ASACOL 400

Israel - English - Ministry of Health

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Active ingredient:
MESALAZINE
Available from:
TRADIS GAT LTD
ATC code:
A07EC02
Pharmaceutical form:
TABLETS ENTERIC COATED
Composition:
MESALAZINE 400 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
TILLOTTS PHARMA AG, SWITZERLAND
Therapeutic group:
MESALAZINE
Therapeutic area:
MESALAZINE
Therapeutic indications:
Ulcerative colitis:-For the treatment of mild to moderate acute exacerbations. -For the maintenance of remission.Crohn's disease:-For the treatment of acute episodes.
Authorization number:
065 99 25654 00
Authorization date:
2014-04-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

20-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

16-06-2020

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

This medicine is dispensed with a doctor’s prescription only

Asacol

400 mg

Enteric-coated tablets

Active ingredient:

mesalazine (5-aminosalicylic acid) 400 mg/tablet

Asacol

800 mg

Enteric-coated tablets

Active ingredient:

mesalazine (5-aminosalicylic acid) 800 mg/tablet

Inactive ingredients and allergens: see section 2 ‘Important information about some of this

medicine’s ingredients’ and section 6 ‘Additional information’.

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

your doctor or pharmacist.

This medicine has been prescribed to treat your illness. Do not pass it on to others. It may

harm them, even if it seems to you that their illness is similar to yours.

1. What is this medicine intended for?

This medicine is intended for treating ulcerative colitis (acute exacerbation of colitis) and

Crohn’s disease (acute episodes) and for preventing recurrent episodes of ulcerative colitis.

Therapeutic group:

aminosalicylates.

2. Before using this medicine

Do not use this medicine if:

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

in this medicine (listed in section 6 ‘Additional information’)

You are sensitive (allergic) to salicylates such as aspirin

You have severe kidney problems

You have severe liver problems

Children under two years old

Special warnings about using this medicine

Before starting treatment with Asacol, tell the doctor if:

- you have ever had any problems with your liver or kidneys, particularly if you are elderly

- you have any problems with the lungs, such as asthma

- you suffered an allergy to sulfasalazine in the past

- you have ever had allergic reactions of your heart such as inflammation of the heart muscle

or heart sac. If you have had previous allergic reactions of your heart that may have been

caused by mesalazine, do not take Asacol. You can take Asacol under supervision if you

have had a previous allergic reaction of the heart that was not caused by mesalazine.

- you have an ulcer of the stomach or intestine, you may take Asacol under supervision.

Kidney stones may develop with use of Asacol. Symptoms may include pain in the sides of

your abdomen and blood in your urine. Take care to drink sufficient amount of liquid during

treatment with Asacol.

Children and adolescents:

The safety and efficacy of Asacol tablets in children have not

been fully established.

Tests and follow-up

Before and during use of this medicine, your doctor may want to monitor you from time to

time, to check that your liver, kidneys, blood and lungs are all right.

There have been a few reports of intact tablets in the stool. What appear to be intact tablets

may sometimes be the remains of the tablet coating. If you often observe tablets or tablet

coating in the stool, you should consult your doctor.

Other medicines and Asacol

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

medications and dietary supplements, tell your doctor or pharmacist.

Particularly tell

your doctor or pharmacist if you are taking:

- medicines that affect the immune system such as azathioprine, 6-mercaptopurine, or

thioguanine

- medicines that prevent the formation of blood clots (anticoagulants such as warfarin)

Using this medicine and food

Take the medicine before meals. You may eat and drink normally (including alcohol), during

treatment with this medicine.

Pregnancy, breastfeeding, and fertility:

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a

baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines:

This medicine is not expected to affect your ability to drive or operate machines.

However, if you are affected in anyway, do not drive or operate machines.

Important information about some of this medicine’s ingredients

This medicine contains lactose (milk sugar).

Patients who are intolerant to lactose should note that this medicine contains a small amount

of lactose. If your doctor has told you that you have an intolerance to certain sugars, consult

your doctor before taking this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, i.e. is essentially

“sodium-free”.

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 take this medicine. Only your

doctor will determine your dose and how you should take this medicine.

The usually recommended dosage in adults is:

To treat ulcerative colitis:

Mild active disease: 2.4 grams (6 tablets of Asacol 400 or 3 tablets of Asacol 800) once daily

or in divided doses.

Moderate active disease: 2.4 grams (6 tablets of Asacol 400 or 3 tablets of Asacol 800) up to

4.8 grams (12 tablets of Asacol 400 or 6 tablets of Asacol 800) per day in divided doses.

You may take up to 2.4 grams once a day or in divided doses. If taking more than 2.4 grams a

day, take in divided doses.

