VERRUMAL SOLUTION

Patient leaflet in accordance with the Pharmacists' Regulations (Preparations) - 1986

This medicine is dispensed with a doctor’s prescription only

VERRUMAL SOLUTION

Solution for topical application

Active ingredients:

Each 100 gr contain:

Fluorouracil 0.5 gr

Salicylic acid 10 gr

For the list of inactive ingredients and allergens in the medicinal product, see section 6.

Read the entire leaflet carefully before you start using this medicine. This leaflet

contains concise information about this medicine.

If you have any further questions, consult with your doctor or pharmacist.

It is recommended to read this leaflet with another family member.

This medicine has been prescribed for you. Do not pass it on to others. It may harm

them, even if it seems to you that their medical condition is similar to yours.

1. What is this medicine intended for?

For the treatment of common warts (warts beneath the soles of the feet in areas where

pressure is applied to the soles of the feet) and flat warts on hands and feet.

Therapeutic group: anti-wart and keratolytic agents.

2. Before using this medicine

Do not use this medicine:

if you are sensitive/allergic to the active ingredients, fluorouracil or salicylic

acid (salicylates), or to any of the other ingredients of this medicine that are

listed in section 6.

if you are breastfeeding.

if you are pregnant or if there is a concern that you may be pregnant.

to treat infants.

on patients suffering from renal insufficiency.

if you are undergoing treatment for chickenpox and/or for herpes zoster; if you

took brivudine, sorivudine and/or their derivatives (antiviral medicines for the

treatment of herpes zoster).

The active ingredient, fluorouracil, concomitantly with brivudine, sorivudine or

their derivatives, may significantly exacerbate the side effects of Verrumal.

Treatment with Verrumal may be started, at the very earliest, four weeks after

completing the treatment for herpes zoster with brivudine or sorivudine.

If you are being treated or were recently treated for a herpes zoster infection,

inform the doctor about the medicines that you are taking or took.

Verrumal is not intended for application on extensive areas of skin (on more than

25 square centimeters) and the medicine should not come in contact with the

eyes or mucous membranes.

Special warnings about using this medicine

Before using Verrumal, tell your doctor:

when you are suffering from diminished activity of or a deficiency in

dihydropyrimidine dehydrogenase (DPD) enzymes. These enzymes play a

significant role in breaking down the active ingredient of the medicine: fluorouracil. A

delay or a decrease in the activity of these enzymes (for example, due to the

administration of DPD inhibitors such as: brivudine or sorivudine) may lead to an

accumulation of the active ingredient, fluorouracil. In any instance of doubt, your

DPD levels or their level of activity should be checked before using Verrumal.

when you are taking phenytoin for the treatment of epileptic seizures. Using

Verrumal while taking phenytoin may increase the levels of phenytoin in the blood.

Therefore, you should regularly monitor the levels of phenytoin in your blood.

in the instance of warts on areas of thin skin, Verrumal should be applied less

frequently; the doctor will examine the treated area more frequently, since it may

result in the formation of scars.

Regular medical examinations are needed if you are suffering from sensory

disturbances, pain and an ability to sense temperature (sensory disturbances such

as those experienced by diabetes patients).

After applying Verrumal, take care that it does not come in contact with textiles or

acrylics (such as acrylic baths). The solution may cause permanent stains.

Keep in mind that Verrumal fluid is flammable before a film is formed! Keep Verrumal

away from open fire and flames.

Do not use Verrumal on bleeding wounds.

Children and adolescents

Do not use Verrumal on infants, because the risk of overdose is higher among children

than among adults. Do not exceed the recommended area of treatment or frequency of

use, particularly in relation to small children.

Tests and follow-up

It is recommended that you consult with your doctor regularly during treatment with this

medicine. Empirically, it has been found that it is recommended in many cases (such

as in cases of protruding warts or warts under the soles of the feet) for the doctor to

remove the necrotic tissue after the treatment with Verrumal.

Drug interactions

If you are taking or have recently taken other medicines, including

nonprescription medications and dietary supplements, tell your doctor or

pharmacist. Particularly if you are taking:

Do not use Verrumal if you are taking or have taken particular antiviral medicines,

such as for chicken pox or herpes zoster (brivudine, sorivudine or their derivatives)

during the last 4 weeks.

You must be particularly careful if you are taking anticonvulsants (phenytoin). It is

known from systemic use of fluorouracil during cancer treatments that if fluorouracil

is administered concomitantly with phenytoin, the phenytoin levels may become

elevated.

Salicylic acid absorption and possible reactions with methotrexate (medicine for the

treatment of rheumatic diseases, cancer and severe psoriasis) and sulphonylurea

(an ingredient of some of the medicines used to lower the blood sugar level (anti-

diabetics)) are possible.

Pregnancy and breastfeeding

If you are pregnant

or are breastfeeding, if you think that you may be pregnant or are

planning to become pregnant, consult with your doctor or pharmacist before using the

medicine.

Do not use Verrumal during breastfeeding, pregnancy or if pregnancy is suspected.

Driving and using machines

No particular means of caution are necessary.

Important information about some of this medicine’s ingredients

Verrumal contains dimethyl sulfoxide, which may cause skin irritation.

3. How to use this medicine?

Always use this medicine according to your doctor's instructions.

Check with your doctor or pharmacist if you are not sure about your dose or about how

to use this medicine.

Only your doctor will determine your dose and how you should use this

medicine.

The recommended dosage is usually:

Apply Verrumal solution two to three times a day on each wart.

Do not apply the medicine on a large area of skin (on more than 25 square

centimeters).

The medicine should not come in contact with the eyes or mucous membranes.

This medicine is not intended for infants.

Do not exceed the recommended dose.

Directions for use

Apply Verrumal solution only on the wart itself and not on the healthy skin surrounding

the wart. If necessary, you may cover the surrounding skin with a protective oily

ointment. If needed, your doctor or pharmacist will recommend a suitable ointment to

you.

Open the bottle by pressing down on the cap and turning it in a counter-clockwise

direction. It is recommended that you wipe off any extra solution from the bottle neck.

In the event of tiny warts, you may apply using a toothpick or similar implement, instead

of a brush, in order to ensure precise application. Always remove the residual thin film

before each new application of Verrumal.

In the event of a wart around or under a nail, make sure that the nail is intact (is not

cracked) in order to prevent the medicine from penetrating the nail bed.

Treatment duration

The average duration of treatment is 6 weeks.

Continue treatment for an additional 7 days after successful healing.

Consult with your doctor or pharmacist if you get the impression that the effect of

Verrumal is too strong or too weak.

If areas of thin skin are afflicted by warts, the solution should be applied less frequently

than in areas with a normal skin thickness (epidermis), since it may result in the

formation of scars.

Close the bottle tightly immediately after use, because the solution dries up quickly if

the bottle remains open.

This medicine is intended for external use only.

If you applied more Verrumal than is recommended

please consult with your doctor.

If a child has accidentally swallowed some of the medicine, immediately see a

doctor or go to a hospital emergency room and bring the medicine package with

you.

If you forget to apply Verrumal

do not apply a double dose in order to compensate for the dose that you forgot.

Continue the treatment as recommended by your doctor.

Adhere to the treatment as recommended by your doctor.

Even if your health improves, do not stop the treatment with this medicine without

consulting with your doctor.

If you stop the treatment with Verrumal before completing the course of

treatment

please consult with your doctor.

Do not take medicines in the dark! Check the label and dose every time you take

medicine. Wear glasses if you need them.

If you have any further questions about using this medicine, consult with your

doctor or pharmacist.

4. Side effects

Like with all medicines, using Verrumal may cause side effects in some users. Do not

be alarmed by this list of side effects; you may not experience any of them.

Very common side effects (affecting more than one in ten users): erythema,

inflammation, irritation, burning sensation, pain and itching of the skin at the site of the

application.

Common side effects (affecting 1-10 in 100 users): bleeding, the formation of a

crust and oozing of the skin at the site of the application.

Skin peeling and a reaction of skin erosion (loss of the top layer of skin) are possible.

Headache is possible.

Uncommon side effects (affecting 1-10 in 1,000 users): skin inflammation, edema

and an ulcer at the site of the application.

An overproduction of tears, itching/tingling and dryness of the eyes are possible.

Rare side effects (affecting 1-10 in 10,000 users): an intense burning sensation may

necessitate discontinuation of the treatment.

Verrumal contains salicylic acid. This ingredient may cause mild irritation, such as a

skin inflammation (dermatitis) or a hypersensitive reaction (allergic reaction upon

contact). This irritation may also be expressed by tingling, redness and blisters beyond

the treated area.

Whitened skin around the treated wart and desquamation (skin erosion) may occur.

If you experience any side

effect, if any side effect gets worse, or if you

experience a side effect not mentioned in this leaflet, consult with your doctor.

