Consumer medicine information

Salofalk Granules Modified Release Granules

Mesalazine

BRAND INFORMATION

Brand name

Salofalk Granules

Active ingredient

Mesalazine

Schedule

What is in this leaflet

This leaflet answers some common questions about SALOFALK GRANULES modified release granules. It does not contain all of the available information.

All medicines have risks and benefits. Your doctor has weighed the possible risks of taking this medicine against the expected benefits.

Ask your doctor or pharmacist if you have any concerns about taking SALOFALK GRANULES.

Keep this leaflet with the medicine. You may want to read it again.

What SALOFALK GRANULES modified release granules is used for

SALOFALK GRANULES contain the active ingredient mesalazine (5-aminosalicylic acid), which is used to treat, and prevent relapse of, mild to moderate attacks of ulcerative colitis (inflammation of the large bowel).

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason. SALOFALK GRANULES are not addictive.

It is not expected to affect your ability to drive a car or operate machinery.

This medicine is only available on a doctor’s prescription.

Before you take it

When you must not take it

Do not take SALOFALK GRANULES modified release granules if:

you are allergic to mesalazine or aspirin-like medicines, or any of the ingredients listed at the end of this leaflet. Signs of allergic reactions may include itchy skin rash, shortness of breath and swelling of the face or tongue.
you suffer from a severe kidney or liver problem
the expiry date (EXP) printed on the pack has passed. If you use this medicine after the expiry date has passed, it may not work as well.
the package is torn or shows signs of tampering.

Do not give this medicine to a child below 6 years of age. The safety and effectiveness of this medicine in this group have not been established.

Before you start to take it

Tell your doctor if:

you have any allergies
you are pregnant or intend to become pregnant or are breastfeeding or wish to breastfeed.
Your doctor will discuss the risks and benefits of taking SALOFALK GRANULES if you are pregnant or breastfeeding.
you have or have had any medical conditions, especially the following:
- lung or breathing problems such as asthma
- you have kidney problems
- you have liver problems
- phenylketonuria.
You have ever developed a severe skin rash or skin peeling, blistering and/or mouth sores after using mesalazine.

SALOFALK GRANULES contain aspartame. Aspartame is a source of phenylalanine. It may be harmful if you have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Kidney stones may develop with use of mesalazine. Symptoms may include pain in sides of abdomen and blood in urine. Take care to drink sufficient amount of liquid during treatment with mesalazine.

Serious skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis have been reported in association with mesalazine treatment. Stop using mesalazine and seek medical attention immediately if you notice any of the symptoms related to these serious skin reactions described in Side effects section below.

If you have not told your doctor about any of the above, tell them before you start to take it.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

This medicine may interfere with the action of the following types of medicines:

anticoagulants, medicines used to stop blood clots, e.g. warfarin.
glucocorticoids, medicines used to treat inflammation or swelling, e.g. prednisolone
sulphonylureas, medicines used to lower blood sugar
methotrexate, medicine used to treat some types of cancer and arthritis
probenecid/ sulphinpyrazone, medicines used to treat gout
spironolactone/frusemide, medicines which lower blood pressure or increase volume of urine
rifampicin, medicine used to treat tuberculosis
azathioprine, medicine used to suppress the immune system
mercaptopurine or thioguanine, medicines used to treat leukaemia
lactulose or similar preparations, medicines which can change the acidity of the content of the bowels.

You may need to use different amounts of these medicines, or you may need to take different medicines when you are taking SALOFALK GRANULES. Your doctor or pharmacist will advise you.

How to take it

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

Adults and the elderly:
For acute ulcerative colitis, take 1.5 g to 3 g SALOFALK GRANULES modified release granules once a day or in 2-3 divided doses.

For long term treatment of ulcerative colitis, take 1.5 g SALOFALK GRANULES modified release granules once a day or in 2-3 divided doses.

Children over 6 years old:
The dose of SALOFALK GRANULES for your child depends on disease severity and body weight. Your doctor will tell you how much your child should take.

