Pentasa

Mesalazine.

PR Tablet:White grey to pale brown, speckled round tablets. Breakmark and embossing: 500 mg on one side, PENTASA on the other side.
Each tablet contains 500 mg mesalazine.
PR Granules: White-grey to pale white-brown granules.
Each sachet contains 2 g mesalazine.
Suppository: White to tan, spotted, oblong suppositories.
Each suppository contains 1 g mesalazine.
Enema: White to slightly yellow suspension with a pH value between 4.4 and 5.0.
Each enema contains 1 g (1 g/100 mL) mesalazine.
Excipients/Inactive Ingredients: PR Tablet: Magnesium stearate, talc, ethylcellulose, povidone, microcrystalline cellulose.
PR Granules: Ethylcellulose, povidone.
Suppository: Magnesium stearate, talc, povidone, macrogol 6000.
Enema: Disodium edetate, sodium metabisulphite, sodium acetate, purified water and hydrochloric acid for pH adjustment.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents. ATC Code: (A07 EC02).
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: It has been established that mesalazine is the active component of sulfasalazine, which is used for the treatment of ulcerative colitis and Crohn's disease.
Based on clinical results, the therapeutic value of mesalazine after oral as well as rectal administration appears to be due to local effect on the inflamed intestinal tissue, rather than to systemic effect. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalazine is inversely correlated with mucosal concentrations of mezalamine.
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 (IBD). The mechanism of action of mesalazine is not fully understood although mechanisms such as activation of the γ-form of peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor-kappa B (NF-κB) in the intestinal mucosa has been implicated. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leucotriene production, and scavenge for free radicals. It is currently unknown which, if any, of these mechanisms play a predominant role in the clinical efficacy of mesalazine.
PR Tablet and PR Granules: 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 metaanalyses, 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: General characteristics of the active substance: Disposition and local availability: The therapeutic activity of mesalazine most likely depends on a local contact of the drug with the diseased area of the intestinal mucosa.
PR Tablet and PR Granules: PENTASA prolonged release tablets and granules consist of ethylcellulose-coated microgranules of mesalazine. The tablet disintegrate upon administration to coated microgranules and enter the duodenum within an hour of administration, independent of food co-administration. Mesalazine is continuously released from the coated microgranules throughout the gastrointestinal tract in any enteral pH conditions.
Suppository: PENTASA suppositories are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. Suppositories cover the rectum.
Enema: PENTASA enemas are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. Enemas have been shown to reach and cover the descending colon.
Absorption: PR Tablet and PR Granules: Bioavailability of Pentasa after oral administration can be estimated to approx. 30%, based on urine recovery data in healthy volunteers. Maximum plasma concentrations are seen 1-6 hours post-dose. A once-daily dosing regimen of mesalazine (1x4 g/d) and a twice-daily dosage (2x2 g/d) results in a comparable systemic exposure (AUC) over 24 hours and indicate a continuous release of mesalazine from the formulation over the treatment period. Steady-state is reached after a treatment period of 5 days following oral administration. (See Table 1.)

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The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic exposure may be increased.
Suppository and Enema: The absorption following rectal administration is low, and depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2 g (1 g x 2), approximately 10% of the dose is absorbed after administration of suppositories and about 15-20% is absorbed after administration of enemas.
Distribution: Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about 80%.
Metabolism: PR Tablet and PR Granules: Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl-mesalazine (acetyl-mesalazine) principally by NAT-1. Some acetylation also occurs through the action of colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient.
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 mg x 3 and 2 g x 3, respectively, implying a dose-dependent acetylation which may be subject to saturation.
Elimination: Once the formulation is not present in the GI tract elimination will follow the plasma half-life of orally or IV administered uncoated mesalazine, which is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes.
PR Tablet and PR Granules: Due to the continuous release of mesalazine from PENTASA throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration.
Enema: The systemic exposure following administration of PENTASA enemas has been shown to be significantly decreased in patients with active ulcerative colitis as compared to those in remission.
Characteristics in patients: PR Tablet and PR Granules: Pathophysiologic changes such as diarrhoea and increased bowel acidity observed during active inflammatory bowel disease has only a minor impact on the delivery of mesalazine to the intestinal mucosa after oral administration. A urine excretion 20-25% of the daily dose has been observed in subjects with accelerated intestinal transit. Likewise, a corresponding increase in faecal excretion has been seen.

PR Tablet and PR Granules: Treatment of mild to moderate ulcerative colitis and Crohn's disease.
Suppository: Treatment of ulcerative proctitis.
Enema: Treatment of ulcerative proctosigmoiditis.

PR Tablet and PR Granules: Ulcerative colitis: Treatment of active disease: Adults: Individual dosage, up to 4 g given once daily or in divided doses.
Children 6 years of age and older: 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 (maximum adult dose).
Maintenance treatment: Adults: Individual dosage. Recommended dosage, 1.5 g to 2 g mesalazine once daily in prolonged release tablets or 2 g mesalazine once daily in prolonged release granules. Can also be taken in divided doses.
Children 6 years of age and older: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 2 g/day (recommended adult dose).
Crohn's disease: Treatment of active disease: Adults: Individual dosage, up to 4 g daily in divided doses.
Children 6 years of age and older: 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 (maximum adult dose).
Maintenance treatment: Adults: Individual dosage, up to 4 g daily in divided doses.
Children 6 years of age and older: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 4 g/day (recommended adult dose).
Note for paediatric population: There is only limited documentation for an effect in children (age 6-18 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.
Suppository and Enema: Paediatric population: There is little experience and only limited documentation for an effect in children.
Suppository: 1 suppository 1-2 times daily.
Enema: 1 enema at bedtime.
Method of Administration: PR Tablet: For oral use.
PENTASA tablets must not be chewed. To facilitate swallowing, the tablets may be dispersed in 50 ml of cold water. Stir and drink immediately.
PR Granules: For oral use.
PENTASA Sachet must not be chewed. The contents of the sachet should be emptied onto the tongue and washed down with some water or juice. Alternatively, the entire content of the sachet can be taken with yoghurt and consumed immediately.
Suppository and Enema: PENTASA Suppositories and Enema are for rectal administration.

