Consumer medicine information

Asacol

Mesalazine

BRAND INFORMATION

Brand name

Asacol

Active ingredient

Mesalazine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Asacol.

What is in this leaflet

This leaflet answers some common questions about ASACOL. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ASACOL against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

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

What ASACOL is used for

This medicine is used to treat and prevent further episodes of ulcerative colitis.

ASACOL contains the active ingredient mesalazine. This is an anti-inflammatory agent used to treat ulcerative colitis. Ulcerative colitis is a disease of the large bowel (colon) or back passage (rectum), in which the lining of the bowel becomes inflamed (red and swollen).

ASACOL acts locally at the site of inflammation (colon, rectum and terminal ileum) to reduce this inflammation.

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.

ASACOL is not addictive.

It is available only with a doctor`s prescription.

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

Before you take ASACOL

When you must not take it

Do not take ASACOL if:

  • you are allergic to mesalazine or any of the other ingredients of this medicine listed at the end of this leaflet. Patients who are intolerant to lactose should note that ASACOL contains a small amount of lactose. If your doctor has told you that you have intolerance to some sugars, contact your doctor before taking this medicine
  • you are allergic to salicylates (e.g. Aspirin)
  • you have severe liver problems
  • you have severe kidney problems.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Children and adolescents

The safety and effectiveness of ASACOL in this age group have not been established.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • any lung problems, e.g. asthma.
  • a liver disease.
  • a kidney disease.
  • suffered an allergy to sulphasalazine in the past.
  • ever had any heart problems such as inflammation of the heart muscle or heart sac. If you have had previous suspected mesalazine-induced allergic reactions, then ASACOL must not be taken.
  • an ulcer of the stomach or intestine, you should take ASACOL with care.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start taking ASACOL.

Taking other medicinces

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

ASACOL may interfere with the following types of medicines:

  • medicines affecting the immune system or anticancer drugs (e.g. azathioprine, or 6-mercaptopurine or thioguanine)
  • medicines that prevent the formation of blood clots (anticoagulants, e.g. warfarin).
  • Non-steroidal anti-inflammatory drugs (e.g. medicines containing aspirin, ibuprofen or diclofenac)

How to take ASACOL

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

If you do not understand the instructions on the packaging, ask your doctor or pharmacist for help.

How much to take

Usual dose: Adults (including the elderly)

To treat acute phases of ulcerative colitis your daily dose is 2.4 g once daily or in divided doses to 4.8 g in divided doses.

To prevent an episode of ulcerative colitis your daily dose is 1.6 g to 2.4 g once daily or in divided doses.

How to take it

This medicine must be swallowed whole preferably with some liquid. Do not chew, crush or break the tablets before swallowing them.

When to take it

ASACOL should be taken before meals.

How long to take it

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take the next dose as normal.

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 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 ASACOL. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking ASACOL

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ASACOL.

Before and while you are taking ASACOL, your doctor may want to monitor you from time to time to check that your liver, kidneys, blood and lungs are all right.

Tell any other doctors, dentists, and pharmacist that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Things you must not do

Do not take ASACOL to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ASACOL.

This medicine helps most people, with ulcerative colitis, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Stop taking ASACOL immediately and seek urgent medical advice

  • If you develop unexplained bruising (without injury), bleeding under your skin, purple spots or patches under your skin, anaemia (feeling tired, weak and looking pale, especially on lips, nails and inside of eyelids), fever (high temperature), sore throat or unusual bleeding (e.g. nose bleeds).
  • 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 shells in the stool, you should consult your doctor.
  • There have been a few reports of kidney stones. Drink plenty of water during treatment.

If you notice any of the following, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • sudden signs of allergic reactions such as rash, itching or hives, shortness of breath, wheezing, coughing, or swelling of limbs, face, lips, mouth, tongue or throat which may cause difficulty swallowing or breathing
  • severe stomach cramps and/or pain, bloody diarrhoea, fever, severe headache, skin rash and increased sensitivity of the skin to sun
  • rash with severe blisters and bleeding of the eyes, mouth, lips, nose and genitals.

