For acute treatment of ulcerative proctitis (up to 20 cm from the anus).

May also be used for acute treatment or maintenance of remission in ulcerative colitis in the region of the rectosigmoid or for painful inflammatory complications of haemorrhoids such as anusitis, cryptitis, anal papillitis and rhagades.

·    For ulcerative colitis (colitis, rectosigmoiditis and proctitis):

Adults:

Acute episode:

1 Asacol suppository in the morning, at midday and in the evening.

Asacol suppositories may be administered in combination with Asacol gastro-resistant tablets.

Maintenance of remission:

During the remission phase, long-term treatment is indicated to prevent recurrence:

1 Asacol suppository in the morning and in the evening.

Long-term treatment with Asacol should also be carried out consistently for maintenance of remission.

·    For painful inflammatory complications of haemorrhoids

-          During the acute phase, 1 Asacol suppository in the morning and in the evening.

-          After the acute symptoms have disappeared, the suppositories should be administered at least for 1 further week.

Elderly population

Except in cases of severely impaired hepatic and renal function, the dosage stated for adults can be administered (see section 4.4 ). No studies have been performed with elderly patients.

Paediatric population

To date, its use and safety in children and adolescents under 18 years have not been sufficiently investigated.

Mode of administration: rectal

The suppositories are for rectal use and must not be swallowed.

The suppositories should be inserted deep into the anus after defaecation.

If one dose or more doses have been missed, the next dose should 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 Drug reaction with eosinophilia and systemic symptoms (DRESS), 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 very rarely been reported. Asacol therapy should be stopped immediately there is a suspicion or evidence of blood dyscrasia (signs of unexplained 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 reintroduced. Caution should be taken in patients with previous myo- or pericarditis of allergic background regardless of its origin.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving mesalazine. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances or tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of mesalazine should be considered.

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 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.

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 little experience and only limited documentation for an effect in children.

No interaction studies have been performed.

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

There have been isolated reports of supposedly altered coagulation (INR values) after combined administration with coumarins (phenprocoumon, warfarin).

Mesalazine can increase the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine. Life-threatening infections can occur. Patients should be closely observed for signs of infection and myelosuppression. Blood counts, especially white blood cell, platelet and lymphocyte counts, should be monitored especially at the start of such combination therapy and at regular intervals (weekly).

If the white blood cell count is stable after 1 month, monthly blood tests for the next three months, followed by quarterly check-ups, appear to be adequate. Apart from interaction studies with purin antimetabolites in adults and children no other interaction studies have been performed in adults or children.

Pregnancy

There are no adequate data from the use of Asacol in pregnant women. However, data on alimited number (627) of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the foetus/newborn child. To date, 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 diarrhoea in the infant cannot be excluded. Therefore, Asacol should only be used during breastfeeding, if the expected benefit outweighs the possible 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

The Asacol clinical trial database includes 246 patients treated with Asacol 500 mg Suppositories. The mesalazine doses were in the range of 1.0 g/day to 1.5 g/day, the treatment duration varied between four weeks and twelve months.

Organ specific adverse drug reactions affecting the heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue have been reported. Most of these undesirable effects have not been reported following Asacol 500 mg suppositories monotherapy, but were observed with oral mesalazine administration. However, it cannot be excluded that these events can also occur with rectal mesalazine use alone.

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 Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see “4.4 Special warnings and precautions for use”).

b)      Tabulated summary of adverse reactions

Undesirable effects relevant for the labelling reported from four double-blind clinical studies and one open label clinical trial, from spontaneous reporting, the literature and the EU Mesalazine Core Safety Profile of 07 April 2011 is listed below. The frequency of some reactions cannot be reliably estimated due to the limitation of the reporting source.

**See section 4.4 for further information

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.

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 suppositories 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 are 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 specific antidote and treatment is symptomatic and supportive.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents; ATC Code: A07EC02

Mechanism of action

Asacol contains mesalazine, also known as5-aminosalicylic acid, which has 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. Under trial conditions cyclo-oxygenase and thus, the release of thromboxane B2 and prostaglandin E2 were inhibited, but the clinical relevance of these effects is not known. 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.

Epidemiological data indicate that continued long-term mesalazine maintenance treatment may reduce the risk of colon cancer.

Clinical efficacy and safety

The acute treatment of ulcerative colitis was investigated in 529 patients with mild to moderately severe symptoms. Of six controlled studies two were placebo-controlled, four studies were reference-controlled or were used as dose finding studies. Duration of treatment varied between four and six weeks. Sigmoidoscopy was used to confirm diagnosis of the disease in the patients. Response to treatment was monitored by means of clinical investigations, self-control by the patients and clinical findings (sigmoidoscopy results) on a daily basis or at intervals of several weeks. Both placebo-controlled studies produced a statistically significant result in favour of mesalazine.

Maintenance of remission in ulcerative colitis was investigated in 503 patients. Of four controlled studies one was placebo-controlled and three reference-controlled. Duration of treatment varied between four and eleven months. The endpoint of the study was occurrence of a relapse on the evidence of sigmoidoscopy. The placebo-controlled study achieved a statistically significant result in favour of mesalazine.

The effect of mesalazine administered via the rectal route (Asacol suppositories) was tested in four double-blind studies in a total of 318 patients. Three studies investigated efficacy in the acute treatment of mild to moderately severe proctitis and proctosigmoiditis; two of the studies were placebo-controlled and one reference-controlled. Treatment lasted for four weeks. Both placebo-controlled studies produced a statistically significant result in favour of mesalazine. The fourth controlled study investigated the effect of a one year maintenance of remission. A significantly superior result was found for 0.5 g and 1 g mesalazine compared with placebo.

Absorption

Only a proportion of mesalazine contained in the suppositories is absorbed and available to the systemic circulation. The mode of action of mesalazine is local rather than systemic. After a single dose of Asacol 500mg suppositories in healthy volunteers the mean C_max and T_max were 211 ng/mL and 2.0 hours for mesalazine and 443 ng/mL and 3.0 hours for N-acetyl mesalazine, respectively. About 43% of mesalazine and about 78% of N-acetyl mesalazine are bound to plasma proteins.

Distribution

Low concentrations of mesalazine and its N-acetyl metabolite 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.

Elimination

The elimination of mesalazine is essentially faecal and urinary in the form of mesalazine and its N-acetyl metabolite. Mesalazine and the main metabolite N-acetyl mesalazine were reported to have biological half-lives of 4.97 hours and 8.32 hours, respectively, following the use of Asacol 500 mg Suppositories in healthy volunteers.

Linearity/non-linearity

No specific studies have been performed.

Pharmacokinetic/pharmacodynamic 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.

Hard fat

Not applicable

Asacol suppositories should be stored in their original pack at a temperature not exceeding 25° C and protected from moisture and direct sunlight.

Keep out of the sight and reach of children.

Asacol 500 mg suppositories are enclosed inside heat-sealed, non-toxic PVC/PE cavities, in strips of five suppositories and then packed in cardboard cartons.

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