For acute ulcerative colitis, the usual dose for a child is 30-50 mg SALOFALK GRANULES modified release granules/kg/day in one single or 2-3 divided doses.

For long term treatment of ulcerative colitis, the usual dose for a child is 15-30 mg SALOFALK GRANULES modified release granules/kg/day in one single or 2 divided doses.

For some conditions, your doctor may prescribe a different dose.

How to take it

Tear open the sachet along the end with the triangular mark.
Pour contents of sachet onto tongue.

Swallow the modified release granules whole without chewing or crushing.
Drink some water to wash down the medicine.

When to take it

Take SALOFALK GRANULES the same time each day. This will help you remember when to take it.

How long to take it

SALOFALK GRANULES helps control your condition but does not cure it. Therefore, you must continue to take your medicine for as long as your doctor tells you to.

If you forget to take it

If you forget to take a dose of SALOFALK GRANULES, leave out that dose completely. Take your next dose at the normal time it is due.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take it, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much SALOFALK GRANULES. Do this even if there are no signs of discomfort or poisoning.

Possible symptoms of overdose may include feeling sick, vomiting and diarrhoea.

While you are taking it

Things you must do

Make sure that all of your doctors and pharmacists know you are taking SALOFALK GRANULES modified release granules. Remind them if any new medicines are about to be started.

Things that you must not do

Do not take this medicine to treat any complaint other than that directed by your doctor. It may not be safe to use it for another complaint.

Do not give your medicine to anyone else, even if they have the same condition as you. It may not be safe for another person to take it.

Do not stop taking your SALOFALK GRANULES modified release granules or change the dosage without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking SALOFALK GRANULES modified release granules.

Like all medicines, SALOFALK GRANULES may have some side effects. Most side effects are mild and may disappear without stopping it. However, some may be serious and need medical attention.

Mild effects:

Tell your doctor or pharmacist if you notice any of the following that are troublesome or ongoing:

headache
mild stomach pains
excessive gas in the stomach or bowel
increased number of bowel motions
diarrhoea
nausea (feeling sick)
rash or itchy skin
dizziness
common cold.

More serious effects:

Tell your doctor immediately if you notice any of the following:

fever, muscle aches and pains, painful joints and chest pain (sometimes spreading to the neck and shoulders, and sometimes fever)
mild skin rash, itching or hives
numbness or weakness of the arms and legs
pain in the upper belly (may be due to inflammation of the pancreas)
worsening of ulcerative colitis.

Stop taking SALOFALK GRANULES and contact your doctor or go to Accident and Emergency at your nearest hospital if any of the following happens:

allergic reaction including swelling of limbs, face, lips, mouth or throat which may cause difficulty in swallowing or breathing
Marked worsening of general health, especially if accompanied by fever and/or sore throat or mouth. Very rarely this can be due to a low white blood cell count (agranulocytosis), which may increase the risk of developing a serious infection.
Reddish non-elevated, target-like or circular patches on the trunk, often with central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes. These serious skin rashes can be preceded by fever and flu-like symptoms.

Other rare events, which have been reported with mesalazine, include:

changes in kidney function and inflammation of the kidney
changes in blood test results such as low white blood cell and/or platelet counts
changes in liver function tests
liver disease with nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine
changes relating to your heart
allergic, inflammatory or other lung conditions
shortness of breath, difficulty breathing, cough, wheezing, chest pain that worsens when breathing
increased sensitivity of the skin to sun and ultraviolet light (photosensitivity)
reversible decrease in semen production (oligospermia)
hair loss and the development of baldness (alopecia)
severe diarrhoea and abdominal pain due to an allergic reaction to this medicine (pancolitis).

Other events with unknown frequency, include:

kidney stones and associated kidney pain

As a precaution, your doctor may have your blood, liver and kidney tested regularly during treatment with this medicine.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking it

Storage

Keep SALOFALK GRANULES in their original package until it is time to take them. If you take them out of their packaging, they may not keep as well.

Keep this medicine in a cool dry place, protected from light where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep SALOFALK GRANULES where children cannot reach them. A locked cupboard at least one- and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

SALOFALK GRANULES are greyish-white cylindrical to round granules. This medicine is available in 4 different strengths, 500 mg, 1 g, 1.5 g and 3 g.