Other rare side effects might include:

  • Changes in kidney function
  • Kidney stones
  • Changes in liver function
  • Changes in blood
  • Hair loss

As a precaution, your doctor may do blood tests to check if there are any changes in your blood, kidney or liver function.

Other side effects not listed above may also occur in some people.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

After taking ASACOL

Storage

Keep your tablets in the packaging until it is time to take them.

If you take the tablets out of the packaging they may not keep well.

Store below 25°C.

Do not store ASACOL 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 damage some medicines.

Keep it where children cannot reach it. 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

ASACOL 400 mg and 800 mg tablets are coated, reddish to brownish oblong tablets with a glossy to matt finish. They are supplied in packs of 60, 90 or 180 tablets. Not all pack sizes are marketed.

Ingredients

Each ASACOL 400 mg tablet contains 400 mg of the active ingredient, mesalazine.

Each ASACOL 800 mg tablet contains 800 mg of the active ingredient, mesalazine.

It also contains the following inactive ingredients:

  • lactose
  • sodium starch glycollate type A
  • magnesium stearate
  • purified talc
  • povidone
  • methacrylic acid copolymer
  • triethyl citrate
  • iron oxide yellow
  • iron oxide red
  • macrogol 6000

Distributor

ASACOL Tablets are supplied in Australia by:

Emerge Health Pty Ltd
Suite 3, 22 Gillman Street
Hawthorn East, VIC. 3123

ASACOL 400mg:
AUST R 261419

ASACOL 800mg:
AUST R 261420

This leaflet was prepared in May 2020.

ASACOL® is a registered trademark of Tillotts Pharma AG, Switzerland

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Asacol

Active ingredient

Mesalazine

Schedule

S4

 

1 Name of Medicine

Mesalazine.

2 Qualitative and Quantitative Composition

Asacol enteric coated tablets contain 400 mg or 800 mg mesalazine as the active ingredient as well as the following inactive excipients: lactose, sodium starch glycollate type A, magnesium stearate, purified talc, povidone, methacrylic acid copolymer, triethyl citrate, iron oxide yellow, iron oxide red, macrogol 6000.

3 Pharmaceutical Form

Asacol enteric coated tablets are reddish to brownish oblong tablets. Asacol consists of a tablet core which is coated with a copolymer providing the tablet a pH-dependent disintegration behaviour. Therefore Asacol tablets resist the acidic environment of the stomach and small intestine, whereas disintegration and drug release occurs from pH 7 onwards to ensure start of drug delivery at the target site, i.e. from the terminal ileum onwards.

4 Clinical Particulars

4.1 Therapeutic Indications

Asacol is indicated for the treatment of mild to moderate ulcerative colitis and maintenance of remission in adults.

4.2 Dose and Method of Administration

Dosage. Adults.

Ulcerative colitis.

Acute disease.

2.4 g per day taken once daily or in divided doses to 4.8 g per day taken in divided doses. The dosage can be adjusted in accordance with the response to treatment.

Maintenance therapy.

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

Elderly population.

The normal adult dose can be taken unless liver or renal function is severely impaired, see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use. No studies have been carried out in the elderly population.

Method of administration.

The tablets must be swallowed whole preferably with some liquid before food intake.
They must not be chewed, crushed or broken before swallowing.
If one or more doses have been missed, the next dose is to be taken as usual.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients of Asacol.
Known hypersensitivity to salicylates.
Severe liver impairment.
Severe renal impairment (GFR < 30 mL/min/1.73 m2).

4.4 Special Warnings and Precautions for Use

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, anaemia, persistent fever or sore throat), and patients should seek immediate medical advice. It is recommended that haematological investigations (differential blood count) are performed prior to initiation of Asacol and whilst on therapy, 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, in particular asthma, should be 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.

Intolerance to carbohydrates.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Nephrolithiasis.

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

Use in hepatic impairment.

There have been reports of increased liver enzyme levels in patients taking preparations containing mesalazine. Caution is recommended if Asacol is 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.