Human experience: There is limited clinical experience with overdose of PENTASA which does not indicate renal or hepatic toxicity. Since PENTASA is an amino salicylate, symptoms of salicylate toxicity such as acid-base balance disorder, hyperventilation, pulmonary edema, vomiting, dehydration and hypoglycaemia may occur. Symptoms of salicylate overdosage are well described in the literature.
There have been reports of patients taking daily doses of 8 grams for a month without any adverse events.
There is no specific antidote and the management of overdose is supportive and symptomatic. The treatment at the hospital includes close monitoring of renal function.
Acute experience in animals: PR Tablet and PR Granules: 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.

Hypersensitivity to mesalazine, any of the excipients, or salicylates.
Severe liver and/or renal impairment.

Most 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). Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment. In case of acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and/or the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other signs of hypersensitivity, therapy should be discontinued immediately.
Caution is recommended in patients with impaired liver function. Liver function parameters like Alanine Aminotransferase (ALT) or Aspartate aminotransferase (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 developing renal dysfunction 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; see Adverse Reactions.
Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported very rarely with mesalazine. 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 mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine, or 6-mercaptopurine or thioguanine. Treatment should be discontinued on suspicion or evidence of these adverse reactions.
Patients with inflammatory bowel disease are at risk of developing 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.
As a guideline, follow-up tests 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.

PENTASA should be used with caution during pregnancy and lactation and only if the potential benefits outweigh the possible hazards in the opinion of the physician. The underlying condition itself (Inflammatory bowel disease/IBD) may increase risks for adverse pregnancy outcome.
Pregnancy: Mesalazine is known to cross the placental barrier and its concentration in umbilical cord plasma is lower than the concentration in maternal plasma. The metabolite acetyl-mesalazine is found at similar concentrations in umbilical cord and maternal plasma. There are no adequate and well controlled studies of PENTASA use in pregnant women. Limited published human data on mesalazine show no increase in the overall rate of congenital malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease.
Blood disorders (pancytopenia, leucopenia, thrombocytopenia, anaemia) have been reported in newborns of mothers being treated with PENTASA.
PR Tablet and PR Granules: Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetal development, parturition or postnatal development.
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.
Breastfeeding: 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. 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.
PR Tablet and PR Granules: There is limited experience of the use of oral mesalazine in lactating women.
Fertility: Animal data on mesalazine show no effect on male and female fertility.

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 and severe cutaneous adverse reactions, including SJS and TEN, have been reported in association with mesalazine treatment (see Precautions). (See Table 2.)

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It is important to note that several of these disorders can also be attributed to the inflammatory bowel disease itself.
Suppository and Enema: Following rectal administration local reactions such as pruritus, rectal discomfort and urge may occur.

Combination therapy with PENTASA and azathioprine, or 6-mercaptopurine or thioguanine have in several studies shown a higher frequency of myelosuppressive effects, and an interaction seems to exist. However, 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.
The concurrent use of mesalazine with other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

Incompatibilities: None known.
Instructions for Use and Handling: Suppository: 1. A visit to the toilet is recommended before inserting a suppository.
2. Open the foil bag at the tear mark.
3. The suppository is inserted in the rectum until resistance is felt and disappeared again.
4. In order to facilitate the administration, the suppository can be moistured with water or moisture cream.
5. If the suppository is discharged within the first 10 minutes, another can be inserted.
Enema: 1. A visit to the toilet is recommended before administration of the enema.
2. Immediately before use take the enema bottle out of the aluminium foil pack and shake it well.
3. To break the seal twist the nozzle clockwise one full turn (the nozzle should then be in the same direction as before turning).
4. Put hand in one of the plastic disposal bags provided in the pack.
5. Hold the container.
6. To administer the enema, lie on the left side with the left leg straight and the right leg bent forward for balance. Carefully insert the applicator tip into the rectum. Maintain sufficient steady hand pressure while dispersing the bottle content. The bottle content should be applied within max. 30-40 seconds.
7. Once the bottle is empty, withdraw the tip with the bottle still compressed.
8. The enema should be retained in the bowel. Remain relaxed in the administration position for 5-10 minutes or until the urge to pass the enema has disappeared.
9. Roll the plastic disposal bag over the empty bottle. Discard it and wash hands.
Special Precautions for Disposal: Enema: The enema may colour the linen and toilet.

Store below 30°C. Store in the original package, as the product is sensitive to light.
Enema: Do not refrigerate or freeze.
Shelf-Life: PR Tablet and Suppository: 3 years.
PR Granules and Enema: 2 years.

GIT Regulators, Antiflatulents & Anti-Inflammatories

A07EC02 - mesalazine ; Belongs to the class of aminosalicylic acid and similar antiinflammatory. Used in the treatment of intestinal inflammation.

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