SALOFALK GRANULES 500 mg modified release granules are available in packs of 100 sachets.

SALOFALK GRANULES 1 g modified release granules are available in packs of 100 sachets.

SALOFALK GRANULES 1.5 g modified release granules are available in packs of 60 sachets.

SALOFALK GRANULES 3 g modified release granules are available in packs of 30 sachets.

Ingredients

Each SALOFALK GRANULES sachet contains 500 mg, 1 g, 1.5 g or 3 g of the active ingredient, mesalazine.

They also contain the following inactive ingredients:

microcrystalline cellulose
hypromellose
colloidal anhydrous silica
methacrylic acid copolymer (500 mg, 1 g, 1.5 g only)
magnesium stearate
simethicone
sorbic acid (1.5 g, 3 g only)
methylcellulose (1.5 g, 3 g only)
triethyl citrate
purified talc
carmellose sodium
aspartame
citric acid
vanilla custard flavour 75016-31 (PI 2187)
povidone
titanium dioxide.

Sponsor

Dr Falk Pharma Australia Pty
Ltd, 815 Pacific Highway,
Chatswood, NSW 2067

Australian Registration Numbers:

500 mg: AUST R 80648

1 g: AUST R 80649

1.5 g: AUST R 143611

3 g: AUST R 214810.

SALOFALK® is a registered trademark of Dr. Falk Pharma GmbH, Germany.

This leaflet was revised in December 2020.

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Salofalk Granules

Active ingredient

Mesalazine

Schedule

1 Name of Medicine

Salofalk Granules mesalazine modified release granules.

Mesalazine.

2 Qualitative and Quantitative Composition

Salofalk Granules modified release granules contain either 500 mg, 1 g, 1.5 g or 3 g mesalazine as the active ingredient.

Excipients of known effects.

Aspartame.
Sucrose.
See Section 4.4 Special Warnings and Precautions for Use.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Salofalk Granules modified release granules are presented as greyish white cylindrical or round granules. They have a functional coating on the particles, which ensures gastro-resistance to allow a reliable distribution and pH-dependent release of the active ingredient, mesalazine, at the intended site of action starting in the ileocaecal region. The granules also contain a matrix system inside the particle core, which releases mesalazine independently of pH.

4 Clinical Particulars

4.1 Therapeutic Indications

Salofalk Granules are indicated in the treatment of acute ulcerative colitis of mild to moderate severity, and for the maintenance of remission and/or the long-term treatment of ulcerative colitis.

4.2 Dose and Method of Administration

For adults and the elderly.

Unless otherwise prescribed, the recommended dose for acute ulcerative colitis is 1.5 g to 3 g/day. For maintenance of remission and/or long-term treatment of ulcerative colitis, the recommended dose is 1.5 g/day.

For children older than 6 years of age.

The recommended dose for acute ulcerative colitis, depending on disease severity, is 30-50 mg mesalazine/kg (bodyweight)/day. For maintenance of remission and/or long-term treatment of ulcerative colitis, the recommended dose is 15-30 mg mesalazine/kg (bodyweight)/day.
Doses may be given in one to three divided doses.
It is generally recommended that half the adult dose may be given to patients up to a bodyweight of 40 kg; and the normal adult dose to those above 40 kg.
Salofalk Granules should not be used in children below 6 years of age, as there is very limited experience with this age group.
Salofalk Granules should be swallowed without chewing or crushing with sufficient fluid. If granules are taken together with meals the gastric passage might be delayed for 1-2 hours, but does not influence the release profile or plasma concentrations of mesalazine.
Salofalk Granules should be taken on a regular basis and consistently, in the treatment of an acute inflammatory episode, in order to achieve the desired therapeutic effect. In general, an acute episode of ulcerative colitis usually subsides by 8 weeks.

4.3 Contraindications

Salofalk Granules and tablets are contraindicated in patients with the following:
hypersensitivity to salicylic acid, salicylic acid derivatives, e.g. mesalazine/5-ASA or to any of the other ingredients;
severe impairment of hepatic and renal function.

