Pentasa

Mesalazine.

Tablet: Each tablet consists of microgranules which contain a core of pure mesalazine.
Granules: Each sachet contains 2 g mesalazine.
Suppository: Each suppository contains granulated mesalazine.
Excipients/Inactive Ingredients: Tablet: Povidone, ethyl cellulose, magnesium stearate, talc and microcrystalline cellulose.
Granules: Ethylcellulose and Povidone.
Suppository: Povidone, magnesium stearate, talc and macrogol 6000.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents (A07 EC02).
Pharmacology: Pharmacodynamics: Granules: 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.
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: Granules: 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. Mesalazine (Pentasa) prolonged release granules consist of ethylcellulose-coated microgranules of mesalazine 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.
Absorption: Bioavailability of Mesalazine (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 coadministration, whereas the systemic exposure may be increased.
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. 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 Mesalazine (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: 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.
Toxicology: Granules: 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.

Tablet: Treatment of chronic inflammatory bowel disease (ulcerative colitis and Crohn's disease).
Granules: Treatment of mild to moderate ulcerative colitis and Crohn's disease.
Suppository: Treatment of chronic inflammatory bowel disease (ulcerative proctitis).

Tablet: Ulcerative Colitis: Adults: Individualize dosage, up to mesalazine 4 g daily in divided doses for active disease, up to 2 g daily in divided doses for maintenance treatment.
Children: Usual Dose: 20-30 mg/kg body weight daily in divided doses for active disease and maintenance treatment.
Crohn's Disease: Active Disease and Maintenance Treatment: Adults: Individualize dosage, usually mesalazine 4 g daily in divided doses.
Children: Individualize dosage, usually 20-30 mg/kg body weight daily in divided doses.
Granules: Ulcerative colitis: Adults: Active disease: Individual dosage, up to 4 g mesalazine once daily or divided into 2-4 doses.
Maintenance treatment: Individual dosage. Recommended dosage, 2 g mesalazine once daily.
Pediatric population: The safety and efficacy in children below 6 years of age have not been established. There is only limited documentation for an effect in children (age 6-18 years).
Children 6 years of age and older: Active disease: 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: 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).
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.
Crohn's disease: Children 6 years of age and older: Treatment of Active Disease: 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).
Children 6 years of age and older: Maintenance Treatment: 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).
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.
Method of administration: Oral use.
The 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: Adults: 1 g (1 supp) 1-2 times daily.
Children >2 years: According to physician's instructions.
Administration: Tablet: Pentasa slow-release tablets must not be chewed. In order to facilitate the administration, the tablets can be halved or suspended in water or juice immediately before use.
A visit to the toilet is recommended before inserting a suppository. Open the foilbag at the tear mark. Place one of the enclosed finger protectors on the insertion finger. The suppository is inserted in the rectum until resistance is felt and disappears 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. Dispose of the foil and the used finger protector.

Tablet/Suppository: There is lack of experience in overdosage. The physician should be contacted if an overdosage is suspected.
Granules: 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 are limited clinical experience with overdose of Mesalazine (Pentasa) which do not indicate renal or hepatic toxicity. Since Mesalazine (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 or any other component of Pentasa, and in case of severe liver or kidney disease.
Granules: Hypersensitivity to mesalazine, any of the excipients, or salicylates.
Severe liver or renal impairment.

In certain cases, patients allergic to sulfasalazine may also suffer allergic reactions to Pentasa (risk of allergy to salicylates).
In case of impaired liver or kidney function, further actions should be discussed with the physician. Pentasa is not recommended for use in patients with impaired kidney function. The kidney function should be regularly monitored, especially during the initial phase of treatment.
Serious changes in the blood components and inflammation of the cardiac muscle and sack (myo- and pericarditis) are seen in rare cases. On suspicion of these adverse reactions, contact the physician and discontinue treatment.
Symptoms can be bleeding, bruises, sore throat and fever or in case of inflammation of the cardiac muscle and sack, fever and chest pain accompanied by shortness of breath.
Granules: Most patients who are intolerant or hypersensitive to sulphasalazine are able to take Mesalazine (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, 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; please 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.
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.
Effects on the Ability to Drive or Operate Machinery: Tablet/Suppository: None.
Granules: Treatment with Mesalazine (Pentasa) is unlikely to affect the ability to drive and/or use machines.
Use in Pregnancy & Lactation: Limited experience. Pentasa should not be used during pregnancy and lactation except on doctor's advice.
Use in Children: Pentasa is not recommended in children <2 years.

Tablet/Suppository: Limited experience. Pentasa should not be used during pregnancy and lactation except on doctor's advice.
Granules: Mesalazine (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 the 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. 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 Mesalazine (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 Mesalazine (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 Mesalazine (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.

Tablet/Suppository: The most frequent adverse reactions seen in clinical trials are diarrhea (3%), nausea (3%), abdominal pain (3%), headache (3%), vomiting (1%), and rash (1%). Hypersensitivity reactions and drug fever may occasionally occur.
Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance: Common (≥1% and <10%): Headache, diarrhea, abdominal pain, nausea, vomiting, rash.
Rare (≥0.01% and <0.1%): Myo- and pericarditis, increased amylase, pancreatitis.
Very Rare (<0.01%): Reversible alopecia, isolated reports of lupus erythematosus-like reactions, increased liver enzymes and bilirubin, hepatotoxicity, abnormal renal function, allergic lung reactions, myalgia, arthralgia, eosinophilia, anemia, aplastic anemia, leukopenia, thrombocytopenia, agranulocytosis, pancytopenia.
Following rectal administration, local reactions eg, pruritus, rectal discomfort and urge may occur.
Several of these adverse reactions can also be attributed to the inflammatory bowel disease itself.
Granules: 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.)

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.

Granules: Incompatibilities: None known.

Tablet/Suppository: Store at room temperature (15-25°C) in the original package.
Granules: Store below 30°C. Store in the original package, as the product is sensitive to light. Do not freeze.
Shelf-Life: Tablet/Suppository: 3 years.
Granules: 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.

Rx