To prevent recurrence of ulcerative colitis episodes:

1.2 grams (3 tablets of Asacol 400) up to 2.4 grams (6 tablets of Asacol 400 or 3 tablets of

Asacol 800) once daily or in divided doses.

For Crohn’s disease:

2.4 grams (6 tablets of Asacol 400 or 3 tablets of Asacol 800) per day in divided doses.

Asacol 400: Do not take more than 12 tablets a day and do not take more than 6 tablets at

once.

Asacol 800: Do not take more than 6 tablets a day and do not take more than 3 tablets at

once.

Do not exceed the recommended dose.

Take this medicine before meals; swallow it whole, preferably with some liquid. Do not chew,

crush or break the tablets before swallowing them. While you are taking this medicine make

sure you drink adequate fluids to avoid dehydration, especially after severe or prolonged

episodes of vomiting and/or diarrhoea, high fever or heavy sweating. This is to prevent

problems with your kidneys.

If you have accidentally taken a higher dose

If you have taken an overdose, or if a child has accidentally swallowed some medicine,

immediately see a doctor or go to a hospital emergency room and bring the medicine

package with you.

If you forget to take the medicine

If you forget to take a tablet at the scheduled time, take the next dose as soon as you

remember, unless it is nearly time to take the next dose. Do not take a double dose to make

up for a forgotten dose.

If you stop taking this medicine

Even if your health improves, do not stop taking this medicine without consulting your doctor

or pharmacist.

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 your doctor or

pharmacist.

4. Side effects

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

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

Organ-specific side effects, affecting the heart, lungs, liver, kidneys, pancreas, skin and

subcutaneous tissue have been reported.

Stop taking the medicine immediately and consult your doctor right away:

if you develop unexplained bruising (without injury), bleeding under your skin, purple

spots or patches under your skin, anemia (feeling tired, weakness, and looking pale,

especially on lips, nails and inside of eyelids), high fever, abdominal pain, headache,

sore throat, rash or unusual bleeding (such as nose bleeds).

lung disease (scarring of lung tissue, allergic reaction) resulting in difficulty in

breathing, cough, wheezing and collection of fluids in the lungs, pneumonia

abnormal liver function tests, hepatitis (inflammation of the liver giving rise to flu-like

symptoms and jaundice)

inflammation of the heart with signs like chest pains or palpitations

disorder of the immune system (lupus-like syndrome) which can cause inflammation

of the heart sac or membranes around the lungs and heart, rash and/or joint pain

kidney problems (such as inflammation and scarring of the kidneys), kidney failure

which may be reversible if treatment is stopped early

reversible decrease in sperm production

Common side effects (may affect up to 1 in 10 people)

- rash

- indigestion

Uncommon side effects (may affect up to 1 in 100 people)

- fever

- high number of white blood cells called eosinophil granulocytes

- sensation of tingling, pricking and numbness

- hives, itching skin

- chest pain

Rare side effects (may affect up to 1 in 1,000 people)

- headache

- dizziness

- diarrhea, stomach pain, flatulence, unpleasant feeling and discomfort in the stomach with an

urge to vomit and vomiting

- increased sensitivity of your skin to sun and ultraviolet light (photosensitivity)

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

- severe reduction in count of blood cells which can cause weakness, bruising or make

infections more likely, low blood cell counts; reduction in blood platelets which increase the

risk of bleeding

- allergic reactions such as rash or skin eruption

- fever that occurs while taking the medicine and which disappears when the medicine is

stopped (drug fever)

- immune system disease that can involve organs and joints

- ulcerative colitis involving the entire large intestine

- abnormal or damaged nerves that cause numbness or tingling

- inflamed pancreas (associated with pain in the upper abdomen and back and being

nauseous)

- hair loss

- muscle and joint pain

Side effects of unknown frequency (frequency cannot be estimated from available data)

- inflammation of the lung membrane (pleurisy)

- intolerance to mesalazine sometimes with worsening symptoms of the disease

- weight loss

- laboratory test results out of normal range

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 your doctor.

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, or by using this link:

https://sideeffects.health.gov.il

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 package. The

expiry date refers to the last day of that month.

Storage conditions:

Do not store above 25°C.

6. Additional information

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

lactose monohydrate

sodium starch glycolate

methacrylic acid-methyl methacrylate copolymer (1:2)

talc micronized

povidone

magnesium stearate

triethyl citrate

ferric oxide red and yellow pigment

macrogol 6000

Each 400 mg tablet contains 76.40 mg lactose monohydrate.

Each 800 mg tablet contains 152.80 mg lactose monohydrate.

What the medicine looks like and contents of the pack

Oblong, reddish-brown tablets. The tablet are available in blister trays of 10 tablets in packs

Asacol 400 mg: 100 tablets per pack

Asacol 800 mg: 60 tablets per pack

Registration holder: Tradis Gat Ltd., 32 Shaham St., Petac Tikva.