Use in renal impairment.

Urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. 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.
It is recommended that all patients have an evaluation of their renal function prior to initiation of Asacol therapy and repeatedly whilst on therapy. As a guideline, follow-up tests are recommended 14 days after commencement of treatment and then every 4 weeks for the following 12 weeks. 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.

Use in the elderly.

Use in 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 Contraindications.

Paediatric use.

As there is only limited documentation for an effect in children (age 6-18 years), administration in this age group is not recommended.

Effects on laboratory tests.

Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalazine.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 Special Warnings and Precautions for Use. 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.
Caution should be exercised when mesalazine is used concomitantly with other known nephrotoxic agents such as NSAIDs and azathioprine, because increased risk of renal adverse effects may occur.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalazine of up to 480 mg/kg/day (similar to the maximal recommended human dose of Asacol on a body surface area basis).
(Category C)
Mesalazine is known to cross the placental barrier, but available data are insufficient to assess the risk of adverse effects on either pregnancy or the health of the foetus/neonate. Nonsteroidal anti-inflammatory drugs inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the foetal ductus arteriosus, foetal renal impairment, inhibition of platelet aggregation, and delay labour and birth. Continuous treatment with nonsteroidal anti-inflammatory drugs during the last trimester of pregnancy should only be given on sound indications. During the last few days before expected birth, agents with an inhibitory effect on prostaglandin synthesis should be avoided.
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 foetus/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.
Oral administration of mesalazine to rats and rabbits during the period of organogenesis at doses up to 480 mg/kg/day (about one to two times the maximum recommended clinical dose of Asacol on a body surface area basis) did not cause embryofetal toxicity or teratogenicity in the presence of maternotoxicity.
Asacol should only be used during pregnancy if the potential benefit outweighs the possible risk.
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, breast-feeding should be discontinued.
In rats, oral administration of mesalazine from late gestation to weaning at doses of 480 mg/kg/day (similar to the maximal recommended clinical dose of Asacol on a body surface area basis) was associated with toxicity to dams and offspring. A dose of 120 mg/kg/day was devoid of toxicity in either generation.

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 Adverse Effects (Undesirable Effects)

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. Treatment related adverse effects in the Asacol group with the highest reporting rate were worsening of ulcerative colitis (3.6%), haematuria (2.9%), and ketonuria (2.1%). Table 1 enumerates treatment related adverse effects that occurred at a frequency of ≥ 1% in the Asacol and placebo treated groups. All adverse effects with Asacol 800 mg tablets were of mild to moderate severity. Discontinuations due to adverse effects occurred in 8.6% of patients in the Asacol group and in 21.3% of patients in the placebo group. Most of the drug related adverse effects that led to study drug discontinuation were related to worsening of ulcerative colitis.
Organ specific adverse effects 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.
Table 2 represents the frequency of adverse effects based on clinical trials and reports from international post-marketing surveillance for all preparations of Asacol, including tablets, suppositories and enemas. The frequency of some adverse effects cannot be reliably estimated due to the limitation of the reporting sources.
An unknown number of the above mentioned adverse effects are probably associated to the underlying IBD rather than Asacol/mesalazine medication. This holds true especially for gastrointestinal adverse effects, arthralgia, and alopecia.
To avoid blood dyscrasia resulting from developing bone marrow depression patients should be monitored with care, see Section 4.4 Special Warnings and Precautions for Use.
Under co-administration of mesalazine with azathioprine or 6-MP or thioguanine, life-threatening infection can occur, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Photosensitivity.

More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.

Reporting suspected adverse effects.

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

4.9 Overdose

There is little 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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mesalazine, also known as 5-aminosalicylic acid, 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.
Under trial conditions mesalazine inhibited the cyclooxygenase and thus, the release of thromboxane B2 and prostaglandin E2, but the clinical meaning of this effect is still unclear. Mesalazine inhibits the formation of platelet activating factor. Mesalazine is also an antioxidant; it has been shown to decrease formation of reactive oxygen compounds and to capture free radicals.

