Consumer medicine information

Mezavant

Mesalazine

BRAND INFORMATION

Brand name

Mezavant

Active ingredient

Mesalazine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mezavant.

SUMMARY CMI

MEZAVANT®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using MEZAVANT?

MEZAVANT contains the active ingredient mesalazine. MEZAVANT is used for the treatment of ulcerative colitis.

For more information, see Section 1. Why am I using MEZAVANT? in the full CMI.

2. What should I know before I use MEZAVANT?

Do not use if you have ever had an allergic reaction to MEZAVANT or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use MEZAVANT? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MEZAVANT and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use MEZAVANT?

  • Your doctor will tell you what dose to take each day.
  • Take your tablets with or without food at the same time each day. The tablets must be swallowed whole and must not be crushed or chewed. Follow all directions given to you by your pharmacist or doctor carefully.

More instructions can be found in Section 4. How do I use MEZAVANT? in the full CMI.

5. What should I know while using MEZAVANT?

Things you should do
  • Remind any doctor or dentist you visit that you are using MEZAVANT. If you are pregnant or intend to become pregnant while using this medicine, tell the doctor immediately.
Things you should not do
  • Do not stop using this medicine suddenly or change the dosage without checking with your doctor.
Driving or using machines
  • MEZAVANT is unlikely to have any effect on your ability to drive or use machines.
Looking after your medicine
  • Store MEZAVANT in a cool dry place where the temperature is below 25°C.

For more information, see Section 5. What should I know while using MEZAVANT? in the full CMI.

6. Are there any side effects?

Common side effects include headache, tiredness, indigestion, mild stomach pains, excessive gas in the stomach or bowel, increased number of bowel motions, nausea, vomiting, rash or itchy skin, fever, loss of strength, muscle or joint or back pain.

Serious side effects include: Acute intolerance syndrome symptoms such as cramping, severe stomach pain, bloody and excessive stools (diarrhoea), fever, headache or rash. Unexplained bruising, rash, anaemia, sore throat, unusual bleeding. Allergic reaction. Severe pain in the back, side or stomach. Trouble urinating, pain or burning during urination. Increased blood pressure.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

MEZAVANT®

Active ingredient(s): mesalazine


Consumer Medicine Information (CMI)

This leaflet provides important information about using MEZAVANT. It does not take the place of talking to your doctor or pharmacist. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using MEZAVANT. The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available. You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on this medicine. You can also download the most up to date leaflet from www.takeda.com/en-au. Those updates may contain important information about the medicine and its use of which you should be aware.

Where to find information in this leaflet:

1. Why am I using MEZAVANT?
2. What should I know before I use MEZAVANT?
3. What if I am taking other medicines?
4. How do I use MEZAVANT?
5. What should I know while using MEZAVANT?
6. Are there any side effects?
7. Product details

1. Why am I using MEZAVANT?

MEZAVANT contains the active ingredient mesalazine (also called 5-aminosalicylic acid or 5-ASA).

MEZAVANT is an anti-inflammatory drug used for the treatment of ulcerative colitis. When MEZAVANT is taken for a flare up of ulcerative colitis, it acts through the entire colon and rectum to treat the inflammation and reduce symptoms. MEZAVANT can also be taken to help prevent re-occurrence of ulcerative colitis.

2. What should I know before I use MEZAVANT?

Warnings

Do not use MEZAVANT if:

  1. you are allergic to mesalazine, or any of the ingredients listed at the end of this leaflet.
  2. you are allergic to a family of drugs known as salicylates (which include aspirin).
  3. Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any kidney problems
  • have previously had inflammation of the heart (which may be the result of an infection in the heart)
  • have had a previous allergic reaction to MEZAVANT or other medicines containing mesalazine or sulphasalazine (other medicines taken for treatment of ulcerative colitis)
  • have narrowing or blockage of the stomach or the gut
  • have skin conditions such as atopic dermatitis or atopic eczema
  • have ever developed severe skin rash or skin peeling, blistering and/or mouth sores
  • have any other medical conditions or take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

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

Some medicines may interfere with MEZAVANT and affect how it works.

These include:

  • mesalazine or sulphasalazine (taken for treatment of ulcerative colitis)
  • non-steroidal anti-inflammatory drugs (for example medicines containing aspirin, ibuprofen or diclofenac)
  • azathioprine or 6-mercaptopurine (known as 'immunosuppressant' medicines).
  • warfarin (taken to prevent blood clots) or other coumarin-type anticoagulants

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MEZAVANT.

