Asacol 800mg MR tablets

Each tablet contains 800 mg of mesalazine (active substance) and 152.75 mg of lactose monohydrate (excipient).

For full list of excipients, see section 6.1

Modified ReleaseTablets

Red-brown, oblong tablets marked 'WC 800'.

Ulcerative colitis: For the treatment of mild to moderate acute exacerbations. For the maintenance of remission.

Crohn's ileo-colitis: For the maintenance of remission.

Swallow whole with water. Do not break, crush or chew the tablets before swallowing.

ADULTS:

Mild acute exacerbations of ulcerative colitis: Three tablets (2.4g) a day in divided doses.

Moderate acute exacerbations of ulcerative colitis: Six tablets (4.8g) a day in divided doses.

Maintenance of remission of ulcerative colitis and Crohn's ileocolitis: Up to three tablets (2.4g) a day in divided doses.

ELDERLY: The normal adult dosage may be used unless renal function is impaired (see section 4.4).

CHILDREN: Not recommended.

A history of sensitivity to salicylates or renal sensitivity to sulfasalazine. Confirmed severe renal impairment (GFR less than 20 ml/min). Hypersensitivity to any of the ingredients. Severe hepatic impairment. Gastric or duodenal ulcer, haemorrhagic tendency.

Geriatric Use

Use in the elderly should be cautious and subject to patients having normal renal function

Intolerance

Discontinue treatment immediately if acute symptoms of intolerance occur including vomiting, abdominal pain or rash. This medicine contains lactose. Patients with the rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because of the presence of lactose monohydrate.

Mesalazine inhibits the thiopurine methyl-transferase (TPMT) activity in vitro and may therefore impair the metabolism of azathioprine and 6-mercaptopurine. Standard haematological indices (including the white cell count) should be monitored repeatedly in patients taking azathioprine, especially at the beginning of such combination therapy, whether or not mesalazine is prescribed.

Renal disorder

Mesalazine is excreted rapidly by the kidney, mainly as its metabolite, N-acetyl-5-aminosalicylic acid. In rats, large doses of mesalazine injected intravenously produce tubular and glomerular toxicity. Asacol should be used with extreme caution in patients with confirmed mild to moderate renal impairment (see section 4.3). Patients on mesalazine should have renal function monitored, (with serum creatinine levels measured) prior to treatment start. Renal function should then be monitored periodically during treatment, for example every 3 months for the first year, then every 6 months for the next 4 years and annually thereafter, based on individual patient history. Physicians should take into account risk factors such as prior and concomitant medications, duration and severity of disease and concurrent illnesses. Treatment with mesalazine should be discontinued if renal function deteriorates. If dehydration develops, normal electrolyte and fluid balance should be restored as soon as possible.

Blood Dyscrasias

Serious blood dyscrasias (some with fatal outcome) have been reported very rarely with mesalazine. Haematological investigations including a complete blood count may be performed prior to initiation and whilst on therapy according to the physician's judgement. Such tests should be done immediately if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Treatment should be stopped if there is suspicion or evidence of blood dyscrasia.

'Asacol' tablets should not be given with lactulose or similar preparations, which lower stool pH and may prevent release of mesalazine.

Concurrent use of other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions (see section 4.4).

Pregnancy

Mesalazine is known to cross the placental barrier, but the limited data available on its use in pregnant women do not allow accurate assessment of possible adverse effects.

Mesalazine should therefore be used with caution during pregnancy and lactation when the potential benefit outweighs the possible hazards in the opinion of the physician.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Lactation

Low concentrations of mesalazine and higher concentrations of its N-acetyl metabolite have been detected in human milk. While the clinical significance of this has not been determined, caution should be exercised when mesalazine is administered to a nursing woman. Hypersensitivity reactions like diarrhoea cannot be excluded. Therefore, if the suckling neonate develops suspected adverse reactions consideration should be given to discontinuation of breast-feeding or discontinuation of treatment of the mother.

No influence.

In Phase III clinical studies in patients with moderate active ulcerative colitis, treated for 6 weeks with either 2.4g/day or 4.8g/day, there was no difference in the adverse event profiles between doses. The events are presented in the table below:

Adverse Events Reported in 2% of Patients in Either Treatment Group

*Adverse events are listed by decreasing frequency as observed in the 4.8 g/day treatment group

Adverse events seen with oral mesalazine products are predominantly gastrointestinal, including nausea, vomiting, diarrhoea, and abdominal pain. Headache and arthralgia/myalgia have also been reported.

Blood and lymphatic system disorders:

Rare (<1/1,000): leucopenia, neutropenia, agranulocytosis, aplastic anaemia and thrombocytopenia.

Cardiac disorders:

Rare (<1/1,000): myocarditis, pericarditis

Nervous disorders:

Common (1/100 to <1/10): headache

Rare (<1/1,000): peripheral neuropathy, vertigo

Respiratory, thoracic and mediastinal disorders:

Rare (<1/1,000): bronchospasm, eosinophilic pneumonia

Very rare (<1/10,000): interstitial pneumonitis

Gastrointestinal disorders:

Common (1/100 to <1/10): nausea, vomiting, diarrhoea, abdominal pain

Rare (<1/1,000): pancreatitis

Very rare(<1/10,000): exacerbation of the symptoms of colitis

Hepato-biliary disorders:

Rare (<1/1,000): abnormalities of hepatic function / abnormal liver function test, hepatitis

Skin and subcutaneous tissue disorders:

Rare (<1/1,000): alopecia, lupus erythematosus-like reactions, rash (including urticaria), bullous skin reactions,

Very rare(<1/10,000): Stevens Johnson syndrome, erythema multiforme

Musculo-skeletal:

Common (1/100 to <1/10: arthralgia/myalgia

Renal and urinary disorders

Rare (<1/1,000): interstitial nephritis and nephrotic syndrome with oral mesalazine treatment, usually reversible on withdrawal. Renal failure has been reported. Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.

General disorders and administration site conditions

Rare (<1/1,000): Drug fever

There is no clinical experience with overdose of Asacol 800 mg. Mesalazine is not metabolized to salicylate. There is no specific antidote for mesalazine overdose and treatment is symptomatic and supportive. It may include intravenous infusion of appropriate electrolytes.

ATC code: A07EC02

Mesalazine is thought to have a topical anti-inflammatory effect on the intestinal mucosa, where it has been shown to inhibit prostaglandin and leukotriene synthesis, release of reactive oxygen species and other actions.

Moderately active ulcerative colitis:

Two active-controlled trials enrolled a total of 687 patients comparing Asacol 4.8 g/day (800 mg formulation) with mesalazine enteric coated tablets 2.4 g/day (400 mg formulation) in patients with mildly to moderately active ulcerative colitis. Both studies were of six weeks duration. Treatment success was defined on the basis of the Physician's Global Assessment (PGA), which took into consideration clinical assessments of rectal bleeding, stool frequency, and the patient's functional assessment and sigmoidoscopic examination. Across the two studies 4.8 g/day provided superior efficacy in patients with moderately active disease.

In the first study a total of 301 patients with mildly to moderately active UC were enrolled. Of these, 169 patients with moderately active disease were assessed for efficacy in a pre-defined subgroup analysis. In these patients, 4.8 g/day gave greater treatment success than 2.4 g/day (72% treatment success compared with 57%).

In the second study a total of 386 patients with mildly to moderately active ulcerative colitis were randomly assigned to treatment. In the 254 patients with moderately active disease, the pre-defined primary efficacy analysis showed that 4.8 g/day gave greater treatment success than 2.4 g/day (72% treatment success compared to 59%).

In both studies, more patients showed improvement on 4.8 g/day compared to 2.4 g/day across the clinical assessments (stool frequency, rectal bleeding, sigmoidoscopy and PGA). In combined studies, 4.8 g/day showed statistically significant superiority in the sigmoidoscopy and PGA scores.

At Week 3, more patients with moderately active disease achieved treatment success on 4.8 g/day compared with 2.4 g/day in each study and in the combined analysis (62% vs. 53%). These differences were not statistically significant.

In combined studies among patients with moderately active disease, the efficacy benefit of 4.8 g/day over 2.4 g/day was consistent across various subgroups including age, gender, race, ulcerative colitis disease history, prior medication usage and extent of disease (proctitis, proctosigmoiditis, left-sided colitis and pancolitis).

Asacol 800mg MR tablets are coated with an acrylic-based resin. Tablets coated with this specific resin have been shown to delay release of mesalazine until it reaches the terminal ileum and beyond.

Based on cumulative urinary recovery of 5-aminosalicylic acid and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) from single dose studies in healthy volunteers, approximately 20% of the orally administered mesalazine in Asacol 800mg MR tablets is systemically absorbed, leaving the remainder available for local action and elimination in the faeces. The absorbed mesalazine is rapidly acetylated in the gut mucosal wall and by the liver to N-Ac-5-ASA which is excreted mainly by the kidney.

The extent of systemic exposure to mesalazine, based on AUC and Ae%, following oral administration of Asacol 800mg MR tablets, is similar in fasted and fed subjects.

Pharmacokinetics studies for Asacol 800mg MR tablets indicated that the tmax for mesalazine and its metabolite, N-Ac-5-ASA, is prolonged, reflecting the modified release characteristics, and ranged from 4 to 12 hours. Large intersubject variability in the plasma concentrations and terminal exponential half-lives (t1/2) of mesalazine and N-Ac-5-ASA is seen following administration of Asacol 800mg MR tablets. The mean (t1/2) for mesalazine and N-Ac-5-ASA are usually about 12 hours, but may vary from 2 to 15 hours.

In patients with mildly to moderately active ulcerative colitis who participated in clinical safety and efficacy studies, the mean plasma concentrations of mesalazine and N-Ac-5-ASA following oral administration of 4.8g/day with the Asacol 800mg MR tablet for 6 weeks (N = 273) were 1931 ng/mL and 2951 ng/mL, respectively. In these studies, the mean plasma concentrations of mesalazine and N-Ac-5-ASA were 967 ng/mL and 1789 ng/mL, respectively, in patients with mildly to moderately active ulcerative colitis who were orally administered 2.4g/day with a mesalazine 400mg modified release tablet for 6 weeks (N = 275). The systemic exposure to mesalazine and N-Ac-5-ASA in patients with moderately active UC is similar to that observed in patients with mildly active UC.

Apart from effects on the kidney (see section 4.4), preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. The latter was studied in rats and rabbits at oral doses up to 480 mg/kg/day and no evidence was detected for teratogenic effects or foetal toxicity due to mesalazine.

Not applicable.

3 years.

This medicinal product does not require any special storage conditions. Keep the bottle tightly closed.

HDPE bottle with a child-resistant closure, cotton, and silica gel desiccant pouches. Pack-sizes of 12, 36 or 180 tablets.

Not all pack sizes may be marketed.

No special requirements.

Warner Chilcott UK Limited

Old Belfast Road,

Millbrook,

Larne,

County Antrim,

BT40 2SH

PL 10947/0012

14/09/2007

29/11/2010