Clinical trials.

Induction of remission in mild-moderate ulcerative colitis.

Asacol 400 mg tablets.

A phase 3, multicentre, randomised, double-blind, double-dummy, placebo controlled study conducted in 53 centres across Japan between 2005 and 2007, compared the efficacy and safety of two doses of Asacol 400 mg tablets (2.4 g/day and 3.6 g/day, given in 3 equally divided doses) versus Pentasa 250 mg Tablets (2.25 g/day, given in 3 equally divided doses) and placebo, for the induction of remission in patients with mild to moderate active UC. Two hundred and twenty nine (229) patients aged 16 to 64 years were enrolled with initial UC Disease Activity Index (UC-DAI) of 3 to 8.
The primary efficacy endpoint was the reduction of the UC-DAI score from baseline to week 8 or at discontinuation. Secondary endpoints of remission rate and efficacy rates were assessed. See Table 3.
Reductions in UC-DAI score verified the superiority of the 3.6 g/day Asacol group to the Pentasa group, and non-inferiority of the 2.4 g/day Asacol group compared to the Pentasa group. The three active groups were also compared to placebo, but only the 3.6 g/day Asacol group demonstrated a statistically significant difference; group difference 2.7 (95% CI: 1.4, 3.9).
The remission rates were 30.3% in the 2.4 g/day Asacol group, 45.3% in the 3.6 g/day Asacol group, 28.6% in the 2.25 g/day Pentasa group, and 9.4% in the placebo group. The efficacy rates were 45.5% in the 2.4 g/day Asacol group, 64.1% in the 3.6 g/day Asacol group, 49.2% in the 2.25 g/day Pentasa group, and 28.1% in the placebo group.

Asacol 800 mg tablets.

A multi-national, multicentre, randomised, placebo-controlled, double-blind phase III study was conducted by Tillotts Pharma in 26 study centres in the Ukraine, Belarus, India, and Turkey to determine the efficacy of Asacol 4.8 g/day (3 x 800 mg tablets, given twice a day) to induce remission after 6 weeks of treatment compared to placebo in patients with mild to moderate UC.
The initial primary efficacy endpoint (as per FDA Guidelines) of the proportion of patients achieving clinical and endoscopic remission at week 6 was modified prior to the unblinding of treatment allocation in order to be consistent with the European Guideline which defined clinical remission (UC-DAI; score of 0 for stool frequency and rectal bleeding and absence of urgency) at week 6 as the only primary efficacy endpoint for the analysis. Endoscopic remission (sigmoidoscopic score of ≤ 1 at week 6) was added as a new secondary endpoint.
For the ITT population clinical remission (primary endpoint) at week 6 was achieved in 42 (30.0%) of the subjects who received Asacol 800 mg tablets and 29 (20.68%) of the subjects who received placebo (p = 0.069; 95% CI of the between group difference = [-0.7%, 19.43%]). The difference between Asacol 800 mg tablets and placebo did not meet the pre-set significance level of p < 0.05 for clinical remission, however, all pre-specified secondary endpoints were met.
For the ITT population week 6 endoscopic remission was achieved in 64 (45.7%) of the subjects who received Asacol 800 mg tablets and 35 (24.8%) of the subjects who received placebo (p < 0.001; 95% CI: 9.7%, 31.3%). Endoscopic remission at week 10 was achieved in 73 (52.1%) of the subjects who received Asacol 800 mg tablets and 52 (36.9%) of placebo-treated subjects (p = 0.010; CI: 3.6%, 26.3%). Clinical remission at week 10 was achieved in 57 (40.7%) of the subjects who received Asacol 800 mg tablets and 30 (21.3%) of placebo-treated subjects (p < 0.001; 95% CI: 8.6%, 29.6%).
A secondary post-hoc analysis was also conducted, in which data form India (identified as the outlier country) were excluded. This reanalysis showed a statistical significant result (p = 0.02) for the primary endpoint; clinical remission at week 6. All secondary endpoints apart from the modified UC-DAI score at week 6 were statistically significant. The results of the secondary endpoints were similar to what was observed with the ITT population, where all secondary endpoints were statistically significant.