4.4 Special Warnings and Precautions for Use

Salofalk Granules should be taken under medical supervision.

Phenylketonuria.

In the case of phenylketonuria, it should be noted that Salofalk Granules contain aspartame as a sweetening agent, equivalent to the following quantities of phenylalanine. See Table 1.

Salofalk granules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take these medicines.

Use in pulmonary function impairment.

Mesalazine should be used/given with caution in patients with pulmonary function impairment, particularly asthma and in patients with known hypersensitivity to sulfasalazine containing preparations. Treatment in the latter patients should be instituted with careful medical supervision. Treatment should be discontinued immediately if symptoms of acute intolerance, e.g. cramps, acute abdominal pain, fever, severe headache and skin rash, occur.

Use in hepatic impairment.

Caution is recommended in patients with impaired hepatic function. Salofalk Granules are contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications).
As mesalazine might cause hepatic impairment due to hypersensitivity reactions, blood parameters, like blood counts and liver function and cholestasis parameters (e.g. ALT, AST, alkaline phosphatase, γGT) may be monitored like the renal parameters.

Blood dyscrasia.

Serious blood dyscrasias have been reported very rarely with mesalazine. Haematological investigations should be performed if patients suffer from unexplained haemorrhages, bruises, purpura, anaemia, fever or pharyngolaryngeal pain. Salofalk Granules should be discontinued in case of suspected or confirmed blood dyscrasia.

Epigastric pain.

Epigastric pain, also commonly associated with inflammatory bowel disease and prednisone or sulfasalazine therapy, should be investigated in order to exclude conditions such as pericarditis, hepatitis and pancreatitis either as adverse drug reactions to mesalazine or secondary manifestations of inflammatory bowel disease. Cardiac hypersensitivity reactions (myocarditis, and pericarditis) induced by mesalazine have been rarely reported. Salofalk Granules should then be discontinued immediately if any of these reactions occur.

Use in renal impairment.

Mesalazine is not recommended in patients with impaired renal function. The blood and renal status should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, checks are recommended 14 days after commencement of treatment, then a further 2 to 3 times at 4-weekly intervals. If the findings are normal, follow-up tests should be conducted every three months or immediately if additional signs of the disorder occur. To check renal function, it is recommended that levels of serum urea (BUN) and creatinine be determined as well as performing a urine sediment test. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment. If this is the case, Salofalk Granules should be discontinued immediately.

Nephrolithiasis.

Cases of nephrolithiasis have been reported with the use of mesalazine, including stones with mesalazine content. Ensure adequate fluid intake during treatment.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment. Salofalk Granules should be discontinued, at the first appearance of signs and symptoms of severe skin reaction, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

Idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving mesalazine. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances or tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of mesalazine should be considered.

Urine discoloration.

Mesalazine may produce red-brown urine discoloration after contact with sodium hypochlorite bleach (e.g. in toilets cleaned with sodium hypochlorite contained in certain bleaches).

Use in the elderly.

Specific clinical data in only elderly patients for mesalazine are not available, but mesalazine has been used in patients up to 75 years of age in clinical trials.

Paediatric use.

Salofalk Granules should not be used in children below 6 years of age, as there is very limited experience with this age group.

Effects on laboratory tests.

Not known to interfere with laboratory tests or physical diagnostic agents.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Studies to evaluate the potential interaction between Salofalk Granules and other drugs have not been performed. In common with other salicylates, interactions may occur during concomitant administration of mesalazine and the following drugs.

Coumarin type anticoagulants.

Possible potentiation of the anticoagulant effect action (increasing the risk of gastrointestinal haemorrhage).

Glucocorticoids.

Possible increase in undesirable gastric effects.

Sulphonylureas.

Possible increase in the blood glucose lowering effects.

Methotrexate.

Possible increase in toxic potential of methotrexate.

Probenecid/sulphinpyrazone.

Possible attenuation of the uricosuric effects.

Spironolactone/frusemide.

