ASACOL™
Mesalazine (5-aminosalicylic acid) 400mg gastro-resistant tablet, 500mg suppositories and enema 1g/100mL and 4g/100mL
Qualitative and Quantitative Composition
ASACOL Gastro-resistant Tablets
Each tablet contains mesalazine (5-aminosalicylic acid) 400mg
ASACOL Suppositories
Each suppository contains mesalazine (5-aminosalicylic acid) 500mg
ASACOL Enemas
Each enema contains mesalazine (5-aminosalicylic acid) 1g in 100mL or 4g in 100mL.
Pharmaceutical Form
Gastro-resistant tablet - coated reddish to brownish oblong tablets, size 15mm length, 6mm width and height.
Suppository - light grey-brown, torpedo-shaped suppositories.
Enemas - brownish suspensions.
Clinical Particulars
Therapeutic indications
Gastro-resistant Tablets
| Ulcerative colitis: | - induction of remission of mild to moderate episodes |
| - maintenance of remission |
| |
| Crohn's disease: | - maintenance of remission |
Suppositories
Treatment of mild to moderate distal (proctitis and proctosigmoiditis) ulcerative colitis and maintenance of remission of distal ulcerative colitis.
Enemas
The Asacol 1g/100ml enema is indicated for the treatment and maintenance of remission of distal ulcerative colitis and proctitis, while the 4g enema is indicated for distal ulcerative colitis unresponsive to other treatment.
Dosage and administration
Gastro-resistant Tablets
Ulcerative colitis
Induction of remission: 2.4 to 4.8 g (6 to 12 tablets) in divided doses (three times a day). The dosage can be adjusted in accordance with the response to the treatment.
Maintenance of remission: 1.2 to 2.4 g (3 to 6 tablets) in divided doses (three times a day).
Crohn's disease
Maintenance of remission: 2.4 g (6 tablets) in divided doses (three times a day).
Suppositories
Adult dose in proctitis and proctosigmoiditis 1 to 2 suppositories to be inserted up to three times daily (tid), after defaecation. The dosage is dependent upon the severity of the disease and it may be possible to reduce the dosage as the condition improves. In severe generalised ulcerative colitis affecting the rectum or rectosigmoid and in cases slow to respond to oral therapy one to two suppositories used morning and evening (bid) may be used as an adjunct to oral therapy. There is no dose recommendation for children.
Enemas
Adult dose 1 g or 4 g administered at night, retained for approximately 8 hours.
Instructions for Use
Before using the enema, it should be warmed in a basin or bowl of warm water for about 10 minutes so that it comes approximately to body temperature. It should be shaken well immediately before insertion. The enema should be inserted with the patient lying on their left side with the left leg extended and the right leg bent. The applicator tip should be carefully inserted into the rectum, the liquid gently pressed out (for at least one minute) and then the tip withdrawn with the container still compressed. The patient should remain relaxed in the administration position for 5-10 minutes or until the urge to pass the enema has disappeared, and then sleep in their usual position if possible without evacuation of the bowels until morning.
Contra-indications
Use in patients with a history of sensitivity to salicylates.
Use in patients with renal impairment (GRF less than 20 ml per minute).
Use in children under 2 years of age.
Special warnings and special precautions for use
Not recommended for use in patients with renal impairment, and caution should be exercised in patients with raised blood urea or proteinuria. The possibility of mesalazine induced nephrotoxicity should be suspected in patients developing impairment of renal function during treatment. It is recommended that all patients have an evaluation of their renal function prior to initiation and periodically while on therapy.
Very rarely serious blood dyscrasias have been reported. Haematological investigations including a complete blood count should be performed if a patient develops signs and symptoms suggestive of blood dyscrasia or infections, such as persistent fever, sore throat, bruising, unexplained bleeding, purpura or anaemia whilst on Asacol. Treatment should be stopped immediately if there is a suspicion or evidence of blood dyscrasia and patients should seek immediate medical advice.
In the elderly, Asacol is recommended only for patients having a normal renal function and should be used with caution.