Manufacturer: Tillotts Pharma, Rheinfelden, Switzerland.

Approved in March 2020.

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

Asacol 400 mg: 659925654

Asacol 800 mg: 1333931029

1.

NAME OF THE MEDICINAL PRODUCT

ASACOL® 400 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each enteric coated tablet contains:

Mesalazine (5-aminosalicylic acid) 400 mg

Excipient with known effect: 76.4 mg lactose, see section 4.4.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Enteric coated Tablet.

Reddish to brownish oblong tablets

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Ulcerative colitis:

For the treatment of mild to moderate acute exacerbations. For the maintenance of

remission.

Crohn's disease

:

For the treatment of acute episodes.

4.2

Posology and method of administration

Posology

Ulcerative colitis:

Mild acute disease: 2.4 g (six tablets) once daily or in divided doses, with concomitant

corticosteroid therapy to be taken when clinically indicated.

Moderate acute disease: 2.4 g to 4.8 g (six to twelve tablets) a day in divided doses, with

concomitant corticosteroid therapy where clinically indicated. 2.4 g may be taken once

daily or in divided doses. Above 2.4 g daily should be taken in divided doses.

The maximum adult dose should not exceed twelve tablets a day and not exceed six tablets

taken together at any one time.

Maintenance of remission:

1.2 to 2.4 g per day once daily or in divided doses.

Crohn’s disease:

2.4 g per day in divided doses.

Elderly population

Use in the elderly should be handled with caution and only for patients having a normal

renal function.

Pediatric population

There is no specific dose recommendation for children.

Method of administration

The tablets should be taken before meals and must be swallowed whole preferably with

some liquid. They must not be chewed, crushed or broken before swallowing

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section

Known hypersensitivity to salicylates

- Severe liver impairment.

- Severe renal impairment (GFR less than 30 mL/min/1.73 m2).

- Children under the age of 2 years.

4.4 Special warnings and precautions for use

Blood tests (differential blood count, liver function parameters such as ALT or AST; serum

creatinine) and urinary status (dip sticks) should be determined prior to and during

treatment, at the discretion of the treating physician. As a guideline, follow-up tests are

recommended 14 days after commencement of treatment and then every 4 weeks for the

following 12 weeks. If the findings are normal, follow-up tests should be carried out every

three months. If additional signs appear, these tests should be performed immediately.

Renal impairment

Caution should be exercised in patients with raised serum creatinine or proteinuria.

The possibility of mesalazine-induced nephrotoxicity should be suspected in patients

developing impairment of renal function during treatment. Patients need to remain

well hydrated whilst taking Asacol to reduce the risk of crystalluria and consequential

kidney damage.

Treatment with Asacol should be stopped immediately if there is evidence of renal

impairment and patients should seek immediate medical advice.

Nephrolithiasis

Cases of nephrolithiasis have been reported with the use of mesalazine including

stones with a 100% mesalazine content. It is recommended to ensure adequate fluid

intake during treatment.

Blood dyscrasia

Serious blood dyscrasia has very rarely been reported. Asacol therapy should be

stopped immediately if there is a suspicion or evidence of blood dyscrasia (signs of

unexplained bleeding, bruising, purpura, anemia, persistent fever or sore throat), and

patients should seek immediate medical advice.

Hepatic impairment

There

have

been

reports

increased

liver

enzyme

levels

patients

taking

preparations

containing

mesalazine.

Caution

recommended

Asacol

administered to patients with liver impairment. Blood tests (liver function parameters

such as ALT or AST) should be performed prior to and during treatment, at the

discretion of the treating physician. As a guideline, follow-up tests are recommended

14 days after commencement of treatment, then a further two to three tests at intervals

of 4 weeks. If the findings are normal, follow-up tests should be carried out every 3

months. If additional symptoms occur, these tests should be performed immediately.

Cardiac hypersensitivity reactions

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have

rarely been reported with Asacol. In case of a suspected mesalazine-induced cardiac

hypersensitivity, Asacol must not be reintroduced. Caution should be taken in patients

with previous myo- or pericarditis of allergic background regardless of its origin.

Pulmonary disease

Patients

with

pulmonary

disease,

particular

asthma,

should

very

carefully

monitored during treatment with Asacol.

Adverse drug reactions to Sulphasalazine

Patients with a history of adverse drug reactions to sulphasalazine therapy should be

kept under close medical supervision. Treatment must be stopped immediately if acute

symptoms of intolerance occur such as abdominal cramps, acute abdominal pain, fever,

severe headache and rash.

Gastric and duodenal ulcers

In case of existing gastric or duodenal ulcers treatment should begin with caution

based on theoretical grounds.

Tablets in stool

A limited number of reports of intact tablets in the stool have been received. What appear to

be intact tablets may in some cases represent largely empty shells of the coated tablets. If

intact tablets are observed in the stool repeatedly, the patient should consult his/her

physician.