Reporting side effects

You can report side effects to the Ministry of Health by following the link ‘Reporting

Side Effects of Drug Treatment’ on the Ministry of Health home page

(www.health.gov.il), which links to an online form for reporting side effects. You can

also use this link: https://sideeffects.health.gov.il.

You can also report by sending an email to the Registration-holder’s patient safety unit:

drugsafety@neopharmgroup.com.

5. How to store the medicine?

Prevent poisoning! To prevent poisoning, keep this, and all other medicines, in a closed

place, out of the reach and sight of children and/or infants. Do not induce vomiting

unless explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry date (exp. date) which is stated on the bottle

label and on the carton. The expiry date refers to the last day of that month.

Storage conditions

Do not store at temperatures below 10˚C or above 25°C.

Do not use this medicine for more than 6 months after you opened the bottle.

Keep the bottle tightly closed immediately after you open it for the first time; otherwise,

the solution dries up quickly and you will not be able to use it properly. Do not use

Verrumal if the medicine has dried up. Do not use this medicine if crystals have formed

in it.

Caution! Flammable fluid! Keep away from open fire and flames.

Do not throw away medicines via wastewater or household waste. Ask the pharmacist

how to throw away medicines that you no longer use. These measures will help protect

the environment.

6. Additional information

In addition to the active ingredients, this medicine also contains:

Ethyl acetate, Ethanol anhydrous, Dimethyl sulfoxide, Methacrylic acid methyl ester

/methacrylic acid butyl ester copolymer, Pyroxyline.

What the medicine looks like and contents of the pack:

Verrumal is a clear, colorless to light yellow-orange solution provided in a glass bottle

at the volume of 13 or 14 ml.

Not all pack sizes may be marketed.

Registration-holder’s name and address: Neopharm Ltd., 8 Hashiloach, P.O.B.

7063, Petach-Tikva 49170.

Manufacturer’s name and address: Almirall Hermal GmbH, Hamburg, Germany.

Registration number of the medicine in the Ministry of Health’s National Drug

Registry: 010-34-24061.

Revised in June 2020.

Verrumal®

1. NAME OF THE MEDICINAL PRODUCT

Verrumal Solution

Solution, topical

Fluorouracil, Salicylic acid

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

100 g of solution contains:

Fluorouracil 0.5 g; salicylic acid 10.0 g

Other excipient with known effect: dimethyl sulfoxide 8.0 g

For a full list of excipients, see Section 6.1.

3. PHARMACEUTICAL FORM

Solution, topical.

Verrumal Solution is a clear, colourless to slightly yellow-orange solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Common warts (special form: plantar warts, on areas of the sole of the foot that are subjected to pressure),

plane juvenile warts of the extremities.

4.2 Posology and method of administration

Posology

Generally Verrumal Solution is applied to every wart two to three times daily.

The average duration of treatments is six weeks. It must be applied consistently every single day.

After successful treatment further treatment should follow for approx. one week.

Children

Verrumal Solution must not be used on babies.

Method of administration

For application to the skin.

Verrumal Solution must only be used on the wart and not on the healthy skin around the wart; if necessary,

cover the surrounding skin with a paste or cream. It is recommended that wipe the brush on the neck of the

bottle before dabbing it on. With very small warts you should use a toothpick or something instead of a

brush for more precise application.

Before reapplying Verumal Solution. the coating should be removed every time by simply pulling it off.

In case of periungual and in particular subungual warts, make sure that the nail matrix is not damaged and

that Verrumal Solution does not get into the nail bed.

The area to be treated should not be larger than 25 cm².

Experience has shown that in many cases, e.g. with very prominent common warts and planar warts on the

soles of the feet, it is better if the dead tissue is removed by a doctor after treatment with Verrumal Solu-

tion.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in Section 6.1.

Verrumal Solution must not be used while breastfeeding , during a pregnancy and also not by women who

cannot rule out a pregnancy (see Section 4.6).

Verrumal Solution must not be used on babies and on patients with renal failure.

Verrumal Solution must not be used at the same time as Brivudine, Sorivudine and analogues. Brivudine,

Sorivudine and analogues are potent inhibitors of the fluorouracil-degrading enzyme dihydropyrimidine

dehydrogenase (DPD) (also see Sections 4.4 and 4.5).

Verrumal Solution is not intended for use on large skin areas (an area of skin no larger than 25 cm

) and it

must not come into contact with the eyes or mucous membranes.

4.4 Special warnings and precautions for use

Verrumal Solution contains the cytostatic 5-fluorouracil.