Possible attenuation of the diuretic effects.

Rifampicin.

Possible attenuation of the tuberculostatic effects.

Lactulose or similar preparations, which lower stool pH.

Possible reduction of mesalazine release from granules due to decreased pH caused by bacterial metabolism.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.
In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine, possible enhanced myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine should be taken into account.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility and reproductive performance were not impaired in rats treated orally with mesalazine prior to and during mating (both sexes) and throughout gestation and lactation (females) at doses up to 320 mg/kg/day, which is about the same as the maximal recommended clinical dose of Salofalk Granules on a body surface area basis.
(Category C)
There was no evidence of embryotoxicity or teratogenicity in rats and rabbits treated orally with mesalazine during the period of organogenesis at respective doses of up to 320 and 495 mg/kg/day representing about the same, and 3.5 times, the maximal recommended clinical dose of Salofalk Granules on a body surface area basis. Oral mesalazine does not show direct or indirect harmful effects with respect to parturition or postnatal development in animals.
Human data on use during pregnancy are limited. No adverse effect of mesalazine on pregnancy or on the health of the foetus/newborn child was shown. To date no other relevant epidemiologic data are available. In one single case after oral use of 2-4 g mesalazine per day during the 3^rd and 5^th months of pregnancy, renal failure in a neonate was reported. Salofalk Granules should only be used during pregnancy if the potential benefit outweighs the possible risk.
In rats, there were no adverse effects on dams or offspring from oral administration of mesalazine during late gestation and throughout lactation at doses up to 320 mg/kg/day which is about the same as the maximal recommended clinical dose of Salofalk Granules on a body surface area basis.
There has been a report of a patient receiving mesalazine suppositories during the lactation period. Twelve hours after the initial dose, the infant developed watery diarrhoea that disappeared on discontinuation of the mesalazine therapy but reappeared on rechallenge. There have been reports of mesalazine and of its metabolite N-acetyl-5-ASA found in breast milk. There is no experience with Salofalk Granules in lactating women. Salofalk Granules should not be used during lactation unless the likely benefit of treatment outweighs the potential hazard. If the infant develops diarrhoea, the treatment should be temporarily discontinued and further medical advice sought.

4.7 Effects on Ability to Drive and Use Machines

Mesalazine is not expected to affect the ability of patients to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.
The most frequent adverse reactions seen in clinical trials of Salofalk Granules are headache (3%), abdominal pain (4%), exacerbation of ulcerative colitis (2%), abnormal hepatic function (2%) and upper respiratory tract infection (1%).
In two clinical trials involving 550 patients with mild to moderate acute ulcerative colitis, tolerability was good. Table 2 shows the adverse events that occurred in at least 5% of patients in the clinical trials.

The following adverse events presented by body system have been reported in international postmarketing surveillance of all Salofalk Granules preparations including Salofalk Granules. In many cases, the relationship to Salofalk Granules treatment has not been established.
The common (≥ 1% to < 10%) adverse events were as follows.

Body as a whole - general disorders.

Headache.

Gastrointestinal system disorders.

Abdominal pain, diarrhoea, nausea and vomiting, dyspepsia, flatulence, exacerbation of ulcerative colitis.

Skin and appendages disorder.

Rash including pruritus, urticaria.
The following additional adverse events were classified as uncommon being reported in < 1% of patients.

Body as a whole - general disorders.

Fever, allergic reaction.

Central and peripheral nervous systems disorders.

Dizziness, paraesthesia, peripheral neuropathy.

Collagen disorders.

Lupus erythematosus syndrome (as observed for preparations with a similar chemical structure).

Gastrointestinal system disorders.

Acute pancreatitis, pancolitis, neonate diarrhoea.

Liver and biliary system disorders.

Hepatitis, increased liver enzyme values (transaminase activity), intrahepatic cholestasis, increased bilirubin, changes in pancreatic enzymes (lipase and amylase increased), eosinophil count increased.

Musculoskeletal system disorders.

Arthralgia, myalgia, myositis.

Myo-, endo-, pericardial and valve disorders.