Elderly population

Use in the elderly should be handled with caution and the product should only be

prescribed to patients having a normal or non-severely impaired liver and renal

function, see section 4.3.

Paediatric population

Safety and effectiveness of Asacol tablets have not been fully established in paediatric

patients.

Pharmaceutical excipients of special interest

Intolerance to carbohydrates

With reference to the presence of lactose monohydrate in the formulation, patients with

rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, i.e. is

essentially “sodium-free”.

4.5 Interaction with other medicaments and other forms of interaction

No interaction studies have been performed.

There is weak evidence that mesalazine might decrease the anticoagulant effect of

warfarin.

In patients who are concomitantly treated with azathioprine, or 6-mercaptopurine or

thioguanine, a possible increase in the myelosuppressive effects of azathioprine, or 6-

mercaptopurine or thioguanine should be taken into account. As a result, life-

threatening infection can occur. Patients should be closely observed for signs of

infection and myelosuppression. Haematological parameters, especially the leucocyte,

thrombocyte, and lymphocyte cell counts should be monitored regularly (weekly),

especially at initiation of such combination therapy, see section 4.4. If white blood cells

are stable after 1 month, testing every 4 weeks for the following 12 weeks followed by

3 monthly monitoring intervals appears to be justified.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data on the use of Asacol in pregnant women. However, data

on a limited number (627) of exposed pregnancies indicate no adverse effect of

mesalazine on pregnancy or on the health of the fetus/newborn child. To date no

other relevant epidemiologic data are available.

In one single case after long-term use of a high dose of mesalazine (2-4 g, orally)

during pregnancy, renal failure in a neonate was reported.

Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with

respect

pregnancy,

embryonic/fetal

development,

parturition

postnatal

development.

Asacol should only be used during pregnancy if the potential benefit outweighs the

possible risk.

Breast-feeding

N-acetyl-5-aminosalicylic acid and to a lesser degree, mesalazine are excreted in

breast milk. The clinical significance of this has not been determined. Only limited

experience during lactation in women is available to date. Hypersensitivity reactions

such as diarrhoea in the infant cannot be excluded. Therefore, Asacol should only be

used during breast-feeding, if the potential benefit outweighs the possible risk. If the

infant develops diarrhoea, the breast-feeding should be discontinued.

Fertility

No effects on fertility have been observed.

4.7 Effects on ability to drive and use machines

Asacol has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

a) Summary of the safety profile

Organ specific adverse drug reactions affecting the heart, lungs, liver, kidneys,

pancreas, skin and subcutaneous tissue have been reported.

Treatment must be stopped immediately if acute symptoms of intolerance occur such

as abdominal cramps, acute abdominal pain, fever, severe headache and rash, see

section 4.4.

b) Tabulated summary of adverse reactions

Undesirable effects relevant for the labeling reported from eight (8) double-blind and

five (5) open clinical studies with 739 patients treated with Asacol 400 mg enteric

coated tablets are listed below.

System

Organ

Class

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

Blood and

lymphatic

system

disorders

eosinophilia

(as part of

an allergic

reaction)

altered blood

counts (aplastic

anemia,

agranulocytosis,

pancytopenia,

neutropenia,

leucopenia,

thrombocytopenia)

Immune system

disorders

hypersensitivity

reactions such as

allergic exanthema,

drug fever, lupus

erythematosus

syndrome,

pancolitis

Nervous system

disorders

paresthesia

headache,

dizziness

peripheral

neuropathy

Cardiac

disorders

myocarditis,

pericarditis

Respiratory,

thoracic and

mediastinal

disorders

allergic and fibrotic

lung reactions

(including

dyspnoea, cough

bronchospasm,

alveolitis,

pulmonary

eosinophilia, lung

infiltration,

pneumonitis),

interstitial

pneumonia,

eosinophilic

pneumonia, lung

disorder

pleurisy

Gastrointestinal

disorders

dyspepsia

abdominal pain,

diarrhoea,

flatulence, nausea,

vomiting

acute pancreatitis

Hepato-biliary

disorders

changes in liver

function

parameters

(increase in

transaminases and

cholestasis

parameters),

hepatitis,

cholestatic hepatitis

Skin and

subcutaneous

tissue disorders

rash

urticaria,

pruritus

photosensitivity*

alopecia

System

Organ

Class

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

Musculoskeletal,

connective

tissue and bone

disorders

myalgia, arthralgia

lupus-like

syndrome with

pericarditis and

pleuropericarditis

as prominent

symptoms as

well as rash and

arthralgia

Renal and

urinary

disorders

Impairment of renal

function including

acute and chronic

interstitial

nephritis, renal

insufficiency,

nephrotic syndrome

and renal failure

which may be

reversible on early

withdrawal

Nephrolithiasis**

Reproductive

system and

breast disorders

oligospermia

(reversible)