Safety and effectiveness in paediatric patients have not been fully established.
Concomitant use of lactulose or similar preparations should be avoided.
Interaction with other medicaments and other forms of interaction
Asacol should not be given with lactulose or similar preparations which lower stool pH and interfere with the correct release of mesalazine.
Mesalazine may increase the immunosuppressive effects of azathioprine and 6-mercaptopurine by inhibition of thiopurine methyltransferase. White blood cell count should be monitored repeatedly especially at initiation of such combination therapy.
Mesalazine may inhibit the action of warfarin. Prothrombin time should be closely monitored if this combination is essential.
Pregnancy and lactation
Animal studies have revealed no evidence of teratogenic effects or foetal toxicity due to mesalazine. Limited clinical studies on the use of mesalazine in pregnancy have shown no detrimental effect on the gestation and foetal outcome.
Low concentrations of mesalazine and low concentrations of its N-acetyl metabolite have been detected in human breast milk. Whilst the clinical significance of this has not been determined, caution should be exercised when mesalazine is administered to a nursing mother.
The use of mesalazine during pregnancy and lactation should be restricted to those cases where in the physician's opinion potential benefits from this therapy outweigh potential risks.
Effects on ability to drive and use machines
No known effects.
Undesirable effects
Adverse reactions occur in a small proportion of patients. These are predominantly gastrointestinal. Nausea, diarrhoea, abdominal pain, fever and headache have been reported.
Asacol has been associated with the exacerbation of the symptoms of colitis.
Pancreatitis, pericarditis, myocarditis, interstitial nephritis and nephrotic syndrome have been reported with oral treatment, usually reversible on withdrawal. Renal failure has been reported rarely, usually reversible on withdrawal.
Rare cases of alopecia have been reported. Some of these are probably related to the autoimmune nature of the underlying disease of inflammatory bowel disease.
Mesalazine induced lupus may be a rare complication with pericarditis and pleuropericarditis as prominent symptoms as well as rashes and arthralgia.
There have been rare reports of allergic lung reactions, eosinophilic pneumonia, hepatitis and blood dyscrasias such as leucopenia, neutropenia, thrombocytopenia, and aplastic anaemia.
Overdose
In principle, the signs and symptoms would be expected to be similar to those observed in cases of salicylate intoxication: mixed acidosis-alkalosis, hyperventilation, pulmonary oedema, dehydration as a result of sweating and vomiting, hypoglycaemia.
Treatment for mixed acidosis-alkalosis
Restoration of the acid-base balance in line with the specific situation and replacement of electrolytes.
Treatment for dehydration due to sweating and vomiting
Administration of fluids
Treatment for hypoglycaemia
Glucose administration.
In addition, gastric lavage and intravenous transfusion of electrolytes to promote diuresis. There is no known antidote.
Pharmacological Properties
Pharmacodynamic properties
Asacol contains mesalazine [ATC A07EC02], or 5-aminosalicylic acid, which has an anti-inflammatory effect through a mechanism that has not yet been fully clarified. Mesalazine inhibits the migration of polymorphnuclear leucocytes and the lipooxygenase of the cells with the concentrations that are reached in the large intestine during treatment. The production of proinflammatory leukotrienes (LTB4 and 5-HETE) in the macrophages of intestinal wall is then inhibited. Mesalazine has inhibited in trial conditions also cyclo-oxygenase and thus, the release of thromboxane B2 and prostaglandin E2, but the clinical meaning of this effect is still unclear. Mesalazine also inhibits formation of tumour necrosis factor α (TNF-α) and of the 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. Furthermore, mesalazine inhibits secretion of water and chloride and increases the reabsorption of sodium in the intestine in experimental colitis in test animals.