4. How do I use MEZAVANT?

How much to take

  • Adults and the elderly:
    The usual daily dose for adults and the elderly is 2.4g to 4.8g (two to four tablets) taken once a day for an acute episode of ulcerative colitis. If you are taking the highest daily dose of 4.8g/day, you should be evaluated after 8 weeks of treatment. Once your symptoms have cleared and to help prevent re-occurrence of another episode, your doctor may direct you to take 2.4g (two tablets) once a day.

Children and Adolescents:
MEZAVANT is not recommended to be given to children under 18 years of age due to lack of data on safety and efficacy.

  • Follow the instructions provided and use MEZAVANT until your doctor tells you to stop.

When to take MEZAVANT

  • Take MEZAVANT at the same time each day. It is important to take MEZAVANT every day for as long as your doctor tells you to, even when you don't have any symptoms of ulcerative colitis.

How to take MEZAVANT

  • MEZAVANT can be taken with or without food. The tablets must be swallowed whole and must not be crushed or chewed.

If you forget to use MEZAVANT

MEZAVANT should be used regularly at the same time each day. If you miss your dose at the usual time, then take them as usual the next day.

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

If you use too much MEZAVANT

If you think that you have used too much MEZAVANT, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using MEZAVANT?

Things you should do

  • make sure that all of your doctors, dentists, and pharmacists know you are taking MEZAVANT. Remind them if any new medicines are about to be started.
  • ensure adequate fluid intake during treatment.

Things you should not do

  • do not stop using this medicine suddenly or change the dosage without checking with your doctor.
  • do not give to children under 18 years of age. MEZAVANT is not suitable for children under 18 years of age as there is not enough information on its effects in children.
  • do not give MEZAVANT to anyone else, even if they have the same condition as you. It may not be safe for another person to take MEZAVANT.
  • do not take MEZAVANT to treat any other complaints unless your doctor tells you to. It may not be safe to use MEZAVANT for another complaint.

Driving or using machines

MEZAVANT is unlikely to have any effect on your ability to drive or use machines.

Looking after your medicine

Keep MEZAVANT tablets in the pack until it is time to take them. Store MEZAVANT in a cool dry place where the temperature stays below 25°C.

Do not store it in the bathroom or near a sink, or in the car or on windowsill.

Do not use this medicine after the expiry date.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • headache
  • tiredness
  • indigestion
  • mild stomach pains
  • bloating or passing wind
  • excessive gas in the stomach or bowel
  • increased number of bowel motions
  • nausea
  • vomiting
  • rash or itchy skin
  • fever
  • loss of strength
  • muscle, joint or back pain
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • if you experience symptoms such as cramping, severe stomach pain, bloody and excessive stools (diarrhoea), fever, headache or rash. These symptoms could be a sign of Acute Intolerance Syndrome which can happen during an acute episode of ulcerative colitis. This is a serious condition which occurs rarely, but means your treatment would have to be stopped immediately
  • if you develop unexplained bruising (without injury), rash, 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)
  • if you develop allergic swelling of face, eyes, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing.
  • widespread rash with blistering of the skin, particularly around the mouth, eyes and genitals
  • allergic skin rash with fever
  • severe pain in the back, side or stomach. Trouble urinating, pain or burning during urination. These could be symptoms of kidney stones
  • increased blood pressure
  • If you notice 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. Your treatment will need to be stopped immediately if you experience these serious conditions.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What MEZAVANT contains

Active ingredient
(main ingredient)
Mesalazine
Other ingredients
(inactive ingredients)
Carmellose sodium, carnauba wax, stearic acid, silicon dioxide, sodium starch glycollate, talc-purified, magnesium stearate, methacrylic acid copolymer, triethyl citrate, titanium dioxide (E171), iron oxide red (CI77491), Macrogol 6000

Do not take this medicine if you are allergic to any of these ingredients.

What MEZAVANT looks like

MEZAVANT 1.2 g tablet (AUST R 155172): Oval shaped red-brown tablets which are stamped with S476.

MEZAVANT is supplied as a 60 tablets pack size.

Who distributes MEZAVANT

Takeda Pharmaceuticals Australia Pty Ltd
Level 39, 225 George Street
Sydney NSW 2000
Australia
Phone: 1800 012 612
www.takeda.com/en-au

This leaflet was prepared in February 2021.