Maintenance of remission in mild-moderate ulcerative colitis.

A multi-centre, randomised, double-blind study was conducted to verify the non-inferiority of Asacol 400 mg tablets (2.4 g/day, given in 3 equally divided doses) to Pentasa 250 mg Tablets (2.25 g/day, given in 3 equally divided doses) for the maintenance of remission in patients with mild to moderate UC. The primary endpoint was the proportion of patients without bloody stools.
One hundred and thirty one (131) outpatients aged 16 to 64 years with quiescent UC (UC-DAI ≤ 2) 2 and a bloody stool score of 0 were included. Over a period of 48 weeks, the two groups were administered either Asacol 2.4 g/day (n = 65) or Pentasa 2.25 g/day (n = 66). A total of 34 patients withdrew from the study. The most frequent reason for withdrawal was relapse of UC based on the discontinuation criteria of a bloody stool score of 1 or more and UC-DAI of 3 or more (Asacol, 10; Pentasa, 13), and the second most common reason was the occurrence of AEs (Asacol, 1; Pentasa, 3).
The proportion of patients without bloody stools after the 48 week treatment period was 76.9% in the Asacol group and 69.2% in the Pentasa group. The difference between the two groups was 7.7% (95% CI: -7.4, 22.8), and the lower limit of CI was more than "-10.0%", the critical value for demonstration of predetermined non-inferiority. The hazard ratio for time to bloody stools was 0.690 (95% CI: 0.353, 1.350). There was no significant difference in the results of the log-rank test between the two groups (p = 0.27), but the time to bloody stools (secondary endpoint) tended to be longer in the Asacol group in comparison with the Pentasa group.
The proportion of patients without relapse was 80.0% in the Asacol group and 79.7% in the Pentasa group. The time to relapse was prolonged in the Asacol group compared to the Pentasa group, but the difference was not statistically significant (p = 0.79). The decrease in UC-DAI at the final assessment was -0.8 in the Asacol group and -0.9 in the Pentasa group, respectively, and the difference between the two groups was not significant.

5.2 Pharmacokinetic Properties

Absorption.

Asacol 400 mg tablets.

After administration of a single dose of 2.4 g mesalazine (as 6 Asacol 400 mg tablets) to healthy volunteers under fasting conditions, quantifiable amounts (> 2.00 nanogram/mL) of mesalazine were observed in plasma after 4.5 h (median tlag). The geometric mean Cmax - value of mesalazine was 722.11 nanogram/mL with a median tmax of about 9.5 h, whereas that of N-acetyl mesalazine was 1437.90 nanogram/mL with a median tmax 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.
The same study showed that when administered with concomitant food intake, 6 Asacol 400 mg tablets (2.4 g mesalazine as a single dose) resulted in quantifiable amounts of mesalazine after 9.0 h (median tlag). The geometric mean Cmax - value of mesalazine was 1725.93 nanogram/mL with a median tmax of about 22.0 h, whereas that of N-acetyl mesalazine was 2235.32 nanogram/mL with a median tmax of 24.0 h.
Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after oral administration under fed conditions approximately 30% of the dose (about 90% as metabolite) was excreted renally within 60 h.
Mesalazine Cmax-values increased 2.39-fold under fed conditions, and the extent of exposure (AUC0-tlast) increased 1.57-fold. Under the same conditions, N-acetyl mesalazine Cmax-values increased 1.55-fold, whereas the extent of exposure only increased by about 1.1-fold.

Asacol 800 mg tablets.

