil metabolising

enzyme (see section 4.4 and 4.5)

Use of Efudix during pregnancy and in breast-feeding mothers is

contraindicated.

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4.4 Special warnings and precautions for use

The hands should be washed carefully after applying Efudix. Also care

should be taken to avoid contact with mucous membranes or the eyes

when applying the cream.

The total area of skin being treated with Efudix at any one time should not

exceed 500 cm

(approximately 23 x 23 cm). Larger areas should be

treated a section at a time.

The normal pattern of response includes: early and severe

inflammatory phases (typically characterised by erythema, which may

become intense and blotchy), a necrotic phase (characterised by skin

erosion) and finally healing (when epithelialisation occurs). The clinical

manifestation of response usually occurs in the second week of Efudix

treatment. However these treatment effects sometimes be more severe

and include pain, blistering and ulceration (see section 4.8). Occlusive

dressing may increase inflammatory reactions of the skin.Exposure to UV-

radiation (e.g natural sunlight, tanning salon) should be avoided.

Pre-existing subclinical lesions may become apparent following Efudix

use.

Any severe skin discomfort during treatment with Efudix may be alleviated

by the use of an appropriate topical steroid cream.

When used according to the approved prescribing information Efudix

should have minimal effect on healthy skin.

Significant systemic drug toxicity is unlikely via percutaneous absorption of

fluorouracil when Efudix is administered as per the approved prescribing

information. However the likelihood of this is increased if the product is

used excessively, especially on skin areas in which the barrier function is

impaired (e.g. cuts) and/or in individuals with deficiency in

dihydropyrimidine dehydrogenase (DPD), see section 4.8. DPD is a key

enzyme involved in metabolising and eliminating fluorouracil.

Determination of DPD activity may be considered where systemic drug

toxicity is confirmed or suspected. There have been reports of increased

toxicity in patients who have reduced activity/deficiency of the enzyme

dihydropyrimidine dehydrogenase. In the event of suspected systemic

drug toxicity, consideration should be given to stopping Efudix treatment.

An interval of at least four weeks should elapse between treatment with

brivudine, sorivudine or analogues and subsequent administration of

Efudix.

The excipients stearyl alcohol and propylene glycol may cause local skin

irritations (e.g. contact dermatitis); the excipients methyl

parahydroxybenzoate and propyl parahydroxybenzoate may cause

allergic reactions (possibly delayed).

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4.5 Interaction with other medicinal products and other forms of interaction

Although no significant drug interactions with Efudix have been reported,

potential drug interactions are possible as indicated below.

Brivudine, sorivudine and analogues are potent inhibitors of DPD, a

fluorouracil metabolising enzyme (see section 4.4). For this reason,

concomitant administration of these drugs with Efudix is contraindicated

(see section 4.3)

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4.6 Fertility, pregnancy and lactation

There are no adequate data from the use of topical fluorouracil in pregnant

women.

Studies in animals have shown that fluorouracil is teratogenic (see section

5.3). The potential risk for humans is unknown, hence Efudix should not

be used during pregnancy (see section 4.3)

Women of childbearing potential should not become pregnant during

topical fluorouracil therapy and should use effective method of

contraception during treatment with fluorouracil 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.

Breast-feeding

No information is available on the excretion of fluorouracil into breast milk.

Studies in animals have shown the fluorouracil is teratogenic (see section

5.3). A risk to the suckling child cannot be excluded, so Efudix should not

be used in nursing mothers (see section 4.3). If use during breastfeeding

is absolutely necessary, breastfeeding must be discontinued.

Fertility

No clinical data in humans are available on the effects of topical

fluorouracil on fertility.

Experiments in various species revealed an impairment of the fertility and

reproductive performance of systemic 5-fluorouracil. The reduced

systemic exposure to 5-FU following its topical administration will reduce

the potential toxicity. The use of topical 5-fluorouracil may impair female

and male fertility. Topical fluorouracil is not recommended in men

attempting to father a child.

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4.7 Effects on ability to drive and use machines

It is unlikely that treatment will have any effect on the ability to drive and

use machines when used according to the dosage instructions.

4.8 Undesirable effects

Within the system organ classes, adverse reactions are listed under

headings of frequency (number of patients expected to experience the

reaction), using the following categories:

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)

Frequency not known (cannot be estimated from the available data)

Adverse reactions associated with exacerbations of normal pattern of

response (see section 4.4) which are related to pharmacological activity of

fluorouracil on the skin are the most frequently reported reactions. Allergic

type skin reactions and reactions related to systemic drug toxicity are very

rarely reported.