Pericarditis, myocarditis, pericardial effusion.

Platelet, bleeding and clotting disorders.

Thrombocytopenia.

Red blood cell disorders.

Aplastic anaemia, haemolytic anaemia.

Reproductive system disorders.

Oligospermia (reversible).

Respiratory, thoracic and mediastinal disorders.

Allergic and fibrotic lung reactions, dyspnoea, cough, bronchospasm, pleural effusion, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis.

Skin and appendages disorders.

Alopecia, allergic exanthema, increased sweating.

Urinary system disorders.

Acute or chronic interstitial nephritis, renal insufficiency, renal failure, nephrotoxicity.

White cell and RES disorders.

Agranulocytosis, leukopenia, neutropenia, pancytopenia.
The following additional adverse events were classified as rare being reported in < 0.1% of patients.

Skin and appendages disorders.

Photosensitivity.
(More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema).
The following additional adverse events were classified as very rare being reported in < 0.01% of patients.

Liver and biliary system disorders.

Cholestatic hepatitis.
The frequency of the following adverse events is not known (i.e. cannot be estimated from the available data):

Urinary system disorders.

Nephrolithiasis (see Section 4.4 Special Warnings and Precautions for Use for further information).

Skin and subcutaneous tissue disorders SOC.

Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).
Severe cutaneous adverse reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see Section 4.4).

Nervous system disorders.

Idiopathic intracranial hypertension (see Section 4.4).

4.9 Overdose

There are limited data on overdosage (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity.
Possible symptoms may include nausea, vomiting and diarrhoea, and symptoms similar to salicylate overdose.
There is no specific antidote. General supportive and symptomatic measures are recommended.
For information on the management of overdosage, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mesalazine has been identified as the active component of sulfasalazine in inflammatory bowel disease and is thought to have a topical action. The mechanism of action by which mesalazine protects the mucosa in chronic inflammatory bowel disease is not yet fully known.
Mesalazine seems to act in multiple ways against several inflammatory mediators and principles. The results of in vitro investigations indicate that inhibition of lipoxygenase may play a role. Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated, as has an influence on leukotriene production. Mesalazine may also function as a radical scavenger of reactive oxygen compounds.

Clinical trials.

The criteria used to evaluate the efficacy of the substance in the therapy of ulcerative colitis are frequency of bowel movements, rectal haemorrhage, abdominal pain, general well being, temperature, extraintestinal manifestations, ESR, and haemoglobin. These criteria have been summarised in the clinical activity index (CAI) to evaluate the efficacy of treatment for ulcerative colitis.
The safety and efficacy of Salofalk Granules (1.5 g to 3 g mesalazine/day) was compared against mesalazine tablets (Salofalk 500 mg tablets, 1.5 g to 3.0 g mesalazine/day) in a double blind randomised multicentre study in 233 patients with mild to moderately active ulcerative colitis over a period of 8 weeks. The primary efficacy criterion, complete response rate (per protocol analysis, PP), was very similar in the granules (68%) and the tablets (70%) groups. The efficacy analysis (PP) showed that more patients treated with mesalazine tablets (47%) had to increase the dose from 1.5 g mesalazine/day to 3.0 g mesalazine/day compared to patients treated with granules (38%). Similar results were obtained by the ITT (intention to treat) analysis: 39% of the granules group, 45% of the tablets group, i.e. more patients came into remission (49%) with the 1.5 g mesalazine/day from granules than from tablets (43%). Granules, therefore, in total were as efficacious and as well tolerated as the tablets at the same dose. Subgroup analyses showed that the response rates to granules were higher in patients with high baseline disease activity (CAI > 8) and with 1 or more extraintestinal manifestations than the tablets (see Table 3).

