Asacol is indicated in adults, children and adolescents above 6 years for:

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.

Posology

Adults

Mild acute disease: 2.4g (six tablets) once daily or in divided doses, with concomitant corticosteroid therapy to be taken when clinically indicated.

Moderate acute disease: 2.4g to 4.8g (six to twelve tablets) a day in divided doses, with concomitant corticosteroid therapy where clinically indicated. 2.4g may be taken once daily or in divided doses. Above 2.4g daily should be taken in divided doses.

Maintenance therapy: 1.2g to 2.4g (three to six tablets) taken once daily or in divided doses.

The maximum adult dose should not exceed twelve tablets a day and not exceed six tablets taken together at any one time.

Elderly population

The normal adult dosage may be taken unless liver or renal function is severely impaired (see sections 4.3 and 4.4). No studies have been carried out in the elderly population.

Paediatric population

There is only limited documentation for an effect in children (age 6-18 years).

Children 6 years of age and older

• Active disease: To be determined individually, starting with 30-50 mg/kg/day in divided doses. Maximum dose: 75 mg/kg/day in divided doses. The total dose should not exceed 4 g/day.

• Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 2 g/day.

It is generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult dose to those above 40 kg.

Method of administration: Oral.

The tablets must be swallowed whole preferably with some liquid before food intake. They must not be chewed, crushed or broken before swallowing. If one or more doses have been missed, the next dose is to be taken as usual.

Blood tests (differential blood count, liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, follow-up tests are recommended 14 days after commencement of treatment and then every 4 weeks for the following 12 weeks. If the findings are normal, follow-up tests should be carried out every three months. If additional signs appear, these tests should be performed immediately.

Renal impairment

Caution should be exercised in patients with raised blood urea or proteinuria. The possibility of mesalazine-induced nephrotoxicity must be considered in patients developing impairment of renal function during treatment. Treatment with Asacol should be stopped immediately if there is evidence of renal impairment and patients should seek immediate medical advice.

Nephrolithiasis

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.

Mesalazine may produce red-brown urine discoloration after contact with sodium hypochlorite bleach (e.g., in toilets cleaned with sodium hypochlorite contained in certain bleaches).

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs), including 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.

Blood dyscrasia

Serious blood dyscrasia has been reported. Asacol therapy should be stopped immediately if there is a suspicion or evidence of blood dyscrasia (signs of unexpected bleeding, haematoma, purpura, anaemia, persistent fever or sore throat) and patients should seek immediate medical advice.

Hepatic impairment

There have been reports of increased liver enzyme levels in patients taking preparations containing mesalazine. Caution is recommended if Asacol is administered to patients with liver impairment.

Cardiac hypersensitivity reactions

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely with Asacol. In case of known previous mesalazine-induced cardiac hypersensitivity Asacol must not be administered. Caution should be taken in patients with previous myocarditis or pericarditis of allergic background regardless of its  origin.

Pulmonary disease

Patients with lung disease, especially asthma, should be monitored with particular care during treatment with Asacol.

Adverse drug reactions to Sulphasalazine

Patients with a history of adverse drug reactions to sulphasalazine therapy should be kept only under close medical supervision. Treatment must be stopped immediately if acute symptoms of intolerance occur such as abdominal cramps, acute abdominal pain, fever, severe headache and rash.

Gastric and duodenal ulcers

In case of existing gastric or duodenal ulcers treatment should begin with caution based on theoretical grounds.

Intolerance to carbohydrates

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Tablets in stool

A limited number of reports of intact tablets in the stool have been received. What appear to be intact tablets may in some cases represent largely empty shells of the coated tablets. If intact tablets are observed in the stool repeatedly, the patient should consult his/her physician.

Elderly population

Use in older people should be handled with caution and the product should only be prescribed to patients having a normal or non-severely impaired liver and renal function, see section 4.3.

Paediatric population

There is only limited documentation for an effect in children (age 6-18 years), see section 4.2

No interaction studies have been performed.

There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine, a possible increase in the myelosuppressive effects of azathioprine, or 6-mercaptopurine or thioguanine should be taken into account. As a result, life-threatening infection can occur. Patients should be closely observed for signs of infection and myelosuppression. Haematological parameters, especially the leucocyte, thrombocyte, and lymphocyte cell counts should be monitored regularly (weekly), especially at initiation of such combination therapy, see section 4.4. If white blood cells are stable after 1 month, testing every 4 weeks for the following 12 weeks followed by 3 monthly monitoring intervals appears to be justified.

Pregnancy

There are no adequate data from the use of Asacol in pregnant women. However, in a limited number of pregnant women exposed to mesalazine (627), no negative effects were found with regard to pregnancy or foetal/neonatal health. No other relevant epidemiological data are currently available.

 In one single case, after long-term use of a high mesalazine dose (2 - 4 g, orally) during pregnancy, renal failure in a neonate was reported . Animal studies with oral mesalazine administration do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Asacol should only be used during pregnancy when the expected benefit outweighs the potential risk.

Breastfeeding

N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. The clinical significance of this has not been determined. Only limited experience during lactation in women is available to date. Hypersensitivity reactions such as infant diarrhoea cannot be excluded. Therefore, Asacol should only be used during breastfeeding when the expected benefit outweighs the potential risk. If the infant develops diarrhoea, breastfeeding should be discontinued.

Fertility

No effects on fertility have been observed.

Asacol has no or negligible influence on the ability to drive and use machines.

a)      Summary of safety profile

Organ specific adverse drug reactions affecting the heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue have been reported.

Treatment must be stopped immediately if acute symptoms of intolerance occur, such as cramps, abdominal pain, fever, severe headache or rash.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).

b)      Tabulated summary of adverse reactions

The evaluation of side effects is based on the following frequencies:

-          Common: ≥ 1/100 and < 1/10,

-          Uncommon: ≥ 1/1,000 and < 1/100,

-          Rare: ≥ 1/10,000 and < 1/1,000,

-          Very rare: < 1/10,000,

-          Not known (cannot be estimated from the available data)

Undesirable effects relevant for the labelling reported from eight (8) double-blind and five (5) open clinical studies with 739 patients treated with Asacol 400 mg GR tablets are listed below:

c)      Description of selected adverse reactions

An unknown number of the above undesirable effects are probably related to the underlying IBD rather than Asacol/mesalazine medication. This holds true especially for gastrointestinal undesirable effects, arthralgia, and alopecia.

To avoid a blood dyscrasia resulting from developing bone marrow depression, patients should be monitored with care, see section 4.4.

Under co-administration of mesalazine with immunosuppressive drugs, such as azathioprine, 6-MP or thioguanine,  life threatening infection can occur, see section 4.5.

Photosensitivity

More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.

d)      Paediatric population

There is only limited safety experience with the use of Asacol tablets in the paediatric population. It is expected that the target organs of possible adverse reactions in the paediatric population are the same as for adults (heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue.

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 the following route:

·         Saudi Arabia:

·         Other GCC States:

There is little data on overdose (e.g., intended suicide with a high oral dose of mesalazine), which do not indicate any renal or hepatic toxicity. There is no known specific antidote and treatment is symptomatic and supportive.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents; ATC code: A07E C02.

Mechanism of action:

Asacol contains mesalazine, also known as 5-aminosalicylic acid, which has an anti-inflammatory effect through a mechanism that has not yet been fully clarified. Mesalazine has been shown to inhibit LTB4-stimulated migration of intestinal macrophages and thus may reduce intestinal inflammation by restricting migration of macrophages to inflamed areas. The production of pro-inflammatory leukotrienes (LTB4 and 5-HETE) in macrophages of the intestinal wall is inhibited. Mesalazine has been shown to activate PPAR-γ receptors which counteract nuclear activation of intestinal inflammatory responses.

Pharmacodynamic effects

Under trial conditions mesalazine inhibited the cyclooxygenase and thus, the release of thromboxane B2 and prostaglandin E2, but the clinical meaning of this effect is still unclear. Mesalazine inhibits the formation of platelet activating factor (PAF). Mesalazine is also an antioxidant; it has been shown to decrease formation of reactive oxygen products and to capture free radicals.

There is a possibility that regular mesalazine use reduces the risk of colorectal cancer. Continued long-term mesalazine maintenance treatment may therefore reduce the risk of colon cancer.

Clinical efficacy and safety

Asacol 800 mg Tablets have been evaluated in 140 patients with mild to moderate active ulcerative colitis in one controlled study lasting for 10 weeks comparing safety and efficacy versus placebo.

This indication was also investigated in seven controlled and three open clinical trials including 787 patients, of whom 559 received Asacol 400 mg Modified Release Tablets. Three studies were placebo-controlled, one of which also compared the efficacy of Asacol to another proprietary oral mesalazine product. Five studies were performed without comparator. The studies included dose ranging of Asacol. One study compared the efficacy of mesalazine versus sulfasalazine. The studies included dose ranging of Asacol from 1.2 g/day to 4.8 g/day. One study used computerised morphometry to assess the efficacy of Asacol compared with a prednisolone enema. These studies established the safety and efficacy of Asacol for the treatment of mild to moderate acute UC at daily doses of 2.4 – 4.8 g mesalazine.

Maintenance of remission of ulcerative colitis

This indication was studied in five controlled and two open clinical trials involving 677 patients, of whom 406 received Asacol 400 mg Modified Release Tablets. Asacol treatment was compared to sulfasalazine in three studies, to another proprietary oral mesalazine product in one study, and to placebo in one study. The dosage varied from 0.8 - 4.4 g mesalazine per day. These studies established the safety and efficacy of Asacol for the maintenance of remission of UC at daily doses of 1.6 – 2.4 g mesalazine.

Maintenance of remission of Crohn's ileo-colitis

This indication was studied in one double blind, one retrospective and two open clinical studies involving 336 patients, of whom 159 received Asacol 400 mg Modified Release Tablets. Asacol treatment was compared to sulfasalazine in one study and to placebo or no specific treatment in three studies. Two studies confirmed efficacy in preventing post-operative recurrence of Crohn's disease. These studies support the safety and efficacy of Asacol in the treatment of quiescent Crohn's disease of the terminal ileum and colon including post-operative patients at a daily dose of 2.4 g mesalazine.

Absorption:

Asacol tablets are coated with a pH responsive polymer which enables the release of mesalazine only at a pH above 7, i.e., within the terminal ileum and colon, which are the main sites of inflammation in IBD. After any initial disruption of the coating mesalazine will continue to be released irrespective of the pH. Asacol tablets have been designed to minimize absorption in the digestive tract.

After a single dose of 2.4 g of mesalazine (6 Asacol 400 mg GR Tablets) in healthy volunteers under fasting conditions quantifiable amounts (> 2.00 ng/mL) of mesalazine were observed in plasma after 4.5 h (median t_lag). The geometric mean C_max –value of mesalazine was 722.11 ng/mL with a median t_max of about 9.5 h, whereas that of N-acetyl mesalazine was 1437.90 ng/mL with a median t_max of 12.0 h.

Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after fasted oral administration approximately 25% of the dose (more than 95 % as metabolite) was excreted renally within 60 h.

Following concomitant food intake in the same study a single dose of 2.4 g of mesalazine resulted in quantifiable amounts of mesalazine after 9.0 h (median tlag). The geometric mean C_max –value of mesalazine was 1725.93 ng/mL with a median tmax of about 22.0 h, whereas that of N-acetyl mesalazine was 2235.32 ng/mL with a median t_max of 24.0 h.

Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after fed oral administration approximately 30% of the dose (about 90 % as metabolite) was excreted renally within 60 h.

Following concomitant food intake, the C_max-values of mesalazine increased 2.39-fold, and the extent of exposure (AUC0-tlast) increased 1.57-fold. Concerning N-acetyl mesalazine after concomitant food intake the C_max-values increased 1.55-fold, whereas its extent of exposure increased about 1.1-fold only.

Distribution:

About 43% mesalazine and about 78% N-acetyl mesalazine are bound to plasma proteins. Approximately 75 % of the administered dose remains in the gut lumen and the mucosal tissue. The mean apparent volume of distribution per kg of body weight (Vd_w) was 59.07 L/kg (geometric mean: 48.86 L/kg) after a single dose of 2.40 g of mesalazine (6 GR tablets of Asacol 400 mg) in healthy volunteers under fasting conditions. Based upon the absorption of 24.8% of the administered dose, this parameter is equal to 14.65 L/kg (geometric mean: 12.12 L/kg).

Low concentrations of mesalazine and N-acetyl mesalazine have been detected in human breast milk. The clinical significance of this has not been determined.

Biotransformation:

Mesalazine is metabolised both by the intestinal mucosa and the liver to the inactive metabolite N-acetyl mesalazine. At least 90% of the drug recovered in the urine after oral administration is found as the main metabolite N-acetyl-mesalazine.

Elimination:

The elimination of mesalazine is essentially urinary and faecal in the form of mesalazine and its N-acetyl metabolite. The geometric mean of total apparent clearance of mesalazine after administration of 2.40 g of mesalazine (6 GR tablets of Asacol 400 mg) in healthy volunteers under fasting conditions was about 135 L/h (geometric mean, CV% = 61.43%, intersubject). The median elimination half-life was 20 h ranging from 5 to 77 h. About 25% of the total dose administered was recovered in the urine within 60 h after fasted administration mainly as N-acetyl mesalazine and as the parent compound (about 1 %).

Linearity/non-linearity:

In a cross-over design with 3 test periods and 3 ascending oral doses of Asacol 400 mg GR Tablets administered 6 hourly over 4 consecutive doses (total daily dose of mesalazine: 3200, 4800, 6400 mg) it was shown that the absorption and elimination kinetics for mesalazine are dose independent for the 3 doses evaluated. For each dose, about ¾ of the dose was available for the therapeutic activity for the colon. Only about ¼ of each dose was absorbed and excreted in the urine, primarily as the metabolite. Based on urine drug excretion, plasma drug C_max's and the combined plasma AUC's, there was a linear dose response for the 3 Asacol tablet doses. The clinical performance of Asacol 400 should be similar for the range of doses evaluated in this study.

Pharmacokinetic/pharmacodynamics relationship(s)

No specific studies have been performed.

Kinetics in specific patient groups:

Kinetics in specific patient groups (e.g., in hepatic and renal insufficiency, genetic polymorphisms) has not been investigated.

No mutagenicity or clastogenic activity was found for mesalazine in the Ames Test and no carcinogenicity in animal trials. In a study on bone marrow in mice no micronucleus induction was demonstrated. In human lymphocytes no micronucleus induction or sister chromatid exchange was demonstrated for the primary metabolite N-acetyl-mesalazine. In studies on rats (360 mg/kg) or rabbits (480 mg/kg) no indications of an increased teratogenic risk were found. Mesalazine did not affect fertility in rats of either sex. The results of reproduction studies in female animal models did not indicate any negative effects on fertility, gestation, labour, parturition, lactation or viability.

Lactose monohydrate

Sodium starch glycolate (type A)

Magnesium stearate (vegetable origin) E 572

Talc E553b

Povidone

Methacrylic acid-methylmethacrylate copolymer (1:2)

Triethylcitrate

Ferric oxide yellow E172

Ferric oxide red E172

Macrogol 6000

Not applicable

Keep out of the reach of children. Do not store above 25°C. Store in the original package to protect the content from moisture and direct sunlight.

Blister strips of aluminium foil and PVC, and outer cardboard carton containing 50 tablets per pack. Each blister contains 10 tablets.

No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.