MEZAVANT® and the MEZAVANT Logo® are registered trademarks used under license from Nogra Pharma Limited.

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Mezavant

Active ingredient

Mesalazine

Schedule

S4

 

1 Name of Medicine

Mesalazine.

2 Qualitative and Quantitative Composition

Mezavant contains 1.2 g of the active ingredient mesalazine.
The Mezavant tablet contains a core of mesalazine (5-aminosalicylic acid), 1.2 g, formulated in a multi-matrix system. This system is coated with methacrylic acid copolymers, Type A and Type B, which are designed to dissolve at approximately pH 7. The matrix of lipophilic and hydrophilic excipients facilitates the extended delivery of effective concentrations of mesalazine through the entire colon with limited systemic absorption.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Gastro-resistant, prolonged release tablets.

Appearance.

The tablets are presented as red-brown, ellipsoidal, film-coated tablets, debossed on one side with S476.

4 Clinical Particulars

4.1 Therapeutic Indications

For the induction and maintenance of remission in patients with mild to moderate, active ulcerative colitis.

4.2 Dose and Method of Administration

Dosage.

Mezavant is intended for once daily, oral administration.

Adults, including the elderly (> 65 years).

For induction of remission: 2.4 to 4.8 g (two to four tablets) should be taken once daily.
For maintenance of remission: 2.4 g (two tablets) should be taken once daily.

Children and adolescents.

Mezavant is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.

Method of administration.

For oral administration. Mezavant tablets must not be crushed or chewed and should be swallowed whole with or without food.

Dosage adjustment.

Specific studies have not been performed to investigate Mezavant in patients with hepatic or renal impairment, dialysis or concomitant disease.

Monitoring advice.

The highest dose of 4.8 g/day is recommended for patients not responding to lower doses of mesalazine. When using the highest dose (4.8 g/day), the effect of the treatment should be evaluated at 8 weeks.

4.3 Contraindications

History of hypersensitivity to salicylates (including mesalazine) or any of the excipients of Mezavant.

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

The majority of patients who are intolerant or hypersensitive to sulfasalazine can take mesalazine preparations without risk of similar reactions. However, caution should be exercised when treating patients allergic to sulfasalazine.

Blood dyscrasias.

Following mesalazine treatment, serious blood dyscrasias have been reported rarely. If the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat, haematological investigations should be performed. If there is suspicion of blood dyscrasia, treatment should be terminated.

Acute intolerance syndrome.

Mesalazine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalazine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhoea, sometimes fever, headache and rash. If acute intolerance syndrome is suspected, prompt withdrawal is required and products containing mesalazine must not be reintroduced.

Cardiac hypersensitivity reactions.

Mesalazine induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely with Mezavant and other mesalazine containing-preparations. Caution should be used in prescribing this medication to patients with conditions predisposing to the development of myo- or pericarditis. If such hypersensitivity reaction is suspected, products containing mesalazine must not be reintroduced.

Severe cutaneous adverse reactions (SCARs).

SCARs such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment. Mesalazine should be discontinued, at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

Obstruction of upper GI tract.

Organic or functional obstruction in the upper gastrointestinal tract may delay onset of action of the product.

Photosensitivity.

Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions.

Use in hepatic impairment.

Caution is recommended if Mezavant is administered in patients with hepatic impairment.

Use in renal impairment.

Reports of renal impairment, including minimal change nephropathy, acute/ chronic interstitial nephritis and renal failure have been associated with preparations containing mesalazine and pro-drugs of mesalazine. For any patient with known renal dysfunction, the risk-benefit of mesalazine treatment should be considered and caution should be exercised in these patients. It is recommended that all patients have an evaluation of renal function prior to initiation of therapy and periodically whilst on treatment.

Use in the elderly.

The usual adult dose may be used (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Mezavant is not recommended for use in children below the age of 18 years due to lack of data on safety and efficacy.

Effects on laboratory tests.

Use of mesalazine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection, because of the similarity in the chromatograms of normetanephrine and mesalazine's main metabolite, N-5-acetylaminosalicylic acid (N-Ac-5-ASA). Consider an alternative selective assay for normetanephrine.

Nephrolithiasis.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

No investigations have been performed on interactions between Mezavant and other drugs. However, there have been reports of interactions between other mesalazine containing products and other drugs.
Caution is recommended for the concomitant use of mesalazine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) and azathioprine as these may increase the risk of renal adverse reactions.
Mesalazine inhibits thiopurine methyltransferase. In patients receiving azathioprine or 6-mercaptopurine and/or any other drugs known to cause myelotoxicity, caution is recommended for concurrent use of mesalazine as this can increase the potential for blood dyscrasias, bone marrow failure, and associated complications.
Administration with coumarin-type anticoagulants e.g. warfarin, could result in decreased anticoagulant activity. Prothrombin time should be closely monitored if this combination is essential.

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 up to 400 mg/kg/day (0.7 times the maximum recommended human dose based on a body surface area comparison). Semen abnormalities and infertility in men, which have been reported in association with sulfasalazine, have not been seen with other mesalazine products during controlled clinical trials.
(Category C)
Congenital malformations and other adverse outcomes (including one event of hydrops fetalis and foetal anaemia in one infant) were reported in infants born to mothers who were exposed to mesalazine during pregnancy. Mezavant should only be used during pregnancy if the benefits outweigh the risks.
Nonsteroidal anti-inflammatory drugs inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the fetal ductus arteriosus, fetal 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.
Oral administration of mesalazine during organogenesis in rats and rabbits at respective doses up to 1,000 and 800 mg/kg/day (2-3 fold the maximal recommended clinical dose of Mezavant on a body surface area basis) was associated with embryofetal toxicity and maternotoxicity. At a dose of 1,000 mg/kg/day in rats, fetuses showed enlarged brain ventricles. There was no evidence of embryotoxicity, maternotoxicity or teratogenicity in rats and rabbits treated orally with mesalazine during the period of organogenesis at doses up to about 500 mg/kg/day.
Mesalazine is excreted in breast milk at low concentration. Acetylated form of mesalazine is excreted in breast milk at higher concentration. Caution should be exercised if using mesalazine while breastfeeding and only if the benefit outweighs the risks. Sporadically acute diarrhoea has been reported in breastfed infants.
In rats, oral administration of mesalazine during late gestation and lactation at doses of 400 and 800 mg/kg/day (similar to the maximal recommended clinical dose of Mezavant on a body surface area basis) was associated with toxicity to dams and offspring. A dose of 320 mg/kg/day was devoid of toxicity in either generation.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Mezavant is considered to have negligible influence on these abilities.

4.8 Adverse Effects (Undesirable Effects)

Mezavant tablets have been evaluated in 664 ulcerative colitis patients in controlled and open label trials. In two 8 week placebo controlled clinical trials involving 535 ulcerative colitis patients, 356 received 2.4 g/day or 4.8 g/day Mezavant tablets and 179 received placebo. The majority of adverse events in the double blind, placebo controlled trials were mild or moderate in severity. The percentage of patients with severe adverse events was higher in the placebo group (6.1% in placebo; 1.1% in 2.4 g/day; 2.2% in 4.8 g/day). The most common severe adverse events were gastrointestinal disorders which were mainly symptoms associated with ulcerative colitis. Treatment related adverse events occurring at a frequency of at least 1% in the two double blind, placebo controlled trials are listed in Table 1.
In a pooled safety analysis of patients with active ulcerative colitis who participated in controlled studies, the majority of subjects did not experience treatment emergent adverse events associated with Mezavant. Of the events reported, the majority were transient, and mild or moderate in severity. The three most frequently reported adverse drug reactions within the pooled safety analysis of the ulcerative colitis patient clinical studies were headache, abdominal pain and nausea. The common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000) treatment related adverse events are listed in Table 2.
In postmarketing experience, the following adverse reactions have been reported. See Table 3.

Descriptions of selected adverse reactions.

Intracranial pressure increased.

Cases of increased intracranial pressure with papilledema (pseudotumor cerebri or benign intracranial hypertension) have been reported with mesalazine use. If undetected, this condition may result in constriction of the visual field and permanent vision loss. Mesalazine should be discontinued, if clinically possible, if this syndrome occurs.

Nephrogenic diabetes insipidus.

Cases of nephrogenic diabetes insipidus have been reported with mesalazine use.

Post-market data.

The following events have been identified during post-approval of mesalazine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalazine:

Hepatobiliary.

Reports of jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal.
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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia).
Mezavant is an aminosalicylate, and signs of salicylate toxicity include tinnitus, vertigo, headache, confusion, drowsiness, pulmonary oedema, dehydration as a result of sweating, diarrhoea and vomiting, hypoglycaemia, hyperventilation, disruption of electrolyte balance and blood pH and hyperthermia.
Conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. Hypoglycaemia, fluid and electrolyte imbalance should be corrected by the administration of appropriate therapy. Adequate renal function should be maintained.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism of action of mesalazine is not fully understood, but appears to have a topical anti-inflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalazine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.
Mesalazine has the potential to inhibit the activation of nuclear factor kappa B (NFκB) and consequently the production of key pro-inflammatory cytokines. More recently, it has been proposed that impairment of PPAR-γ nuclear receptors (γ-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. PPAR-γ receptor agonists have shown efficacy in ulcerative colitis and evidence has been accumulating that the mechanism of action of mesalazine may be mediated by PPAR-γ receptors.
The pharmacodynamic actions of mesalazine occur in the colonic/rectal mucosae local to the delivery of drug from Mezavant into the lumen. There is emerging information that severity of colonic inflammation in ulcerative colitis patients may be inversely correlated with mucosal concentrations of mesalazine. However, plasma concentrations representing systemically absorbed mesalazine are not believed to contribute extensively to efficacy.

Clinical trials.

In two similarly designed, Phase III, placebo controlled studies (Studies SPD476-301 and SPD476-302) in 623 randomised patients with mild to moderate, active ulcerative collitis (UC), Mezavant 2.4 g/day and 4.8 g/day achieved statistical superiority over placebo in terms of the number of patients achieving remission from UC after 8 weeks of treatment. Using a modified Ulcerative Colitis Disease Activity Index (UC-DAI), remission was defined as a UC-DAI score of < 1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in sigmoidoscopy score from baseline. Study 302, included a comparator, mesalazine delayed release (modified release/enteric coated) 2.4 g/day 3 times daily, as an internal reference arm. Table 4 summarises the results for the primary variable of remission in the two studies.
A randomised, open label extension study to studies 301 and 302 was designed to assess the long-term safety and tolerability of Mezavant 2.4 g/day administered once daily and in 2 divided doses (1.2 g twice daily) in the Maintenance of UC in remission over 12 months. This study (Study 303) included an 8-week Acute Extension Phase during which Mezavant 4.8 g/day was administered twice daily, and a 12-month Maintenance Phase during which Mezavant 2.4 g/day was administered either [1.2 g] twice daily or once daily. Efficacy was a secondary objective of this uncontrolled extension study.
The 12 month safety results from the SPD476-303 study are consistent with previously reported safety data. The efficacy endpoints were: time to relapse for the Maintenance phase; and the percentage of subjects in remission at the end of the study for the Acute and Maintenance phases.
Time to relapse was defined as the time at which a subject withdrew from the Maintenance Phase due to a requirement for alternative UC medication denoted by "Lack of Efficacy/Relapse". The proportion of subjects withdrawing due to a need for alternative UC medication in the Maintenance Phase Efficacy population was low. Both treatment groups had similar times to relapse for the duration of the Maintenance Phase. At 12 months (360 days), the proportion of subjects who had not relapsed was approximately 88% in the Mezavant 2.4 g/day once daily group and 92% in the Mezavant 2.4 g/day twice daily group.
Remission was defined as modified UC-DAI ≤ 1 with a score of 0 for rectal bleeding and stool frequency, and at least a 1-point reduction from parent study baseline in the sigmoidoscopy score. Overall 59.5% of subjects achieved remission at the end of the Acute Extension Phase (month 2). At month 12 of the Maintenance Phase, 64.4% of subjects in the Mezavant 2.4 g/day once daily group and 68.5% of subjects in the Mezavant 2.4 g/day twice daily group met the strict remission criteria; no statistically significant differences were observed between treatment groups.

5.2 Pharmacokinetic Properties

Absorption.