In another study the efficacy and safety of Salofalk Granules of different dosages (1.5 g, 3.0 g, 4.5 g/day) were compared in 321 patients with mild to moderately active ulcerative colitis in a double blind manner for a treatment period of 8 weeks. Complete response (CAI ≤ 4) was obtained by 50% in the 1.5 g dose group, by 66% in the 3.0 g group (in comparison to 1.5 g: p = 0.014) and by 55% in the 4.5 g group (in comparison to 1.5 g: not significant, p = 0.318). The 3.0 g/day dose appears to be the optimal dose.
In a double blind, randomised comparative study, the efficacy and tolerability of once daily (o.d.) 3.0 g Salofalk Granules was compared with three time daily (t.i.d.) 1.0 g Salofalk Granules in 380 patients with active ulcerative colitis over a period of eight weeks. The data show that for Salofalk Granules, a daily dose of 3 g mesalazine given o.d. is therapeutically equivalent to the conventional t.i.d. dosage regimen for the induction of remission (CAI ≤ 4) in patients with mild to moderate ulcerative colitis. The clinical remission rate in the PP analysis set (primary analysis) was 84.4% in the o.d. group and 81.3% in the t.i.d. group. The resulting p-value for the noninferiority test (predefined margin: -15%) was 0.0007 with a 95% CI of (-11.4%, 17.6%). With the achieved lower boundary of the derived 95% CI of 3.1%, an even narrower margin for the noninferiority was kept. Remission rates in ITT analysis set were very similar, 80.8% in the o.d. group and 77.4% in the t.i.d. group. ITT test result (p = 0.0007) and 95% CI (-11.4%, 18.1%) agreed with the PP analysis. Once daily dosing of Salofalk Granules was as safe and well tolerated as three times daily dosing of Salofalk Granules.
Results of the various studies show that oral delayed release Salofalk Granules are well tolerated in patients with ulcerative colitis.

5.2 Pharmacokinetic Properties

General considerations.

The efficacy of mesalazine (5-ASA) appears to be determined not by the systemic but the local availability of the substance at the target site.
There is no pharmacokinetic data in the elderly using Salofalk Granules.

Absorption.

The systemic absorption of mesalazine decreases in the intestinal tract from proximal to distal segments. Because of low systemic absorption rates from oral delayed release preparations or rectal applications forms of mesalazine, the main elimination route is via faeces.

Distribution.

The plasma protein binding of mesalazine and acetylated mesalazine is 43% and 78%, respectively.

Metabolism.

Metabolism of mesalazine occurs mainly in the intestinal mucosa and to a lesser extent in the liver. The main metabolite is N-acetyl-5-aminosalicylic acid, similar to mesalazine this is predominantly eliminated by the renal and faecal routes. It appears to have no therapeutic activity or specific toxic effects. The acetylation step appears irreversible. As metabolism occurs mainly in the intestinal mucosa it has not been possible to differentiate between a rapid and slow acetylation form as in the case of sulfasalazine/sulfapyridine.

Excretion.

Systemically absorbed mesalazine and N-acetyl-5-ASA are eliminated mainly via kidneys.
Less than 1% mesalazine and about 24% N-acetyl-5-ASA based on the administered mesalazine dose are excreted in the urine. Biliary excretion is a minor route of elimination.

Salofalk Granules.

Salofalk Granules are gastric juice resistant and release mesalazine in the terminal ileal region in a pH dependent manner due to the Eudragit-L coating. The release of mesalazine from the granules is prolonged due to the matrix granule structure. Owing to the granule size, under starved condition transit from the stomach to the small intestine is fast (0.65 + 0.40 hours). For the granules, food intake may cause a shift of 1 to 2 hours to a longer t_lag value (lag time after which mesalazine concentrations are first detectable in blood plasma) and a longer t_max value, but does not cause dose dumping due to the small granule size. Food does cause a slight increase in C_max and AUC values.
Pharmacokinetic data are summarised in Table 4 for Salofalk Granules and Salofalk tablets (granules: 3 x 500 mg mesalazine/day, tablets: 3 x 2 (250 mg) mesalazine/day, steady-state conditions, 24 healthy volunteers).