General

disorders and

administration

site conditions

pyrexia,

chest pain,

intolerance to

mesalazine with

C-reactive

protein

increased

and/or

exacerbation of

symptoms of

underlying

disease

Investigations

blood creatinine

increased,

weight

decreased,

creatinine

clearance

decreased,

amylase

increased, red

blood cell

sedimentation

rate increased,

lipase

increased, BUN

increased

*see section c)

**see section 4.4 for further information

c) Description of selected adverse reactions

An unknown number of the above mentioned undesirable effects are probably associated

to the underlying IBD rather than Asacol/mesalazine medication. This holds true especially

for gastrointestinal undesirable effects, arthralgia, and alopecia.

To avoid blood dyscrasia resulting from developing bone marrow depression patients

should be monitored with care, see section 4.4.

Under

co-administration

mesalazine

with

immunosuppressive

drugs,

such

azathioprine or 6-MP or thioguanine, life-threatening infection can occur, see section 4.5.

Photosensitivity

More severe reactions are reported in patients with pre-existing skin conditions such as

atopic dermatitis and atopic eczema.

d) Paediatric population

There is only limited safety experience with the use of Asacol tablets in the paediatric

population. It is expected that the target organs of possible adverse reactions in the

paediatric population are the same as for adults (heart, lungs, liver, kidneys, pancreas,

skin and subcutaneous tissue).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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/

4.9 Overdose

There are rare data on overdose (e.g. intended suicide with high oral doses of

mesalazine), which do not indicate renal or hepatic toxicity. There is no specific

antidote and treatment is symptomatic and supportive.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agents, ATC code: A07EC02

Mechanism of Action

Asacol contains mesalazine also known as 5-aminosalicylic acid, which has an anti-

inflammatory effect through a mechanism that has not yet been fully clarified.

Mesalazine has been shown to inhibit LTB4-stimulated migration of intestinal macrophages

and thus may reduce intestinal inflammation by restricting migration of macrophages to

inflamed areas. The production of pro-inflammatory leukotrienes (LTB4 and 5-HETE) in

macrophages of the intestinal wall is inhibited. Mesalazine has been shown to activate

PPAR-γ receptors which counteract nuclear activation of intestinal inflammatory responses.

Pharmacodynamic effects

Under trial conditions mesalazine inhibited the cyclooxygenase and thus, the release of

thromboxane B

and prostaglandin E

, but the clinical meaning of this effect is still unclear.

Mesalazine inhibits the formation of platelet activating factor (PAF). Mesalazine is also an

antioxidant; it has been shown to decrease formation of reactive oxygen products and to

capture free radicals.

Clinical efficacy and safety

Mild to moderate acute ulcerative colitis

Asacol 800 mg Tablets have been evaluated in 140 patients with mild to moderate

active ulcerative colitis in one controlled study lasting for 10 weeks comparing safety

and efficacy versus placebo. This indication was also investigated in seven controlled

and three open clinical trials including 787 patients, of whom 559 received Asacol 400

mg Modified Release Tablets. Three studies were placebo-controlled, one of which

also compared the efficacy of Asacol to another proprietary oral mesalazine product.

Five studies were performed without comparator. The studies included dose ranging

of Asacol. One study compared the efficacy of mesalazine versus sulfasalazine. The

studies included dose ranging of Asacol from 1.2 g/day to 4.8 g/day. One study used

computerised

morphometry

assess

efficacy

Asacol

compared

with

prednisolone enema. These studies established the safety and efficacy of Asacol for

the treatment of mild to moderate acute UC at daily doses of 2.4 – 4.8 g mesalazine.

Maintenance of remission of ulcerative colitis

The efficacy of Asacol 400 was investigated in a double-blind randomised placebo-

controlled study including 264 patients. Treatment success in the two Asacol 400

groups (0.8 g/day and 1.6 g/day) was compared by endoscopic evaluation at the 6-

month endpoint with the placebo group by using the Fischer exact test. In the intention-

to-treat analysis of all patients, 42 of 87 patients (48.3%) in the placebo group

treatment success compared to 57 of the 90 patients (63.3% [CI, 52.8% to 73.8%]) in

the group receiving 0.8 g/day (P= 0.050) and 61 of the 87 patients (70.1% [CI, 59.9%

to 80.3%]) in the group receiving 1.6 g/day (P= 0.005). Asacol 400 mg GR Tablets

were safe and effective in maintaining remission in quiescent ulcerative colitis.

5.2 Pharmacokinetic properties

Absorption

Asacol tablets are coated with a pH responsive polymer which enables the release of

mesalazine only at a pH above 7, i.e. within the terminal ileum and colon, which are

the main sites of inflammation in IBD. After any initial disruption of the coating

mesalazine will continue to be released irrespective of the pH. Asacol tablets have

been designed to minimise absorption in the digestive tract.