The dihydropyrimidine dehydrogenase (DPD) enzyme plays an important part in the fluorouracil degrada-

tion. An inhibition, deficiency or reduced activity of this enzyme MAY lead to fluorouracil accumulation.

Where applicable, the determination of the DPD enzyme activity is indicated before starting treatment with

fluoropyrimidines. Patients who are taking phenytoin at the same time as fluorouracil should regularly be

examined for elevated phenytoin plasma levels.

If areas of skin with thin epidermis are affected by warts, Verrumal Solution shall be applied less

frequently and checked more often during treatment, as scars may form due to the salicylic acid contained

in Verrumal Solution severely softening the corneous layer.

With warts that are very prone to cornification, it is sometimes appropriate to pretreat them with a salicylic

acid plaster.

Verrumal Solution should not be used on bleeding lesions.

Strict medical supervision is required with patients with somatosensory disorders (e.g. with Diabetes

mellitus).

Close the bottle tightly after every use as the preparation may otherwise dry out quickly and no longer be

able to be applied properly. Once dried, Verrumal Solution cannot be used anymore. Apart from this, the

solution must no longer be used if crystals have formed.

Make sure that the Verrumal Solution does not come into contact with textiles or acrylic (e.g. acrylic baths)

when applying, as the solution may cause stains that cannot be removed (before the coating is formed).

Fire warning: keep away from open fire and flames.

Dimethyl sulfoxide may cause skin irritation.

4.5 Interaction with other medicinal products and other forms of interaction

The dihydropyrimidine dehydrogenase (DPD) enzyme plays an important part in the fluorouracil

degradation. Antiviral nucleoside analogues such as Brivudine and Sorivudine may lead to a drastic

increase in plasma concentrations of fluorouracil or other fluoropyrimidines and therefore to an associated

rise in toxicity.

For this reason, a time interval of at least 4 weeks should be adhered to between the use of fluorouracil and

Brivudine, Sorivudine and analogues.

In the event of nucleoside analogues, such as Brivudine and Sorivudine, accidentally being administered to

patients who are being treated with fluorouracil, effective measures should be taken to reduce fluorouracil

toxicity. Admission to hospital is also advised, as necessary. All measures should be taken to prevent

systemic infection and dehydration.

With the simultaneous administration of phenytoin and systemic fluorouracil, an increase in the plasma

concentration of phenytoin was reported that led to phenytoin intoxication symptoms (see Section 4.4).

Resorbed salicylic acid may interact with methotrexate and sulphonylureas.

4.6 Fertility, pregnancy and lactation

Verrumal Solution is contraindicated during pregnancy and lactation (see Section 4.3).

4.7 Effects on ability to drive and use machines

Verrumal Solution has no or only negligible effect on the ability to drive and use machines.

4.8 Undesirable effects

Undesirable effects are listed hereunder in accordance with the MedDRA System Organ Class and in

decreasing frequency. Assessment of frequency of the undesirable effects is based on 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); unknown (frequency unable to be assessed from

available data).

System organ class

Frequency

Side effect

General diseases and complaints at

the site of application

Very common

Appearing at the

administration site: erythema, inflammations,

irritations (including burning), pain, pruritus

Common

Appearing at the

administration site: bleeding, skin erosion,

crusting

Uncommon

Appearing at the

administration site: dermatitis, edema,

ulceration

Diseases of the skin and

subcutaneous tissue

Common

Skin exfoliation

Diseases of the nervous system

Common

Headaches

Eye diseases

Uncommon

Dry eyes, eye itching, increased tear secretion

In rare cases, severe burning may lead to treatment being stopped.

Due to the effect of the severe softening of the corneal layer there may be whitish discolorations or

exfoliation of the skin, particularly in the area around the wart.

As a result of the salicylic acid content slight irritation such as dermatitis or contact-allergic reactions

which may also manifest themselves by itching, reddening and blisters beyond the area of contact (so-

called spreading reactions) may occur with accordingly susceptible patients when using this medicinal

product.

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://sideeffects.health.gov.il/

and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com

4.9 Overdose

When applying Verrumal Solution to a 25 cm² area of skin, an amount of 0.2 g Verrumal Solution and

therefore 1 mg of fluorouracil (FU) is applied. 1 mg of FU corresponds to a dose of 0.017 mg/kg of body

weight with a person weighing 60 kg. Systemic intoxications occur with intravenous administration of 15

mg per kg body weight and are therefore ruled out as a result of this thousandfold safety profile. The safety

profile also increases even more considerably as FU is not percutaneously resorbed to any significant

degree from Verrumal Solution (see also Section 5.2).

