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

Last Updated on eMC 03-Apr-2012 View changes  | Shire Pharmaceuticals Limited Contact details

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 a 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 4.8g (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 (4.8g/day), the effect of the treatment should be evaluated at 8 weeks.

For maintenance of remission: 2.4g (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 <30ml/min/1.73m2) and/or severe hepatic impairment.

4.4 Special warnings and precautions for use

Reports of renal impairment, including minimal change nephropathy, and acute / chronic interstitial nephritis have been associated with preparations containing mesalazine and pro-drugs of mesalazine. Mezavant XL 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, whilst 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 XL 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 XL 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.

4.5 Interaction with other medicinal products and other forms of interaction

No investigations of interactions between Mezavant XL and other drugs have been performed. However, there have been reports of interactions between products containing mesalazine 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, caution is recommended for concurrent use of mesalazine as this can increase the potential for blood dyscrasias (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 XL is recommended to be administered with food (see sections 4.2 and 5.2).

4.6 Pregnancy and lactation

Pregnancy

Limited experience with mesalazine in pregnancy does not indicate an increased risk of drug induced congenital malformations. 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. Mesalazine should be used during pregnancy only when clearly indicated. Caution should be exercised when using high doses of mesalazine.

Lactation

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 XL is considered to have negligible influence on these abilities.

4.8 Undesirable effects

The three most frequently reported adverse drug reactions within the pooled safety analysis of ulcerative colitis patient clinical studies were headache, abdominal pain and nausea. No individual ADR was reported at a frequency greater than 10%.

Other events reported with Mezavant XL were less frequent and the incidences are presented below:

Adverse Drug Reactions (ADRs) Associated with Mezavant XL

System/Organ Class

Incidence Category

Adverse drug reaction

Blood and lymphatic system disorders

Uncommon

(≥1/1000 to <1/100)

Thrombocytopenia

Unknown

Agranulocytosis*, Aplastic anaemia*, Leukopenia*, Neutropenia*, Pancytopenia*

Nervous system disorders

Common

(≥1/100 to <1/10)

Headache

Uncommon

(≥1/1000 to <1/100)

Dizziness, Somnolence, Tremor

Unknown

Neuropathy*

Ear and labyrinth disorders

Uncommon

(≥1/1000 to <1/100)

Ear pain

Cardiac disorders

Uncommon

(≥1/1000 to <1/100)

Tachycardia

Unknown

Myocarditis# , Pericarditis#

Vascular disorders

Common

(≥1/100 to <1/10)

Hypertension

Uncommon

(≥1/1000 to <1/100)

Hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon

(≥1/1000 to <1/100)

Pharyngolaryngeal pain

Unknown

Hypersensitivity pneumonitis (including interstitial Pneumonitis, allergic alveolitis, eosinophilic pneumonitis)#

Bronchospasm*

Gastrointestinal disorders

Common

(≥1/100 to <1/10)

Abdominal distension, Abdominal pain, Diarrhea, Dyspepsia, Vomiting, Flatulence, Nausea

Uncommon

(≥1/1000 to <1/100)

Colitis, Pancreatitis, Rectal polyp

Hepatobiliary disorders

Common

(≥1/100 to <1/10)

Liver Function Test abnormal (e.g. ALT; AST, Bilirubin)

Unknown

Hepatitis#, Cholelithiasis*

Skin and subcutaneous tissue disorders

Common

(≥1/100 to <1/10)

Pruritus, Rash

Uncommon

(≥1/1000 to <1/100)

Acne, Alopecia, Urticaria

Unknown

Angioedema*

Musculoskeletal and connective tissue disorders

Common

(≥1/100 to <1/10)

Arthralgia associated with myalgia, Back pain

Unknown

Systemic-lupus erythematosus-like syndrome*

Renal and urinary disorders

Unknown

Interstitial nephritis#, Nephrotic syndrome*

General disorders and administration site conditions

Common

(≥1/100 to <1/10)

Asthenia, Pyrexia

Uncommon

(≥1/1000 to <1/100)

Face oedema, Fatigue,

#Denotes post marketing experiences reported with Mezavant XL.

*Denotes adverse drug reactions reported for mesalazine formulations in general.

Mesalazine induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.

See also section 4.4

4.9 Overdose

Mezavant XL 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

Mode 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 (NFкB) and consequently the production of key proinflammatory cytokines. More recently, it has been proposed that impairment of PPAR-γ nuclear receptors, (γ-form of the 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.

Pharmacodynamic Effects

The Mezavant XL 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 XL was investigated in two similarly designed, Phase III, placebo controlled studies (SPD476-301 and SPD476-302) in 623 randomised patients with mild to moderate, active Ulcerative Colitis. Mezavant XL 2.4g/day and 4.8g/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 302, included a comparator, mesalazine modified release 2.4g/day (0.8g administered in 3 divided doses), as an internal reference arm. On the primary variable of remission, the following results were achieved:

Study 301 (n=262#)

 
 

Placebo

Mezavant XL 2.4g/day in two divided doses

Mezavant XL 4.8g/day once daily

 

% patients in remission

12.9

34.1*

29.2*

 

Study 302 (n=341#)

 

Placebo

Mezavant XL 2.4g/day once daily

Mezavant XL 4.8g/day once daily

Mesalazine modified release 2.4g/day in three divided doses

% patients in remission

22.1

40.5*

41.2*

32.6NS

#Based on the ITT population; * Statistically different from placebo (p<0.025); NSNot significant (>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 XL 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 XL 1.2g 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 XL and complete release of mesalazine occurred after approximately 17.4 hours.

The total absorption of mesalazine from Mezavant XL 2.4g or 4.8g 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 XL 1.2g, 2.4g and 4.8g 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 1.2g and 4.8g Mezavant XL. Maximum plasma concentrations (Cmax) of mesalazine increased approximately dose proportionately between 1.2g and 2.4g and less than dose proportional between 2.4g and 4.8g Mezavant XL, with the dose normalised value at 4.8g representing, on average, 74% of that at 2.4g based on geometric means.

In a single and multiple dose pharmacokinetic study of Mezavant XL 2.4 and 4.8g 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 2.4g and 4.8g dose, respectively, above that expected on the basis of single dose pharmacokinetics.

Administration of a single dose of Mezavant XL 4.8g 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 XL was administered with food in the Phase 3 trials.

In a single dose pharmacokinetic study of Mezavant XL, 4.8g was administered in the fasted state to 71 healthy male and female volunteers (28 young (18-35yrs); 28 elderly (65-75yrs); 15 elderly (>75yrs)). Increased age resulted in increased systemic exposure (up to 2-fold, based on AUC0-t, 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 a 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 XL 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 18L 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 2.5μg/mL and up to 10μg/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 XL 2.4g and 4.8g were, on average, 7-9 hours and 8-12 hours, respectively.

Special patient populations:

There are no data in patients with hepatic impairment taking Mezavant XL. 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 adult subjects (18-35 years, mean creatinine clearance 124 ml/min) after a 4.8g single dose of Mezavant XL. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance. The potential impact on the safe use of Mezavant XL 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 XL, 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

Film-coating:

Talc

Methacrylic Acid – Methyl Methacrylate Copolymer (1:1)

Methacrylic Acid – Methyl Methacrylate Copolymer (1:2)

Triethylcitrate

Titanium Dioxide (E171)

Red Ferric Oxide (E172)

Macrogol 6000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store below 25°C.

Store in the original package in order to protect from moisture

6.5 Nature and contents of container

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

Packs contain 60 or 120 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Shire Pharmaceutical Contracts Ltd

Hampshire International Business Park

Chineham

Basingstoke

Hampshire

RG24 8EP

United Kingdom

8. Marketing authorisation number(s)

PL 08081/0040

9. Date of first authorisation/renewal of the authorisation

13/12/2011

10. Date of revision of the text

13/12/2011

Company contact details

Shire Pharmaceuticals Limited

Company image
Address

Hampshire International Business Park, Chineham, Basingstoke, Hampshire , RG24 8EP

Medical Information Direct Line

0800 055 6614

Customer Care direct line

+44 (0)1256 894 107

Telephone

+44 (0)1256 894 000

Medical Information e-mail

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Active ingredients

mesalazine

Legal categories

POM - Prescription Only Medicine

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