- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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).
Interference with Laboratory TestsUse 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.
PregnancyLimited 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.
Breast-feedingMesalazine 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.
FertilityData on mesalazine show no sustained effect on male fertility.
|Adverse Drug Reactions (ADRs) Associated with Mezavant|
|System/Organ Class||Incidence Category||Adverse drug reaction|
|Blood and lymphatic system disorders||Uncommon||Thrombocytopenia*|
|Not known||Aplastic anaemia*, Leukopenia*, Neutropenia*, Pancytopenia*|
|Immune system disorders||Rare||Face oedema|
|Not known||Hypersensitivity*, Anaphylactic shock, Angioedema, Stevens-Johnson syndrome, Drug rash with eosinophilia and systemic symptoms (DRESS)|
|Nervous system disorders||Common||Headache*|
|Uncommon||Dizziness, Somnolence, Tremor|
|Ear and labyrinth disorders||Uncommon||Ear pain|
|Not known||Myocarditis*, Pericarditis*|
|Respiratory, thoracic and mediastinal disorders||Uncommon||Pharyngolaryngeal pain*|
|Not known||Hypersensitivity pneumonitis (including interstitial Pneumonitis, allergic alveolitis, eosinophilic pneumonitis) Bronchospasm|
|Gastrointestinal disorders||Common||Abdominal distension, Abdominal pain*, Colitis, Diarrhoea*, Dyspepsia, Vomiting, Flatulence, Nausea|
|Uncommon||Pancreatitis, Rectal polyp|
|Hepatobiliary disorders||Common||Liver Function Test abnormal* (e.g. ALT; AST, Bilirubin)|
|Not known||Hepatitis, Cholelithiasis|
|Skin and subcutaneous tissue disorders||Common||Pruritus, Rash*|
|Uncommon||Acne, Alopecia, Urticaria|
|Musculoskeletal and connective tissue disorders||Common||Arthralgia, Back pain|
|Not known||Systemic-lupus erythematosus-like syndrome|
|Renal and urinary disorders||Rare||Renal failure*|
|Not known||Interstitial nephritis*, Nephrotic syndrome*|
|General disorders and administration site conditions||Common||Asthenia, Fatigue, Pyrexia*|
Reporting of suspected adverse reactionsReporting 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
Mechanism of actionMesalazine 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 effectsThe 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 safetyMezavant was investigated in two similarly designed, Phase3, placebo controlled studies (SPD476-301 and SPD476-302) in 623 randomised patients with mild to moderate, active Ulcerative Colitis. Mezavant 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 SPD476-302, included a comparator, mesalazine pH 7-dependent 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 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*||32.6NS|
Absorption:Gamma-scintigraphy studies have shown that a single dose of Mezavant 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 and complete release of mesalazine occurred after approximately 17.4 hours. The total absorption of mesalazine from Mezavant 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 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. 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, 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 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 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 was administered with food in the Phase 3 trials.In a single dose pharmacokinetic study of Mezavant, 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 approximately 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 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 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 2.4g and 4.8g were, on average, 7-9 hours and 8-12 hours, respectively.
Hepatic ImpairmentThere 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 4.8g single dose of Mezavant.
Renal impairmentSystemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
ElderlyThe 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.
Tablet core:Carmellose sodiumCarnauba WaxStearic AcidSilica, Colloidal HydratedSodium Starch Glycolate (Type A)TalcMagnesium Stearate
Film-coating:TalcMethacrylic Acid Methyl Methacrylate Copolymer (1:1)Methacrylic Acid Methyl Methacrylate Copolymer (1:2)TriethylcitrateTitanium Dioxide (E171)Red Ferric Oxide (E172)Macrogol 6000
Shire Pharmaceuticals Limited
Hampshire International Business Park, Chineham, Basingstoke, Hampshire, RG24 8EP
+44 (0) 8000 556 614
+44 (0)1256 894 107
+44 (0)1256 894 000