Pentasa

Mesalazine.

Prolonged-release tablet: Prolonged Release Tablets 500 mg: Each tablet contains 500 mg mesalazine.
Prolonged Release Tablets 1 g: Each tablet contains 1 g mesalazine.
Prolonged-release granules: Each sachet contains 2 g mesalazine.
Suppository: Each suppository contains 1 g mesalazine.
Rectal suspension: Each bottle of rectal suspension contains 1 g (1g/100ml) mesalazine.
Excipients/Inactive Ingredients: Prolonged-release tablet: Magnesium stearate, talc, ethylcellulose, povidone, microcrystalline cellulose.
Prolonged-release granules: Ethylcellulose and Povidone.
Suppository: Magnesium stearate, talc, povidone, macrogol 6000.
Rectal suspension: 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 (Prolonged-release tablet and Suppository).
Based on clinical results, the therapeutic value of mesalazine after oral and 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 mesalazine.
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.
Prolonged-release tablet and Prolonged-release 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 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: 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.
Prolonged-release tablet and Prolonged-release granules: PENTASA prolonged release tablets/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 and Rectal suspension: PENTASA suppositories and rectal suspensions 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. Rectal suspensions have been shown to reach and cover the descending colon.
Absorption: Prolonged-release tablet and Prolonged-release 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 (1 × 4 g/d) and a twice-daily dosage (2 × 2 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.)

Click on icon to see table/diagram/image

The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic exposure may be increased.
Suppository and Rectal suspension: 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 (suppository) and about 15-20% (rectal suspension) are absorbed after administration.
Distribution: Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about 80%.
Metabolism: 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.
Prolonged-release tablet and Prolonged-release granules: 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 × 3 and 2 g × 3, respectively, implying a dose-dependent acetylation which may be subject to saturation.
Elimination: Due to the continuous release of mesalazine from PENTASA throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. However, 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.
Characteristics in Patients: Prolonged-release tablet and Prolonged-release 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.
Rectal suspension: The systemic exposure following administration of PENTASA rectal suspension has been shown to be significantly decreased in patients with active ulcerative colitis as compared to those in remission.
Toxicology: Preclinical Safety Data: Toxic renal effects have been demonstrated in all species tested. Rat and monkey dosages and plasma concentrations at the No Observed Adverse Effect Levels (NOAELs) exceed those used in humans by a factor of 2-7.2.
No significant toxicity associated with the gastrointestinal tract, liver or haematopoietic system in animals has been observed.
In vitro test systems and in-vivo studies showed no evidence of mutagenic or clastogenic effects. Studies of the tumourigenic potential carried out in mice and rats showed no evidence of any substance-related increase in the incidence of tumours.
Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryo-foetal development, parturition or postnatal development.
Mesalazine is deemed not to pose a risk to the environment at the doses prescribed for use in patients.

Prolonged-release tablet: Treatment of ulcerative colitis and Crohn's disease.
Prolonged-release granules: Treatment of mild to moderate ulcerative colitis.
Suppository: Treatment of ulcerative proctitis.
Rectal suspension: Treatment of ulcerative proctosigmoiditis.

Posology: Ulcerative colitis: Treatment of active disease: Prolonged-release tablet: Adults: Individual dosage, up to 4 g daily in divided doses.
Children 6 years of age and older: Individual dosage, usually 20-30 mg/kg bodyweight daily in divided doses.
Maintenance treatment: Adults: Individual dosage, usually 2 g daily in divided doses.
Children 6 years of age and older: Individual dosage, usually 20-30 mg/kg bodyweight daily in divided doses.
Prolonged-release granules: Adults: Individual dosage, up to 4 g given once daily or in divided doses.
Prolonged-release tablet: Crohn's disease: Treatment of active disease and maintenance treatment: Adults: Individual dosage, up to 4g daily in divided doses.
Children 6 years of age and older: Individual dosage, usually 20-30 mg/kg bodyweight daily in divided doses.
Suppository: Posology: 1 suppository 1-2 times daily.
Rectal suspension: Posology: Adults: 1 rectal suspension at bedtime.
Paediatric population: Prolonged-release tablet and Prolonged-release granules: There is only limited documentation for an effect in children (age 6-18 years).
Suppository and Rectal suspension: There is little experience and only limited documentation for an effect in children.
Method of administration: Prolonged-release tablet: PENTASA tablets must not be chewed. To facilitate swallowing, the tablets may be dispersed in 50 ml of cold water. Stir and drink immediately.
Prolonged-release granules: PENTASA granules must not be chewed. The contents of the sachet should be emptied onto the tongue and washed down with some water or orange juice. Alternatively, the entire content of the sachet can be taken with yogurt and consumed immediately.
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.
Rectal suspension: 1. A visit to the toilet is recommended before administration of the rectal suspension.
2. Immediately before use take the rectal suspension 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 the hand in one of the plastic disposal bags provided in the pack.
5. Hold the container. Lubricate top part of rectal applicator.
6. To administer the rectal suspension, 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 rectal suspension should be retained in the bowel. Remain relaxed in the administration position for 5-10 minutes or until the urge to pass the rectal suspension has disappeared. Try to retain the rectal suspension overnight.
9. Roll the plastic disposal bag over the empty bottle. Discard it and wash hands.

Acute experience 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: There is limited clinical experience with overdose of PENTASA which do not indicate renal or hepatic toxicity. But 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 over dosage is 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.

Hypersensitivity to mesalazine, any of the excipients/components of the product, 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 (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. In case of acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever and 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 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 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. Refer to 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 with mesalazine content have been reported during treatment with mesalazine. Adequate fluid intake must be ensured 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.
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).
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.
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. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetal development, parturition or postnatal development. 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.
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. 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.
Fertility: Animal data on mesalazine show no effect on male and female fertility.

Summary of the safety profile: 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 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 Precautions).
Prolonged-release tablet: (See Table 2.)

Click on icon to see table/diagram/image

Prolonged-release granules and Suppository: (See Table 3.)

Click on icon to see table/diagram/image

Rectal suspension: (See Table 4.)

Click on icon to see table/diagram/image

It is important to note that several of these disorders can also be attributed to the inflammatory bowel disease itself.
Suppository and Rectal suspension: 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.

Incompatibilities: None known.
Special Precautions for Disposal: No special requirements.
Any unused product or waste should be disposed of in accordance with local requirements.
Rectal suspension: The rectal suspension may colour the linen and toilet.

Shelf Life: Prolonged-release tablet and Suppository: 3 years.
Prolonged-release granules and Rectal suspension: 2 years.
Prolonged-release tablet, Prolonged-release granules and Rectal suspension: Store below 30°C. Store in the original package, as the product is sensitive to light.
Prolonged-release tablet and Prolonged-release granules: Do not freeze.
Rectal suspension: Do not refrigerate or freeze.
Suppository: Store below 25°C. Store in the original package, as the product is sensitive to light.

GIT Regulators, Antiflatulents & Anti-Inflammatories

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

POM