After administration of a single dose of 2.4 g mesalazine (as 3 Asacol 800 mg tablets) to healthy volunteers under fasting conditions, quantifiable amounts (> 2.00 nanogram/mL) of mesalazine were observed in plasma after 4.5 h (median tlag). The geometric mean Cmax-value of mesalazine was 387.86 nanogram/mL with a median tmax of 14.0 h, whereas that of N-acetyl mesalazine was 971.09 nanogram/mL with an identical median tmax, i.e. 14.0 h.
Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after oral fasted administration approximately 23% of the dose (more than 95% as metabolite) was excreted renally within 60 h.
The same study showed that when administered with concomitant food intake, 3 Asacol 800 mg tablets (2.4 g mesalazine as a single dose) resulted in quantifiable amounts of mesalazine after 14.5 h (median tlag). The geometric mean Cmax-value of mesalazine was 653.56 nanogram/mL with a median tmax of about 30.0 h, whereas that of N-acetyl mesalazine was 1245.46 nanogram/mL with a median tmax of 30.0 h.
Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after oral administration under fed conditions, approximately 23% of the dose (more than 95% as metabolite) was excreted renally within 60 h.
Mesalazine Cmax-values increased 1.69-fold, and the extent of exposure (AUC0-tlast) increased 1.23-fold. Under the same conditions, N-acetyl mesalazine Cmax-values increased 1.28-fold, whereas the extent of exposure remained practically unchanged.

Distribution.

Asacol 400 mg tablets.

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 (Vdw) was 59.07 L/kg (geometric mean: 48.86 L/kg) after a single dose of 2.40 g of mesalazine (6 Asacol 400 mg tablets) 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).

Asacol 800 mg tablets.

About 43% mesalazine and about 78% N-acetyl mesalazine are bound to plasma proteins. Approximately 77% of the administered dose remains in the gut lumen and the mucosal tissue. The mean apparent volume of distribution per kg of body weight (Vdw) was 147.73 L/kg (geometric mean: 76.06 L/kg) after a single dose of 2.40 g of mesalazine (3 Asacol 800 mg tablets) in healthy volunteers under fasting conditions. Based upon the absorption of 23.2% of the administered dose, this parameter is equal to 34.27 L/kg (geometric mean: 17.65 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.

Metabolism.

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.

Excretion.

Asacol 400 mg tablets.

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 Asacol 400 mg tablets) in healthy volunteers under fasting conditions was about 135 L/h (geometric mean, CV% = 61.43%, inter-subject). 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%).

Asacol 800 mg tablets.

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 (3 Asacol 800 mg tablets) in healthy volunteers under fasting conditions was about 318 L/h (geometric mean, CV% = 137.67%, inter-subject). The median elimination half-life was 17 h ranging from 10 to 50 h.
About 23% 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 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 Cmax and the combined plasma AUC values, there was a linear dose response for the 3 Asacol tablet doses. The clinical performance of Asacol 400 mg tablets should be similar for the range of doses evaluated in this study.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxicity was observed with mesalazine in assays for bacterial gene mutation in vitro, mammalian cell sister chromatid exchange, chromosomal aberrations in Chinese hamster ovary cells in vitro, or chromosomal damage in vivo.

Carcinogenicity.

There was no evidence of carcinogenicity in rats or mice treated with mesalazine in the diet for two years at respective doses up to 480 and 2000 mg/kg/day. In rats, estimated respective exposures (plasma AUC) of mesalazine and its metabolite N-acetyl-5-aminosalicyclic acid were about 4- and 2.5-fold the corresponding clinical exposures at the maximum recommended dose of Asacol. In mice, the highest dose tested was about twice the maximum recommended human dose on a body surface area basis.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

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

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Asacol 400 mg: store below 25°C.
Asacol 800 mg: store below 25°C.

6.5 Nature and Contents of Container

Asacol 400 mg / 800 mg tablets are available in PVC/aluminium blister strips, each containing ten tablets. Asacol tablets are presented as coated, reddish to brown oblong tablets with a glossy to matt finish.
The blister strips are packed in cartons containing either 60, 90 or 180 tablets. Not all pack sizes may be marketed.
Asacol 400 mg: AUST R 261419.
Asacol 800 mg: AUST R 261420.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Formula: C7H7NO3. Molecular weight: 153.1.

CAS number.

89-57-6.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes