Mezavant XL 1200mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Mesalazine
Available from:
CST Pharma Ltd
ATC code:
A07EC02
INN (International Name):
Mesalazine
Dosage:
1.2gram
Pharmaceutical form:
Modified-release tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 01050100; GTIN: 5055946807195

PACKAGE LEAFLET: INFORMATION FOR THE USER

Mezavant® XL 1200mg, gastro-resistant, prolonged release tablets

(mesalazine)

This medicine is available as above name but will be referred to as Mezavant XL throughout the

following leaflet.

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

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

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

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Mezavant XL is and what it is used for

2. What you need to know before you take Mezavant XL

3. How to take Mezavant XL

4. Possible side effects

5. How to store Mezavant XL

6. Contents of the pack and other information

1. WHAT MEZAVANT XL IS AND WHAT IT IS USED FOR

Pharmacotherapeutic group: Aminosalicylic acid and similar agents.

Mezavant XL gastro-resistant, prolonged release tablets contain the active substance mesalazine,

which is an anti-inflammatory drug for the treatment of ulcerative colitis.

Ulcerative colitis is a disease of the colon (large bowel) and rectum (back passage), where the lining

of the gut becomes red and swollen (inflamed) resulting in symptoms of frequent and bloody stools

together with stomach cramps.

When given for an acute episode of ulcerative colitis, Mezavant XL acts through the entire colon and

rectum to treat the inflammation and reduce symptoms. The tablets can also be taken to help prevent

reccurrence of ulcerative colitis.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE MEZAVANT XL

Do not take Mezavant XL

If you are allergic (hypersensitive) to a family of drugs known as salicylates (which include aspirin)

If you are allergic (hypersensitive) to mesalazine or any of the other ingredients of this medicine

(listed in section 6 of this leaflet)

If you have severe kidney or severe liver problems

Warnings and precautions

Talk to your doctor before using Mezavant XL

If you have any kidney or liver problems

If you have previously had inflammation of the heart (which may be the result of an infection in the

heart)

If you have had a previous allergic reaction to sulphasalazine (another medicine used to treat

ulcerative colitis)

If you have narrowing or blockage of the stomach or the gut

If you have lung problems

Before and periodically during treatment with Mezavant XL, your doctor may take samples of your

urine and blood to check that your kidneys and liver are working well and that your blood is healthy.

Children and adolescents

Mezavant XL is not recommended to be given to children under 18 years of age due to lack of data on

safety and efficacy.

Other medicines and Mezavant XL

Studies have shown that Mezavant XL does not interfere with the following antibiotics, used to treat

infections: amoxicillin, metronidazole or sulfamethoxazole.

However, Mezavant XL may interact with some other medicines. Tell your doctor or pharmacist if you

are taking, have recently taken or might take any other medicines.

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 which reduce the

activity of your body’s immune system).

Coumarin-type anticoagulants (medicines which increase the time it takes for your blood to clot)

e.g. warfarin

Mezavant XL with food and drink

Mezavant XL should be taken with food at the same time each day. The tablets should be swallowed

whole and must not be crushed or chewed.

Pregnancy and breast-feeding

Since mesalazine crosses the placenta in pregnancy and is excreted in breast milk in small quantities,

due care should be taken if using Mezavant XL in pregnancy or whilst breast-feeding.

If you are pregnant or breast feeding, think you might be pregnant or are planning to have a baby ask

your doctor for advice about taking Mezavant XL.

Interference with laboratory tests

If you are undergoing urine tests, it is important to tell the doctor or nurse you are taking, or have

recently taken this medicine as it can affect some results.

Driving and using machines

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

3. HOW TO TAKE MEZAVANT XL

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if

you are not sure.

The recommended dose for adults 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 treatment. Once your symptoms have cleared and to help prevent

reoccurrence of another episode, your doctor should direct you to take 2.4g (two tablets) once a day.

Remember to take your tablets at the same time each day with food. The tablets should be swallowed

whole and must not be crushed or chewed.

Whilst taking this medicine ensure you drink fluids to remain well hydrated especially after severe or

prolonged episodes of vomiting and/or diarrhoea, high fever or heavy sweating.

Mezavant XL is not recommended to be given to children under 18 years of age due to lack of data on

safety and efficacy.

If you take more Mezavant XL than you should

If you take too much Mezavant XL you may have one or more of the following symptoms: tinnitus

(ringing in ears), dizziness, headache, confusion, drowsiness, shortness of breath, excess loss of

water (associated with sweating, diarrhoea and vomiting), low blood sugar (which can cause light-

headedness), rapid breathing, changes in the blood chemistry and increased body temperature.

If you do take too many tablets, contact your doctor, pharmacist or hospital casualty department

straight away. Take your tablet pack with you.

If you forget to take Mezavant XL

It is important to take your Mezavant XL tablets every day, even when you don’t have any symptoms

of ulcerative colitis. Always finish the prescribed course.

If you forget to take your tablets then take them as usual the next day. Do not take a double dose to

make up for a forgotten tablet.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Tell your doctor immediately

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 tongue, lips and around eyes

If you develop increased pressure in brain causing headache which may originate behind your eyes

and worsen with eye movements, with blurred or dimmed vision, double vision, seeing light flashes,

difficulty seeing to the side, and brief or permanent vision loss. These may be associated with

dizziness, nausea, vomiting, ringing in ears

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Common side effects, occurring in less than 1 in 10 patients are: headache; changes in blood

pressure, flatulence (passing wind); nausea (feeling sick); bloated or painful stomach; inflammation

which causes abdominal pain or diarrhoea; diarrhoea; indigestion; vomiting (being sick); abnormal

liver function test; itching; rash, joint pain; back pain; weakness, fatigue (feeling extremely tired); fever

(high temperature).

Uncommon side effects, seen in less than 1 in 100 patients are: a reduction in blood platelets which

increases the risk of bleeding and bruising; dizziness; feeling sleepy or tired; trembling or shaking; ear

pain; racing heartbeat; throat pain; an inflamed pancreas (associated with pain in upper abdomen and

back and feeling sick); rectal polyp (a non-cancerous growth in the back passage causing symptoms

such as constipation and bleeding); acne; hair loss; muscle pain; hives; swollen face.

Rare side effects, seen in less than 1 in 1000 patients are: kidney failure; severe reduction in the

number of white blood cells that makes infection more likely

; increased sensitivity of your skin to sun

and ultraviolet light (photosensitivity).

The following side effects have been reported but it is not known exactly how often they occur:

Severe reduction in blood cells which can cause weakness or bruising; low blood cell counts; allergic

reaction (hypersensitivity); serious allergic reaction which causes difficulty in breathing or dizziness;

serious illness with blistering of the skin, mouth, eyes and genitals; allergic reaction which causes skin

rash, fever and inflammation of internal organs; neuropathy (abnormal or damaged nerves giving a

sensation of numbness and tingling); inflammation of the heart and lining around the heart;

inflammation of the lung; difficulty in breathing or wheezing; gall stones; hepatitis (inflammation of the

liver giving rise to flu-like symptoms and jaundice); allergic swelling of tongue, lips and around eyes;

skin redness; skin rash typically on face, skin sensitivity to sunlight along with joint pain, arthritis,

fatigue and overall feeling sickness; kidney problems (such as inflammation and scarring of the

kidney),

reversible decrease in sperm production.

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this

leaflet.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard

or search for MHRA Yellow Card in the Google Play or Apple App

Store. By reporting side effects, you can help provide more information on the safety of this medicine.

5. HOW TO STORE MEZAVANT XL

Keep out of the sight and reach of children

Do not store above 25°C. Store in the original package in order to protect from moisture.

Do not use this medicine after the expiry date which is stated on the box after “EXP”. The expiry

date refers to the last day of the month

Do not throw away any medicines via waste water or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help to protect the environment.

If the tablets become discoloured or show any other signs of deterioration, you should seek the

advice of your pharmacist who will tell you what to do.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Mezavant XL contains

The active substance is mesalazine.

Each tablet contains 1200mg mesalazine.

The other ingredients are: carmellose sodium, carnauba wax, stearic acid, colloidal hydrated silica,

sodium starch glycolate (Type A), talc, magnesium stearate, methacrylic acid – methyl methacrylate

copolymer (1:1), methacrylic acid – methyl methacrylate copolymer (1:2), triethyl citrate, titanium

dioxide (E171), red iron oxide (E172) and macrogol 6000.

What Mezavant XL looks like and contents of the pack

Mezavant XL is a red-brown, oval shaped tablet marked ‘S476’ on one side and plain on reverse.

Mezavant XL is supplied in foil blister strips which are contained in a cardboard box.

The pack contains 60 or 120 tablets.

PL: 15814/1344

POM

Manufactured by Cosmo SpA, Via C. Colombo 1, 20020 Lainate-Milan, Italy.

Procured from within the EU and repackaged by the Product Licence holder: O.P.D. Laboratories Ltd.,

Unit 6 Colonial Way, Watford, Herts WD24 4PR.

Leaflet revision and issue date (ref): 10.05.2019.

Mezavant is a registered trademark of Nogra Pharma Limited, Ireland.

Detailed information on this medicine is available on the website of: www.mhra.gov.uk.

To request a copy of this leaflet in Braille, large print or

audio please call 01923 332 796.

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Mezavant XL 1200mg, gastro-resistant, prolonged release tablets.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1200mg mesalazine.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Gastro-resistant, prolonged release tablets.

Red-brown, ellipsoidal, film-coated tablet, debossed on one side with S476.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

For the induction of clinical and endoscopic remission in patients with mild to

moderate, active ulcerative colitis. For maintenance of remission.

4.2

Posology and method of administration

Mezavant XL is intended for once daily, oral administration. The tablets must not be

crushed or chewed and should be taken with food.

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. The highest dose of 4.8g/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.

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

Children and adolescents

Mezavant XL is not recommended for use in children below the age of 18 years due

to a lack of data on safety and efficacy.

Specific studies have not been performed to investigate Mezavant XL in patients with

hepatic or renal impairment (see sections 4.3 and 4.4).

4.3

Contraindications

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

excipients of Mezavant XL.

Severe renal impairment (GFR <30 ml/min/1.73 m

) and/or severe hepatic

impairment.

4.4

Special warnings and precautions for use

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. Mezavant should be used with

caution in patients with confirmed mild to moderate renal impairment. It is

recommended that all patients have an evaluation of renal function prior to initiation

of therapy and at least twice a year, while on treatment.

Patients with chronic lung function impairment, especially asthma, are at risk of

hypersensitivity reactions and should be closely monitored.

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 (see sections 4.5 and 4.8).

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

been reported rarely with Mezavant and with 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.

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 sulphasalazine. 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.

There have been reports of increased liver enzyme levels in patients taking

preparations containing mesalazine. Caution is recommended if Mezavant is

administered to patients with hepatic impairment.

Caution should be exercised when treating patients allergic to sulphasalazine due to

the potential risk of cross sensitivity reactions between sulphasalazine and

mesalazine.

Organic or functional obstruction in the upper gastrointestinal tract may delay onset

of action of the product.

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

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

intake during treatment.

This medicine contains less than 1 mmol sodium (23 mg) per the maximum

recommended dose (4 tablets), that is to say essentially ‘sodium-free’.

Interference with Laboratory Tests

Use of mesalazine may lead to falsely 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-acetylaminosalicylic acid (N-Ac-5-ASA). An alternative, selective

assay for normetanephrine should be considered.

4.5

Interaction with other medicinal products and other forms of interaction

Drug-drug interaction studies in healthy adult subjects have been conducted with

Mezavant to investigate any effect of Mezavant on the pharmacokinetics and safety of

three commonly used antibiotics. There were no clinically significant interactions of

Mezavant with amoxicillin, metronidazole or sulfamethoxazole.

However, the following drug-drug interactions have been reported for products

containing mesalazine.

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 active substances 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 (see sections 4.4 and 4.8).

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.

Mezavant is recommended to be administered with food (see sections 4.2 and 5.2).

4.6

Fertility, pregnancy and lactation

Pregnancy

There is limited experience with mesalazine in pregnancy. Mesalazine crosses the

placental barrier, but provides foetal concentrations much lower than those seen with

adult therapeutic use. Animal studies do not indicate harmful effects of mesalazine in

pregnancy, embryonal/foetal development, parturition or postnatal development.

Adverse outcomes (including disturbances in blood counts such a leukopenia,

thrombocytopenia, and anemia) were reported in infants born to mothers who were

exposed to mesalazine during pregnancy. Mesalazine should be used during

pregnancy only when the benefits outweigh the risks. Caution should be exercised

when using high doses of mesalazine.

Breast-feeding

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 breast-feeding and only if the benefit outweighs

the risks. Sporadically acute diarrhoea has been reported in breast fed infants.

Fertility

Data on mesalazine show no sustained effect on male fertility.

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

Undesirable effects

The most frequently reported adverse drug reactions (ADRs) within the pooled

safety analysis of clinical studies with Mezavant, including 3,611 patients,

were

colitis

(including

ulcerative

colitis)

5.8%,

abdominal

pain

4.9%,

headache 4.5%, liver function test abnormal,

2.1%, diarrhoea 2.0%,

nausea 1.9%.

Adverse reactions are listed by System Organ Class (see table below). Within

each

system

organ

class,

adverse

reactions

listed

under

headings

frequency using the categories: very common (

1/10); common (

1/100 to <

1/10); uncommon (

1/1,000 to < 1/100); rare (

1/10,000 to < 1/1,000); not

known (cannot be estimated from the available data).

Adverse Drug Reactions (ADRs) Associated with Mezavant

System/Organ Class

Incidence

Category

Adverse drug reaction

Uncommon

Thrombocytopenia*

Rare

Agranulocytosis*

Blood and lymphatic

system disorders

Not known

Aplastic anaemia*,

Leukopenia*, Neutropenia*,

Pancytopenia*

Uncommon

Face oedema

Immune system

disorders

Not known

Hypersensitivity*,

Anaphylactic shock,

Angioedema, Stevens-Johnson

syndrome, Drug rash with

eosinophilia and systemic

symptoms (DRESS)

Common

Headache*

Uncommon

Dizziness, Somnolence, Tremor

Nervous system

disorders

Not known

Intracranial pressure increased,

neuropathy

Ear and labyrinth

disorders

Uncommon

Ear pain

Uncommon

Tachycardia

Cardiac disorders

Not known

Myocarditis*, Pericarditis*

Common

Hypertension

Vascular disorders

Uncommon

Hypotension

Uncommon

Pharyngolaryngeal pain*

Respiratory, thoracic and

mediastinal disorders

Not known

Hypersensitivity pneumonitis

(including interstitial

Pneumonitis, allergic alveolitis,

eosinophilic pneumonitis),

Bronchospasm

Common

Abdominal distension,

Abdominal pain*, Colitis,

Diarrhoea*, Dyspepsia,

Vomiting, Flatulence, Nausea

Gastrointestinal

disorders

Uncommon

Pancreatitis, Rectal polyp

Common

Liver Function Test abnormal*

(e.g., ALT; AST, Bilirubin)

Hepatobiliary disorders

Not known

Hepatitis, Cholelithiasis

Common

Pruritus, Rash*

Uncommon

Acne, Alopecia, Urticaria

Skin and subcutaneous

tissue disorders

Rare

Photosensitivity

Common

Arthralgia, Back pain

Uncommon

Myalgia

Musculoskeletal and

connective tissue

disorders

Not known

Systemic-lupus erythematosus-

like syndrome, Lupus-like

syndrome

Rare

Renal failure*

Renal and urinary

disorders

Not known

Interstitial nephritis*,

Nephrotic syndrome*,

Nephrolithiasis*

Reproductive system and

breast disorders

Not known

Oligospermia (reversible)

General disorders and

administration site

conditions

Common

Asthenia, Fatigue, Pyrexia*

*See section 4.4.

Description of selected adverse reactions

Increased intracranial pressure

Cases of increased intracranial pressure with papilledema (pseudotumor

cerebri or benign intracranial hypertension) have been reported with the use of

mesalamines. If undetected, this condition may result in restriction of the

visual field and may progress to permanent loss of vision. Mesalamine should

be discontinued, if this syndrome occurs.

Photosensitivity

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

such as atopic dermatitis and atopic eczema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal

product is important. It allows continued monitoring of the benefit/risk balance

of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via Yellow Card Scheme, Website:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the

Google Play or Apple App Store.

4.9

Overdose

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

Pharmacotherapeutic group: Aminosalicyclic acid and similar agents

ATC code: A07E C02

Mechanism of action

Mesalazine is an aminosalicylate. 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 (NF

B) and consequently the production of key proinflammatory cytokines.

More recently, it has been proposed that impairment of PPAR-

nuclear receptors, (

form of the peroxisome proliferator-activated receptors) may be implicated in

ulcerative colitis. PPAR-

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-

receptors.

Pharmacodynamic effects

The Mezavant tablet contains a core of mesalazine (5-aminosalicylic acid) 1.2g

formulated in a multi-matrix system. This system is coated with methacrylic acid –

methyl methacrylate copolymer (1:1) and methacrylic acid – methyl methacrylate

copolymer (1:2), which are designed to delay release of mesalazine until exposure to

approximately pH 7.

Clinical efficacy and safety

Mezavant was investigated in two similarly designed, Phase 3, placebo-controlled

studies (SPD476-301 and SPD476-302) in 623 randomised patients with mild to

moderate, active Ulcerative Colitis. Mezavant 2.4 g/day and 4.8 g/day administered

with food achieved statistical superiority over placebo in terms of the number of

patients achieving remission from Ulcerative Colitis after 8 weeks treatment. Using

the 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 SPD476-302,

included a comparator, mesalazine pH 7-dependent modified release 2.4 g/day (0.8 g

administered in 3 divided doses), as an internal reference arm. On the primary

variable of remission, the following results were achieved:

Study SPD476-301 (n=262

#

)

Placebo

Mezavant

2.4g/day in two

divided doses

Mezavant

4.8g/day once

daily

% patients in

remission

12.9

34.1*

29.2*

Study SPD476-302 (n=341

#

)

Placebo

Mezavant

2.4g/day once

daily

Mezavant

4.8g/day once

daily

Mesalazine pH

7-dependent

modified

release

2.4g/day in

three divided

doses

% patients in

remission

22.1

40.5*

41.2*

32.6

Based on the ITT Population; * Statistically different from placebo (p<0.025);

significant (p>0.05)

5.2

Pharmacokinetic properties

The mechanism of action of mesalazine (5-ASA) is not fully understood but appears

to be topical, and therefore the clinical efficacy of Mezavant does not correlate with

the pharmacokinetic profile. A major pathway of clearance of mesalazine is via

metabolism to N-acetyl-5-aminosalicylic acid (Ac-5-ASA), which is

pharmacologically inactive.

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 through the colon,

indicating that mesalazine had spread throughout this region of the gastrointestinal

tract. Complete disintegration of Mezavant and complete release of mesalazine

occurred after approximately 17.4 hours.

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 (median) and reached a maximum by 9-12 hours (median) on average for the

doses studied. The pharmacokinetic parameters are highly variable among subjects.

Mesalazine systemic exposure in terms of area under the plasma concentration-time

curve (AUC) was 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 less than dose proportional 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.

In a single and multiple dose pharmacokinetic study of Mezavant 2.4 and 4.8 g

administered with standard meals in 56 healthy volunteers, plasma concentrations of

mesalazine were detectable after 4 hours and were maximal by 8 hours after the single

dose. At steady state (achieved generally by 2 days after dosing), 5-ASA

accumulation was 1.1- to 1.4- fold for the 2.4 g and 4.8 g dose, respectively, above

that expected on the basis of single dose pharmacokinetics.

Administration of a single dose of Mezavant 4.8 g with a high fat meal resulted in

further delay in absorption and mesalazine plasma levels were detectable after

approximately 4 hours following dosing. However, a high fat meal increased systemic

exposure of mesalazine (mean Cmax by 91%; mean AUC 16%) compared to results

in the fasted state. Mezavant was administered with food in the Phase 3 trials.

In a single dose pharmacokinetic study of Mezavant, 4.8 g was administered in the

fasted state to 71 healthy male and female volunteers (28 young (18-35 years); 28

elderly (65-75 years); 15 elderly (>75 years)). Increased age resulted in increased

systemic exposure (up to approximately 2-fold, based on AUC

, AUC0

and Cmax)

to mesalazine and its metabolite N-acetyl-5-aminosalicylic acid but did not affect the

percentage of mesalazine absorbed. Increased age resulted in a slower apparent

elimination of mesalazine, though there was high between-subject variability.

Systemic exposures in individual subjects were inversely correlated with renal

function as assessed by estimated creatinine clearance.

Distribution

Following dosing of Mezavant the distribution profile of mesalazine is presumed to

be the same as that of other mesalazine containing products. Mesalazine has a

relatively small volume of distribution of approximately 18 L confirming minimal

extravascular penetration of systemically available drug. Mesalazine is 43% bound

and N-acetyl-5-aminosalicylic 78 - 83% bound to plasma proteins when in vitro

plasma concentrations are up to 2.5

g/mL and up to 10

g/mL respectively.

Biotransformation

The only major metabolite of mesalazine is N-acetyl-5-aminosalicylic acid, which is

pharmacologically inactive. Its formation is brought about by N-acetyltransferase-1

(NAT-1) activity in the liver and in the cytosol of intestinal mucosal cells.

Elimination

Elimination of absorbed 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. The apparent terminal half-lives for mesalazine and its major metabolite after

administration of Mezavant 2.4 g and 4.8 g were, on average, 7-9 hours and 8-12

hours, respectively.

Hepatic Impairment

There are no data in patients with hepatic impairment taking Mezavant. Systemic

exposure to mesalazine increased by up to 2-fold in elderly subjects (>65 years, with

a mean creatinine clearance of 68 – 76 ml/min) compared with younger adult subjects

(18-35 years, mean creatinine clearance 124 ml/min) after a 4.8 g single dose of

Mezavant.

Renal impairment

Systemic exposures in individual subjects were inversely correlated with renal

function as assessed by estimated creatinine clearance.

Elderly

The potential impact on the safe use of Mezavant in the elderly population in clinical

practice should be considered. Furthermore, in patients with renal impairment, the

resultant decrease in the rate of elimination and increased systemic concentration of

mesalazine may constitute an increased risk of nephrotoxic adverse reactions (see

section 4.4).

In different clinical studies with Mezavant, mesalazine plasma AUC in females

appeared up to 2-fold higher than in males.

Based on limited pharmacokinetic data, 5-ASA and Ac-5-ASA pharmacokinetics

appear comparable between Caucasian and Hispanic subjects.

Pharmacokinetics data have not been investigated in elderly people.

5.3

Preclinical safety data

Effects in nonclinical studies were observed only at exposures considered sufficiently

in excess of the maximum human exposure indicating little relevance to clinical use.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Carmellose sodium

Carnauba Wax

Stearic Acid

Silica, Colloidal Hydrated

Sodium Starch Glycolate (Type A)

Talc

Magnesium Stearate

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