Gamma-scintigraphy studies have shown that a single dose of Mezavant 1.2 g passed rapidly and intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labelled tracer in the colon, indicating that mesalazine had spread throughout this region of the gastrointestinal tract.
The total absorption of mesalazine from Mezavant 2.4 g or 4.8 g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose.
In a single dose study, Mezavant 1.2 g, 2.4 g and 4.8 g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalazine were detectable after 2 hours and reached a maximum by 9 to 12 hours on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects (Table 5). Mesalazine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was slightly more than dose proportional between 1.2 g and 4.8 g Mezavant. Maximum plasma concentrations (Cmax) of mesalazine increased approximately dose proportionately between 1.2 g and 2.4 g and sub-proportionately between 2.4 g and 4.8 g Mezavant, with the dose normalised value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means.
Administration of a single dose of Mezavant 4.8 g with a high fat meal resulted in further delay in absorption and plasma concentrations of mesalazine were detectable 4 hours following dosing. However, a high fat meal increased systemic exposure of mesalazine (mean Cmax increased by 91%; mean AUC increased by 16%) compared to results in the fasted state. The observed differences in mesalazine exposure due to concomitant food intake are not considered to be clinically significant. Therefore, Mezavant can be taken without regard to food.
In a single and multiple dose pharmacokinetic study of Mezavant 2.4 g or 4.8 g was administered once daily with standard meals to 28 healthy volunteers per dose group. Plasma concentrations of mesalazine were detectable after 4 hours and were maximal by 8 hours after the single dose. Steady state was achieved generally by 2 days after dosing. The mean AUC at steady state was only modestly greater (1.1- to 1.4-fold) than predictable from single dose pharmacokinetics.

Distribution.

Following dosing of Mezavant, the distribution profile of mesalazine is presumed to be the same as that for other mesalazine containing products. Mesalazine has a relatively small volume of distribution of approximately 18 L, confirming minimal extravascular penetration of systemically available drug, which is consistent with the absence of any significant secondary pharmacology. Mesalazine is 43% bound to plasma proteins when in vitro plasma concentrations are 2.5 microgram/mL.

Metabolism.

The only major metabolite of mesalazine (5-aminosalicylic acid) is N-acetyl-5-aminosalicylic acid, which is pharmacologically inactive. Its formation is brought about by N-acetyltransferase (NAT) activity in the liver and in the cytosol of intestinal mucosal cells, principally by NAT-1. Although this enzyme is known to be subject to genetic polymorphism, NAT-1 genotypes have been shown not to be predictive of mesalazine efficacy or toxicity.

Excretion.

Elimination of mesalazine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation). However, there is also limited excretion of the parent drug in urine. Of the approximately 21% - 22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine at steady state after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid.

Special patient populations.

Geriatrics.

No pharmacokinetic information is available in patients who are 65 years or older.

Paediatrics.

No pharmacokinetic information is available in patients who are less than 18 years of age.

Gender.

No consistent effect of gender on Mezavant pharmacokinetics has been observed.

Renal insufficiency.

No pharmacokinetic information is available in patients with mild, moderate, and severe renal impairment.

Hepatic insufficiency.

No pharmacokinetic information is available for patients with hepatic impairment.

Race.

No pharmacokinetic information is available which examines Mezavant in different races.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxicity was observed in assays for bacterial gene mutation in vitro, mammalian cell sister chromatid exchange or chromosomal damage in vivo.

Carcinogenicity.

There was no evidence of carcinogenicity in mice or rats treated with mesalazine in the diet for two years at respective doses up to 2,000 and 480 mg/kg/day, associated with corresponding plasma exposures (AUC) of 8- and 3-fold clinical exposure at the maximum recommended dose of Mezavant.

6 Pharmaceutical Particulars

6.1 List of Excipients

Carmellose sodium, carnauba wax, stearic acid, silicon dioxide, sodium starch glycollate, talc-purified, magnesium stearate, methacrylic acid copolymer, triethyl citrate, titanium dioxide (E171), iron oxide red (CI77491), macrogol 6000. 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.
For interactions, please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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. Store in the original package.

6.5 Nature and Contents of Container

Container type.

Tablets are packed in polyamide/aluminium/PVC foil blister packs with aluminium push-through foil.

Pack size.

60 or 120 tablets.
Not all sizes may be marketed.

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

Formula.

C7H7NO3.

Chemical structure.


CAS number.

89-57-6.

Molecular weight.

153.14.
Mesalazine dissolves in dilute solutions of alkali hydroxides and in dilute hydrochloric acid. It is very slightly soluble in water and practically insoluble in acetone, alcohol, and ether. The pKa values are 2.3 and 5.8.

7 Medicine Schedule (Poisons Standard)

Poisons standard S4.

Summary Table of Changes