Pharmacokinetic properties
Asacol tablets are coated with a polymer [Eudragit™ S] which allows the active principle to be released when the intraluminal pH is above 7, that is within the terminal ileum and colon, which are the sites of inflammation. Asacol tablets have been designed to minimise absorption of mesalazine in the digestive tract. Absorption by the oral route is approximately 26%. Consequently, 74% of the administered dose remains within the terminal ileum and colon, being available to exert a topical anti-inflammatory effect. Mesalazine is metabolised both by the liver and the intestinal mucosa into an inactive derivative, N-acetyl-5-aminosalicylic acid. Mesalazine has an elimination half-life of less than one hour. The elimination of mesalazine is essentially urinary and faecal, in the form of mesalazine and its N-acetyl metabolite.
As with the tablets 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 500mg mesalazine in healthy volunteers the mean Cmax and tmax were 211 ng/mL and 2 hours for mesalazine and 443 ng/mL and 3 hours for N-acetyl 5-ASA respectively. Acetylation of mesalazine to N-acetyl 5-ASA occurs in the gastrointestinal wall and in the liver. N-acetyl 5-ASA is predominantly excreted in the urine. Mesalazine is reported to have a half-life of about 5 hours and about 40% are bound to plasma proteins. N-acetyl 5-ASA is reported to have a half-life of about 8 hours and about 80% are bound to plasma proteins. Low concentrations of mesalazine and low concetrations of its N-acetyl metabolite have been detected in human breast milk.
Also as with the tablets only a proportion of mesalazine contained in the enemas is absorbed and available to the systemic circulation. The mode of action of mesalazine is local rather than systemic. After a single dose of 4g mesalazine in healthy volunteers the mean Cmax and tmax were 874 ng/mL and 1.5 hours for mesalazine and 1700 ng/mL and 4.3 hours for N-acetyl 5-ASA respectively. Acetylation of mesalazine to N-acetyl 5-ASA occurs in the gastrointestinal wall and in the liver. N-acetyl 5-ASA is predominantly excreted in the urine. Mesalazine is reported to have a half-life of about 3 hours and about 40% are bound to plasma proteins. N-acetyl 5-ASA is reported to have a half-life of about 3 hours and about 80% are bound to plasma proteins. Low concentrations of mesalazine and low concetrations of its N-acetyl metabolite have been detected in human breast milk.
Preclinical safety data
Because mesalazine is the active ingredient in sulfasalazine and the pharmacology of sulfasalazine is well known, extensive separate pharmacological investigations with mesalazine in animal tests have not been performed. Toxicity of mesalazine after oral administration has been investigated in several studies with both single and repeated doses, and there has been no significant toxicity. When a dose of 1g/kg per day was administered repeatedly to rats, it caused damage in kidneys and gastro-intestinal tract. Mesalazine was not mutagenic in the Ames test, and it has not shown carcinogenic properties in investigations with mice and rats. Teratogenic effects were not observed in rats (dose 360 mg/kg) or rabbits (dose 480 mg/kg). Furthermore, mesalazine did not affect the reproductive ability of either male or female rats.
Pharmaceutical Particulars
List of excipients
Asacol gastro-resistant tablets
Tablet core: lactose monohydrate, sodium starch glycollate, magnesium stearate (plant origin), talc, povidone
Film-coating: methacrylic acid - methyl methacrylate copolymer, talc, dibutyl phthalate, ferric oxide red and yellow (E172), macrogol 6000.
Asacol suppositories
Hard fat
Asacol enemas
Xanthan gum, sodium metabisulphite, sodium benzoate, purified water
Incompatibilities
None.
Shelf life
3 years (all presentations)
Special storage precautions
Asacol tablets, suppositories and enemas should not be stored above 25°C. They should be stored in a dry place. The suppositories and enemas should be stored away from direct sunlight.
Asacol must not be used past the expiry date marked on the packaging.
Asacol must be kept out of the reach of children.
Nature and contents of container
Asacol tablets: Packs of 100 tablets in a blister pack (PVC/aluminium)
Asacol suppositories: PVC/polyethylene laminate foil strips of five suppositories packed in an outer cardboard carton containing 20 suppositories.
Asacol enemas: single bottles made of polyethylene containing 100mL of suspension.
Directions for use/handling
The suppositories and enemas are for rectal use and must not be swallowed.
| 