The total quantity of mesalazine and N-acetyl-5-ASA eliminated by the renal pathway over 24 hours is equivalent to about 25% to 32%, respectively of the administered dose of Salofalk Granules and Salofalk tablets. About 30% of this amount is absorbed in the ileocaecal area and about 90% in total in the ileocaecal and ascending colon regions. Therefore, about 80 to 90% mesalazine of administered dose is available in the descending colon, sigmoid and rectum where absorption of mesalazine is low.
Granule and tablet preparations radiolabelled with ¹⁵³Sm (Samarium) showed the following gastrointestinal distribution (means ± S.D.) (see Table 5).

Plasma C_max values of mesalazine and Ac-5-ASA during steady state were about 1.4-fold and 1.2-fold higher after once daily dosing (o.d.) when compared to values obtained after dosing three times daily (t.i.d.) dosing of the same daily dose. Plasma trough levels at the end of the dosing interval were only slightly (0.3 and 0.4 times, mesalazine and Ac-5-ASA, respectively) lower after o.d. dosing when compared to that after t.i.d. dosing. There is no indication of systemic drug accumulation, when given o.d.
The administration of a single oral dose of Salofalk Granules, 20 mg/kg bodyweight, in 13 children with active colonic inflammatory bowel disease (IBD) (age range: 5.9 to 15.8 years) showed that the pharmacokinetics of systemic exposure in children corresponds with those in adults. Salofalk Granules was safe and well tolerated.

5.3 Preclinical Safety Data

Genotoxicity.

There was no evidence of genotoxic potential with mesalazine in bacterial gene mutation assays, of chromosomal damage in mouse haematopoietic cells following a single oral dose, or of increases in sister chromatid exchange frequencies in Chinese hamster bone marrow following a single intraperitoneal dose.

Carcinogenicity.

There was no evidence of carcinogenicity in rats treated with mesalazine in the diet for 127 weeks at doses up to 320 mg/kg/day, associated with plasma concentrations of mesalazine and N-acetyl-5-ASA of 1 and 6-fold the respective clinical plasma concentrations associated with a 1500 mg dose of Salofalk Granules.

6 Pharmaceutical Particulars

6.1 List of Excipients

Salofalk Granules 500 mg and 1 g granules contain the following excipients: microcrystalline cellulose, hypromellose, colloidal anhydrous silica, methacrylic acid copolymer, magnesium stearate, simethicone, triethyl citrate, purified talc, carmellose sodium, aspartame, citric acid, vanilla custard flavour 75016-32 (PI 2187, contains sucrose), povidone and titanium dioxide.
Salofalk Granules 1.5 g granules contain the following excipients: microcrystalline cellulose, hypromellose, colloidal anhydrous silica, methacrylic acid copolymer, magnesium stearate, simethicone, sorbic acid, methylcellulose, triethyl citrate, purified talc, carmellose sodium, aspartame, citric acid, vanilla custard flavour 75016-32 (PI 2187, contains sucrose), povidone and titanium dioxide.
Salofalk Granules 3 g granules contain the following excipients: microcrystalline cellulose, hypromellose, colloidal anhydrous silica, methacrylic acid copolymer, magnesium stearate, simethicone, sorbic acid, methylcellulose, triethyl citrate, purified talc, carmellose sodium, aspartame, citric acid, vanilla custard flavour 75016-32 (PI 2187, contains sucrose), povidone and titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Salofalk modified release granules are available in aluminium sachets of 500 mg, 1 g, 1.5 g or 3 g doses of mesalazine.
500 mg sachets are available in packs of 50, 100 or 300 sachets.
1 g sachets are available in packs of 50, 100 or 150 sachets.
1.5 g sachets are available in packs of 6, 60 or 100 sachets.
3 g sachets are available in packs of 6, 30 or 50 sachets.
Not all pack sizes are currently available in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Mesalazine is a white to greyish, voluminous powder, slightly pink in colour. It is practically insoluble in ethanol (90%), methanol (70%), water, ether, and chloroform, soluble in HCl (warmed 10% solution); soluble in NaOH (10% solution, with salt formation).
Proper name: 5-Aminosalicylic Acid, chemical name: 2-hydroxy-5-aminobenzoic acid, also referred to as 5-amino salicylic acid or 5-ASA. C₇H₇NO₃ = 153.1.

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