Each slow-release tablet consists of microgranules which contain a core of pure mesalazine and the following excipients: Povidone, ethylcellulose, magnesium stearate, talc and microcrystalline cellulose.
Each sachet (prolonged-release granules) contains 1 g, 2 g and 4 g of mesalazine, respectively.
Each suppository contains granulated mesalazine and the following excipients: Povidone, magnesium stearate, talc and macrogol 6000.
Each enema contains mesalazine 1 g and the following excipients: Disodium edetate, sodium metabisulphite, sodium acetate, purified water and hydrochloric acid for pH adjustment.
Mesalazine is 5-aminosalicylic acid.
Excipients/Inactive Ingredients: PR granules: Ethylcellulose, povidone.
Pharmacotherapeutic Group: Intestinal anti-inflammatory agents. ATC Code: A07 EC02.
Pharmacology: Pharmacodynamics: PR granules: Mesalazine is the active component of sulfasalazine, which has been used for a long time in the treatment of ulcerative colitis and Crohn's disease.
The therapeutic value of mesalazine appears to be due to local effect on the inflamed intestinal tissue, rather than to systemic effect. Increased leucocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4, and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leucotriene production, and scavenge for free radicals. The mechanism of action of mesalazine is, however, still not understood.
The risk of colorectal cancer (CRC) is slightly increased in ulcerative colitis. Observed effects of mesalazine in experimental models and patient biopsies support the role of mesalazine in prevention of colitis-associated CRC, with down regulation of both inflammation dependent and non-inflammation dependent signalling pathways involved in the development of colitis-associated CRC.
However, data from meta-analyses, including both referral and non-referral populations, provide inconsistent clinical information regarding the benefit of mesalazine in the carcinogenesis risk associated with ulcerative colitis.
Pharmacokinetics: PR granules: General characteristics of the active substance: Disposition and local availability: The therapeutic effect of mesalazine most likely depends on a local contact of the drug with the diseased area of the intestinal mucosa.
PENTASA prolonged release granules consist of ethylcellulose coated microgranules of mesalazine. Following administration, mesalazine is released continuously throughout the gastrointestinal tract in any enteral pH conditions.
The microgranules enter the duodenum within an hour of administration, independent of food co-administration. The average small intestinal transit time is approximately 3-4 hours in healthy volunteers.
Biotransformation: Mesalazine is metabolised into N-acetyl-mesalazine (acetyl-mesalazine) both pre-systemically by the intestinal mucosa and systemically in the liver. Some acetylation also occurs through the action of colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient.
Acetyl-mesalazine is believed to be clinically inactive, but this remains still to be confirmed.
Absorption: Based on urine recovery data in healthy volunteers, 30-50% of an oral dose is absorbed predominantly from the small intestine.
Mesalazine is detectable in plasma already 15 minutes after administration. Maximum plasma concentrations are seen 1-4 hours post-dose. The plasma concentration of mesalazine decreases gradually, and is no longer detectable 12 hours post-dose. The plasma concentration curve for acetyl-mesalazine follows the same pattern, but the concentration is generally higher and the elimination is slower.
The metabolic ratio of acetyl-mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after daily doses of 500 mgx3 and 2 gx3, respectively, implying a dose-dependent acetylation which may be subject to saturation.
Mean steady-state plasma concentrations of mesalazine are approximately 2 μmol/l, 8 μmol/l and 12 μmol/l after 1.5 g, 4 g and 6 g daily dosages, respectively. For acetyl-mesalazine, the corresponding concentrations are 6 μmol/l, 13 μmol/l and 16 μmol/l.
The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic absorption will be reduced.
Distribution: Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about 80%.
Elimination: The plasma half-life of mesalazine is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes. Due to the continuous release of mesalazine throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. Tests have shown that steady-state is reached after a treatment period of 5 days following oral administration. Both mesalazine and acetyl-mesalazine are excreted with the urine and faeces. The urinary excretion consists mainly of acetyl-mesalazine.
Characteristics in Patients: The delivery of mesalazine to the intestinal mucosa after oral administration is only slightly affected by pathophysiologic changes such as diarrhoea and increased bowel acidity observed during active inflammatory bowel disease. A reduction in systemic absorption to 20-25% of the daily dose has been observed in patients with accelerated intestinal transit. Likewise, a corresponding increase in faecal excretion has been seen.
In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination may constitute an increased risk of kidney damage.
Tablet: Treatment of mild to moderate ulcerative colitis and Crohn's disease.
PR granules: Treatment of mild to moderate ulcerative colitis.
Suppository: Treatment of chronic inflammatory bowel disease located in the rectum (ulcerative proctitis).
Enema: Treatment of chronic inflammatory bowel disease located in the colon and rectum (ulcerative proctosigmoiditis).
SR tab/PR tab: Ulcerative colitis: Adult:
Acute: Up to 4 g daily in divided doses. Maintenance: 2 g once daily. Children:
20-30 mg/kg daily. Crohn's disease: Adult:
Up to 4 g daily in divided doses. Children:
20-30 mg/kg/day in divided doses.
See Table 1.
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In general: Children (≥6 years):
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.
No reduction of dose.
1 g (1 supp) 1-2 times daily.
A visit to the toilet is recommended before inserting a suppository. Open the foil bag at the tear mark. The suppository is inserted in the rectum until resistance is felt and disappeared again. In order to facilitate the administration, the suppository can be moistured with water or moisture cream. If the suppository is discharged within the first 10 min, another can be inserted.
1 enema at bedtime according to physician's instructions.