As a serum level of barely over 5 mg/dl is reached after the percutaneous resorption of salicylic acid (also

see Section 5.2), salicylate intoxications are practically ruled out if Verrumal Solution is used as prescribed

(also see Section 5.2).

Early symptoms of salicylate intoxication can only occur with serum levels over 30 mg/dl. They include

ringing in the ears, tinnitus with hearing difficulty, nosebleeds, nausea, vomiting, irritability a feeling of

dryness with mucous membranes.

Therefore, systemic intoxications are unlikely for both active ingredients if applied to the skin as prescribed

(see above). However, clearly exceeding the recommended frequency of application increases the

frequency and the severity of local reactions at the site of application.

Children

Small children have a different ratio of body surface to body mass to adults. Therefore significantly

exceeding the maximum recommended treatment area or treatment frequency increases the risk of

salicylate intoxication, especially in small children.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other dermatics, wart product and keratolytic treatment

ATC code: D11AF

Mechanism of action of fluorouracil

The active ingredient fluorouracil (FU) belongs to the cytostatics that act as anti-metabolites.

As a result of its structural similarity with to Thymine (5-Methyluracil), which is present in nucleinic acids,

FU prevents formation and use of this and in this way inhibits both DNA and RNA synthesis.

Consequently the growth of the wart virus is inhibited resulting in the inhibited growth of the kinds of cells

in particular which are in an the accelerated growth stage, as with warts, and therefore absorb FU in

increased amounts.

Thymine Fluorouracil

Mechanism of action of salicylic acid

Salicylic acid was added because of its keratolytic properties, to facilitate penetration of the active

ingredient, which is especially difficult in warts. The same is achieved by the solubilizing agent for the

active ingredient FU, dimethyl sulfoxide. The keratolytic action of salicylic acid is based on direct effect on

the intercellular glue substances or desmosomes promoting the keratinization process.

5.2 Pharmacokinetic properties

In a resorption study on pigs it could be proved that there was no fluorouracil in the serum after the

cutaneous application, even in large amounts of Verrumal Solution i.e. the active ingredient was not

resorbed in an amount that could be detected using standard analytical methods (HPLC).

According to more recent analysis, the fluorouracil resorption rate in people after use of Verrumal Solution

is significantly less than 0.1 %.

After application on the skin, Verrumal Solution forms a strong white looking film on the skin once the

solution has evaporated. Thus, an occlusive effect is achieved to benefit the difficult penetration of the

active ingredient particularly with warts.

Animal experiments and human pharmacokinetic studies show that salicylic acid penetrates quickly

depending on the basis and penetration influencing factors, such as skin condition.

Salicylic acid is metabolized by the conjugation with glycine into salicyluric acid, with gluconic acid from

the phenolic OH group into ether glucuronide and on the COOH group into ester glucuronide, while via

hydroxylation it is metabolized into gentisic or dihydroxybenzoic acid. The half-life of systemically

resorbed salicylic acid is between 2 and 3 hours in the normal dose range and can increase to 15 to 30

hours with high posology as a consequence of the liver's limited capacity to conjugate salicylic acid.

With a topical application of salicylic acid, no toxic undesirable effects are generally expected (if all

contraindications are observed!) as a serum level over 5 mg/ml can barely be reached. Early symptoms of

salicylate intoxication can only occur with serum levels over 30 mg/dl.

5.3 Preclinical safety data

There are no known mutagenic, carcinogenic and teratogenic effects from salicylic acid to date.

6. PHARMACEUTICAL DATA

6.1 List of the excipients

Ethyl acetate

Ethanol, anhydrous

Dimethyl sulfoxide

Methacrylic acid methyl ester/methacrylic acid butyl ester copolymer

Pyroxyline

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

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

Once opened : 6 months

6.4 Special precautions for storage

Do not store above 25° C.

Do not store at temperature below 10° C.

Flammable!

6.5 Nature and contents of container

13 ml glass bottle

14 ml glass bottle

6.6 Special precautions for disposal

No special requirements.

7. MANUFACTURER

Almirall Hermal GmbH

Scholtzstrasse 3

D-21465 Reinbek

Hamburg, Germany

8. REGISTRATION HOLDER

Neopharm Ltd.

Hashiloah 8, POB 7063

Petach Tiqva 49170

Israel

9. REGISTRATION NUMBER:

010-34-24061

Revised in June 2020.