After a single dose of 2.4 g of mesalazine (6 Asacol 400 mg enteric coated Tablets) in

healthy volunteers under fasting conditions quantifiable amounts (> 2.00 ng/mL) of

mesalazine were observed in plasma after 4.5 h (median t

). The geometric mean

–value of mesalazine was 722.11 ng/mL with a median t

of about 9.5 h,

whereas that of N-acetyl mesalazine was 1437.90 ng/mL with a median t

of 12.0 h.

Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl

mesalazine in collected urine after fasted oral administration approximately 25% of the

dose (more than 95 % as metabolite) was excreted renally within 60 h.

Following concomitant food intake in the same study a single dose of 2.4 g of

mesalazine resulted in quantifiable amounts of mesalazine after 9.0 h (median t

The geometric mean C

–value of mesalazine was 1725.93 ng/mL with a median t

of about 22.0 h, whereas that of N-acetyl mesalazine was 2235.32 ng/mL with a

median t

of 24.0 h.

Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl

mesalazine in collected urine after fed oral administration approximately 30% of the

dose (about 90 % as metabolite) was excreted renally within 60 h.

Following concomitant food intake the C

-values of mesalazine increased 2.39-fold,

and the extent of exposure (AUC

0-tlast

) increased 1.57-fold. Concerning N-acetyl

mesalazine

after

concomitant

food

intake

-values

increased

1.55-fold,

whereas its extent of exposure increased about 1.1-fold only.

Distribution

About 43% mesalazine and about 78% N-acetyl mesalazine are bound to plasma

proteins.

Approximately 75 % of the administered dose remains in the gut lumen and the

mucosal tissue.

The mean apparent volume of distribution per kg of body weight (Vd

) was 59.07 L/kg

(geometric mean: 48.86 L/kg) after a single dose of 2.40 g of mesalazine (6 enteric

coated tablets of Asacol 400 mg) in healthy volunteers under fasting conditions. Based

upon the absorption of 24.8% of the administered dose, this parameter is equal to

14.65 L/kg (geometric mean: 12.12 L/kg).

Low concentrations of mesalazine and N-acetyl mesalazine have been detected in

human breast milk. The clinical significance of this has not been determined.

Biotransformation

Mesalazine is metabolised both by the intestinal mucosa and the liver to the inactive

metabolite N-acetyl mesalazine. At least 90% of the drug recovered in the urine after

oral administration is found as the main metabolite N-acetyl-mesalazine.

Elimination

The elimination of mesalazine is essentially urinary and faecal in the form of

mesalazine and its N-acetyl metabolite. The geometric mean of total apparent

clearance of mesalazine after administration of 2.40 g of mesalazine (6 enteric coated

tablets of Asacol 400 mg) in healthy volunteers under fasting conditions was about

135 L/h (geometric mean, CV% = 61.43%, intersubject). The median elimination half-

life was 20 h ranging from 5 to 77 h. About 25% of the total dose administered was

recovered in the urine within 60 h after fasted administration mainly as N-acetyl

mesalazine and as the parent compound (about 1 %).

Linearity/non-linearity

In a cross-over design with 3 test periods and 3 ascending oral doses of Asacol 400

mg enteric coated Tablets administered 6 hourly over 4 consecutive doses (total daily

dose of mesalazine: 3200, 4800, 6400 mg) it was shown that the absorption and

elimination kinetics for mesalazine are dose independent for the 3 doses evaluated.

For each dose, about ¾ of the dose was available for the therapeutic activity for the

colon. Only about ¼ of each dose was absorbed and excreted in the urine, primarily

as the metabolite. Based on urine drug excretion, plasma drug C

’s and the

combined plasma AUC’s, there was a linear dose response for the 3 Asacol tablet

doses. The clinical performance of Asacol 400 should be similar for the range of doses

evaluated in this study.

Pharmacokinetic/ pharmacodynamics relationship(s)

No specific studies have been performed.

5.3 Preclinical safety data

Preclinical data with mesalazine reveal no special hazard for humans based on

conventional studies of safety pharmacology, genotoxicity, carcinogenicity or toxicity

to reproduction.

Renal toxicity (renal capillary necrosis and epithelial damage in the proximal

convoluted tubule or the whole nephron) has been seen in repeat-dose toxicity

studies with high oral doses of mesalazine.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipient(s)

lactose monohydrate

sodium starch glycolate (type A)

methacrylic acid-methyl methacrylate copolymer (1:2)

talc micronized

povidone

magnesium stearate

triethyl citrate

ferric oxide red and yellow pigment (E172)

macrogol 6000

6.2 Incompatibilities

None.