Blood and lymphatic system disorders

Very rare: Haematological disorders, associated with systemic drug

toxicity, e.g. pancytopenia, neutropenia, thrombocytopenia.

Immune system disorders

Very rare: Allergic conditions (e.g. hypersensitivity and allergic reactions).

Nervous system disorders

Frequency not known: Dysgeusia, headache, dizziness.

Eye disorders

Frequency not known: Conjunctival irritation, keratitis, increased

lacrimation.

Gastrointestinal disorders

Very rare: Diarrhoea haemorrhagic, diarrhoea, vomiting, abdominal pain,

stomatitis, associated with systemic drug toxicity.

Frequency not known: Nausea.

Skin and subcutaneous tissue disorders

Very rare: Pruritus, urticaria, rash (usually local but also generalised if

associated with systemic drug toxicity); erythemas including erythema

multiforme; dermal and epidermal conditions (such as skin burning

sensation, skin exfoliation, skin swelling); skin and subcutaneous skin

ulcerations; dermatitis and eczema conditions (such as contact dermatitis,

skin irritation); blisters, and alopecia.

Exposure to sunlight may increase the intensity of the reaction. See also

normal pattern of response in section 4.4

General disorders and administration site conditions

Application and installation site reactions (localised skin reactions

associated with use of Efudix; see also under skin and subcutaneous

disorders), pain.

The following undesirable effects are associated with systemic drug

toxicity (see section 4.4)

General disorders and administration site conditions

Very rare: Pyrexia, chills and mucosal inflammation, associated with

systemic drug toxicity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal

product is important.

It allows continued monitoring of the benefit/risk balance

of the medicinal product. Any suspected adverse events should be reported to

the Ministry of Health according to the National Regulation by using an online

form

https://forms.gov.il/forms/Resources/DowloadSetup/AGFormsDownloadToolb

ar.htm?formid=AdversEffectMedic@moh.gov.il

4.9 Overdose

If Efudix is accidentally ingested, signs of fluorouracil overdosage may

include nausea, vomiting and diarrhoea. Stomatitis and blood dyscrasias

may occur in severe cases. Appropriate measures should be taken for the

prevention of systemic infection and daily white cell counts should be

performed.

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5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pyrimidine analogues, ATC code: L01BC02

Efudix is a topical cytostatic preparation which exerts a beneficial

therapeutic effect on neoplastic and pre-neoplastic skin lesions while

having less effect on normal cells. The pattern of response follows this

sequence: erythema, vesiculation, erosion, ulceration, necrosis and

epithelisation.

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5.2 Pharmacokinetic properties

Fluorouracil is minimally systemically absorbed when applied topically to

intact skin. When applied to the skin, the skin’s barrier function is

pathologically altered (e.g., as in ulceration), and the absorption rate can

increase to 60%. In patients with AK, 2.4 – 6% of the topical dose was

absorbed systemically. Similarly, under occlusion, significantly more

fluorouracil is absorbed.

Fluorouracilmay be metabolised by catabolic or anabolic routes which are

similar to that of endogenous uracil.

5.3 Preclinical safety data

There is evidence from animal work that fluorouracil is teratogenic.

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6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

White soft paraffin, Stearyl alcohol, , Propylene glycol, Polysorbate 60,

Methyl parahydroxybenzoate, Propyl parahydroxybenzoate, Purified water

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6.2 Incompatibilities

None known.

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6.3 Shelf life

The expiry date of the product is indicated on the packaging materials.

Shelf life after first opening the immediate packaging: 90 days for the 20g

tube.

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6.4 Special precautions for storage

Storage

The recommended maximum storage temperature for Efudix cream is 30 °C.

Dilution

Efudix cream should not be diluted.

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6.5 Nature and contents of container

Efudix cream is supplied in a 20g aluminium tube with a plastic screw cap.

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in

accordance with local requirements.

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7. MARKETING AUTHORISATION HOLDER

ICN Polfa Rzeszow, Poland

2 PRZEMYSLOWA ST., 35-959 RZESZOW, POLAND

for

MEDA Pharma GmbH & Co. KG., Bad Homburg, Germany

BENZSTRASS. 1, 61352 BAD HOMBURG, GERMANY

8. MARKETING AUTHORISATION NUMBER

062 40 21478

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9. LICENSE HOLDER

MegaPharm Ltd. P.O. Box 519, Hod HaSharon 4510501, Israel

The content of this leaflet was approved by the Ministry of Health in

December 2011 and updated according to the guidelines of the Ministry of

Health in August 2018