Pentasa enema is protected by a foil bag which must not be removed until immediately before use. A visit to the toilet is recommended before administration. Remove the foil bag. Shake the plastic container well before use. Turn the tip 1 turn on the container. Place the hand into the enclosed plastic bag and grab hold of the container. Position the patient to prepare for the administration of the rectal suspension. Carefully insert the tip into the rectum and slowly press out the liquid, might be administered by pressing more times. Pull out the tip while the container is still compressed. Remain in position for 5-10 min or until the urge, if any, has disappeared. Roll the bag on the container before discharge.
Administration: PR granules:
For oral use.
The granules must not be chewed. The contents of the sachet should be emptied onto the back of the tongue and washed down with some water or juice. It is important to take the doses regularly and consequently to obtain the wanted effect.
Tablet/PR granules/Suppository/Enema: Acute toxicity in animals: Single oral doses of mesalazine up to 5 g/kg in pigs or a single intravenous dose of mesalazine at 920 mg/kg in rats were not lethal.
Human Experience: No cases of overdose have been reported.
PR granules: Acute toxicity in human: There is only limited clinical experience with overdose of PENTASA which do not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive. There have been reports of patients taking daily doses of 8 grams for a month without any adverse events.
Management of overdose in man: Symptomatic treatment at hospital. Close monitoring of renal function.
Hypersensitivity to mesalazine, any of the excipients, or salicylates.
Severe liver or renal impairment.
Gastric or duodenal ulcer.
Children <2 years.
Most of the patients who are intolerant or hypersensitive to sulphasalazine are able to take PENTASA without risk of similar reactions. However, caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates). In case of acute symptoms of intolerance, i.e. abdominal cramps, acute abdominal pain, fever, severe headache and rash, the treatment should be discontinued immediately.
Caution is recommended in patients with impaired liver function. Liver function parameters like ALT or AST should be assessed prior to and during treatment, at the discretion of the treating physician.
The drug is not recommended for use in patients with renal impairment. The renal function should be monitored regularly (e.g. serum creatinine), especially during the initial phase of treatment. Urinary status (dip sticks) should be determined prior to and during treatment at the discretion of the treating physician. Mesalazine induced nephrotoxicity should be suspected in patients who develop abnormal renal function during treatment. The concurrent use of other known nephrotoxic agents should increase monitoring frequency of renal function.
Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment.
Mesalazine induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported very rarely. Blood test for differential blood count is recommended prior to and during treatment, at the discretion of the treating physician. As stated in Interactions, concomitant treatment with azathioprine, 6-mercaptopurine or thioguanine can increase the risk of blood dyscrasia. Treatment should be discontinued on suspicion or evidence of these adverse reactions.
As a guideline, follow-up tests of blood and urine are recommended 14 days after commencement of treatment, then a further two to three tests at intervals of 4 weeks. If the findings are normal, follow-up tests should be carried out every three months. If additional symptoms occur, these tests should be performed immediately.
Effects on Ability to Drive and Use Machines: Treatment with PENTASA is unlikely to affect the ability to drive and/or use machines.
Pregnancy: Mesalazine should be used with caution during pregnancy and lactation and only if the potential benefits for the mother outweigh the possible risks for the foetus in the opinion of the physician.
Mesalazine is known to cross the placental barrier, and its concentration in umbilical cord plasma is one tenth of the concentration in maternal plasma. The metabolite acetyl-mesalazine is found in the same concentration in umbilical cord and maternal plasma. From several observational studies no teratogenic effects are reported and there is no evidence of significant risk of use in humans. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development. Blood disorders (pancytopenia, leucopenia, thrombocytopenia and anaemia) have been reported in new-borns of mothers being treated with PENTASA.
In one single case after long-term use of a high dose of mesalazine (2-4 g, orally) during pregnancy, renal failure in a neonate was reported.
Lactation: Mesalazine is excreted in breast milk. The mesalazine concentration in breast milk is lower than in maternal blood, whereas the metabolite, acetyl-mesalazine appears in similar or increased concentrations. There is limited experience of the use of oral mesalazine in lactating women. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions like diarrhoea in the infant cannot be excluded. If the infant develops diarrhoea, breast-feeding should be discontinued.
The most frequent adverse reactions seen in clinical trials are diarrhoea, nausea, abdominal pain, headache, vomiting and rash.
Hypersensitivity reactions and drug fever may occasionally occur.
Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance: See Table 2.
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It is important to note, that many of these side effects can also be caused by the inflammatory bowel disease.
Concurrent treatment with PENTASA and azathioprine, 6-mercaptopurine or thioguanine have in several studies shown a higher frequency of myelosuppressive effects, and an interaction seems to exist. The mechanism behind the interaction is not fully established. Regular monitoring of white blood cells is recommended and dosage regime of thiopurines should be adjusted accordingly.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.
Tablet/Suppository: When stored at room temperature in unopened original package, stable for 3 years.
PR granules: Store below 30°C. Protect from light. Do not freeze.
Enema: When stored at original packing at room temperature (30°C), stable for 2 years.
Shelf-Life: PR granules: 2 years.
A07EC02 - mesalazine ; Belongs to the class of aminosalicylic acid and similar antiinflammatory. Used in the treatment of intestinal inflammation.
SR tab 500 mg x 100's. PR tab 1 g x 60's. Sachet (PR granules) (white-grey to pale white-brown) 1 g x 50's. 2 g x 60's. 4 g x 30's. Supp 1 g x 28's. Enema 1 g/100 mL x 7's.