6.3 Shelf life

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

6.4 Special precautions for storage

Do not store above 25° C.

6.5 Nature and contents of container

Pack of 100 tablets in a blister pack (PVC/aluminium).

6.6 Special precautions for disposal and other handling

Not applicable.

7.

Manufacturer:

Tillotts Pharma AG, SWITZERLAND

8.

Registration Holder and Importer:

Tradis Gat Ltd. 32 Shacham St. Petach Tikva ISRAEL

9.

Registration Number: 065-99-25654

Approved on March 2020

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ( ןכדועמ(

05.2013

05.2013

)

)

___ ךיראת

11/11/2014

_________

םושירה רפסמו תילגנאב רישכת םש

065-99-25654-00

Asacol 400

133-39-31029-00

Asacol 800

___ םושירה לעב םש מ"עב תג סידרט

_________________________________

! דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Indication

contraindications

Posology, dosage &

administration

Special Warnings and

Special Precautions

for Use

Short monitoring intervals early after the

start of Asacol therapy will discover rare

acute renal reactions. In the absence of an

acute renal reaction monitoring intervals

can be extended to every 3 months and

then annually after 5 years. If additional

laboratory or clinical signs of renal

impairment appear, these tests should be

performed immediately. Treatment with

Asacol should be stopped immediately if

there is evidence of renal impairment and

patients should seek immediate medical

advice.

Hepatic impairment

There have been reports of increased liver

enzyme

levels

patients

taking

preparations

containing

mesalazine.

Caution is recommended if Asacol is

administered

patients

with

liver

impairment. Blood tests (liver function

parameters such as ALT or AST) should

performed

prior

during

treatment, at the discretion of the treating

physician. As a guideline, follow-up tests

recommended

days

after

commencement of treatment, then a

further two to three tests at intervals of 4

weeks. If the findings are normal, follow-

up tests should be carried out every 3

months. If additional symptoms occur,

these

tests

should

performed

immediately.

Cardiac hypersensitivity reactions

Mesalazine-induced

cardiac

hypersensitivity

reactions

(myo-

pericarditis) have been reported rarely

with Asacol. In case of a suspected

mesalazine-induced

cardiac

hypersensitivity Asacol must not be

reintroduced. Caution should be taken in

patients

with

previous

myo-

pericarditis

allergic

background

regardless of its origin.

Gastric and duodenal ulcers

In case of existing gastric or duodenal

ulcers

treatment

should

begin

with

caution based on theoretical grounds.

Intolerance to carbohydrates

Patients with rare hereditary problems of

galactose intolerance, the Lapp lactase

deficiency

glucose-galactose

malabsorption

should

take

this

medicine.

Tablets in stool

A limited number of reports of intact tablets

in stool have been received. What appear to

be intact tablets may in some cases represent

largely empty shells of the coated tablets.If

Use in the older people

should be handled with

caution and the product

should only be

prescribed to patients

having a normal and

renal function,see

section 4.3.

intact tablets are observed in the stool

repeatedly, the patient should consult his/

her physician.

Older people

Use in the older people should be handled with

caution and the product should only be

prescribed to patients having a normal or non-

severely impaired liver and renal function, see

section 4.3.

Interaction with Other

Medicaments and Other

Forms of Interaction

Mesalazine decreases the

absorption of Digoxin

The uricosuric

activity of

probenecid and

sulfinpyrazone, the

diuretic effect of

furosemide and

the activity of

spironolactone can

be reduced.

Gastrointestinal

side-effects of

glucocorticoids

can be increased.

Asacol tablets

should not be given

with lactulose or

similar preparation,

which lower stool

pH and may

prevent release of

mesalazine

There is weak evidence that mesalazine might

decrease the anticoagulant effect of warfarin.

In patients who are concomitantly treated

with azathioprine, or 6-mercaptopurine or

thioguanine, a possible increase in the

myelosuppressive effects of azathioprine, or

6-mercaptopurine or thioguanine should be

taken into account. As a result, life-

threatening infection can occur. Patients

should be closely observed for signs of

infection and myelosuppression.

Fertility, pregnancy and

Lactation

Breast-feeding

Hypersensitivity reactions such as

diarrhoea in the infant cannot be excluded.

Adverse events

Blood and lymphatic system disordersVery

rare: agranulocytosis,

Immune system disorder

Very rare: drug fever, pancolitis

Nervous system disorders

Uncommon:

paresthesia.

Rare:

dizziness.

Very rare:

peripheral neuropathy.

Respiratory, thoracic and mediastinal

disorders

Very rare: fibrotic lung reactions (including

dyspnoea, cough, bronchospasm, alveolitis,

pulmonary eosinophilia, lung infiltration,

pneumonitis), interstitial pneumonia,

Gastrointestinal disorders

Common: dyspepsia.

Rare:

flatulence, nausea, vomiting.

Hepato-biliary disorders

Very rare:

changes in liver function

parameters (increase in transaminases and

cholestasis parameters), hepatitis, cholestatic

hepatitis.

Skin and subcutaneous tissue disorders

Uncommon: urticaria, pruritus.

Renal and urinary disorders

Very rare:

renal insufficiency, nephrotic

syndrome, renal failure which may be

reversible on early withdrawal.

Reproductive

system

and

breast

disorders

Very rare:

oligospermia (reversible).

General disorders and administration

site conditions

Uncommon:

pyrexia, chest pain.

Investigations

Not known:

blood creatinine increased,

weight

decreased,

creatinine

clearance

decreased, amylase increased, red blood cell

sedimentation

rate

increased,

lipase

increased, BUN increased.

Under co-administration of mesalazine with

immunosuppressive

drugs,

such

azathioprine or 6-MP or thioguanine, life-

threatening

infection

occur, see

section 4.5.

תושקובמה תורמחהה תונמוסמ ובש ,ןולעה ב"צמ בוהצ עקר לע

.

ונמוס תורמחה רדגב םניאש םייוניש )ןולעב( ב הנוש עבצ םייוניש אלו יתוהמ ןכות קר ןמסל שי . .טסקטה םוקימב ...ךיראתב ינורטקלא ראודב רבעוה

16/11/2014

ןכרצל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכרצל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ( ןכדועמ(

05.2013

05.2013

)

)

___ ךיראת

11/11/2014

_________

םושירה רפסמו תילגנאב רישכת םש

065-99-25654-00

Asacol 400

133-39-31029-00

Asacol 800

___ םושירה לעב םש מ"עב תג סידרט

_________________________________

! דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט תויוותה שמתשהל ןיא יתמ ?רישכתב תודחוימ תורהזא שומישל תועגונה :הפורתב רפס ,לוקאסאב לופיטה תלחתה ינפל :םא אפורל מ םעפ יא תלבס תובוגת בלב תויגרלא .בלה סיכ וא בלה רירש לש תקלד ןוגכ תלבס םא רבעב בלב תויגרלא תובוגתמ רשא יכ תודושח לאסמ ידי לע ומרגנ

,ןיז הז הרקמב לוטיל רוסא ןתינ .לוקאסא ךל התייה םא תוריהזב לוקאסא לוטיל רבעב אל רשא בלב תיגרלא הבוגת לאסמ ידי לע המרגנ

.ןיז שמתשהל ןיא ילבמ הפורתב ינפל אפורב ץעוויהל :לופיטה תלחתה ןיב תובוגת

Mesalazine

תא ריבגהל יושע

דחוימב

שי

עדייל

תא

אפורה

וא

חקורה :תויתופורת םרגנה

ןוסיחה תכרעמ יוכיד

ידי-לע

azathioprine

mercaptopurin

םא

התא

:חקול

,ןירפויתאזא

ו ןירופוטפקרמ- ןינאוגוית

העפשהה תא ריבגהל לוכי ןיזאלאסמ .ןוסיחה תכרעמ תא תאכדמה

- ןירפראו תא תיחפהל לוכי ןיזאלאסמ .םדה תשירק תדגונ העפשהה :הקנהו ןוירה שמתשת דציכ :הפורתב :יאוול תועפות תוחיכש

לוכיע יישק תוחיכש יתלב

םיארקנה םינבל םד יאת לש הובג רפסמ םיליפוניזואא םיטיצולונרג

השוחת רסוחו רורקד ,ץוצקע תשוחת

רועב דוריג ,תדפרס

הזח באכ תורידנ םיזג דואמ תורידנ

תחרפת וא החירפ ןוגכ תויגרלא תובוגת תירוע

הפורתה תליטנ ןמזב עיפומה םוח ( התליטנ תא םיקיספמ רשאכ םלענהו

drug fever

ברעל הלוכי רשא ןוסיחה תכרעמב הלחמ םיקרפמו םירביא

רסוחל םימרוגה םימוגפ וא םיניקת אל םיבצע ץוצקעל וא השוחת ,תוניקת אל דבכ ידוקפת תוקידב

הכיפה הניה רשא ערז רוצייב הדירי העודי אל תורידת

לקשמב הדירי

חווטהמ תוגרוח רשא הדבעמ תוקידב תואצות .ילמרונה תושקובמה תורמחהה תונמוסמ ובש ,ןולעה ב"צמ בוהצ עקר לע

( ונמוס תורמחה רדגב םניאש םייוניש ןולעב ב ) .הנוש עבצ םייוניש אלו יתוהמ ןכות קר ןמסל שי .טסקטה םוקימב ....ךיראתב ינורטקלא ראודב רבעוה

13/11/2014

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