Pentasa

Pentasa

mesalazine

Manufacturer:

Ferring

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Mesalazine.
Description
SR tab: Each tablet contains 500 mg mesalazine.
PR tab:
Each tablet contains 1 g mesalazine.
PR granules: 1 g: Each sachet contains 1 g mesalazine.
2 g: Each sachet contains 2 g mesalazine.
Enema: Each rectal suspension contains 1 g (1g/100ml) mesalazine.
Suppository: Each suppository contains 1 g mesalazine.
Excipients/Inactive Ingredients: SR tab & PR tab: Magnesium stearate, talc, ethylcellulose, povidone, microcrystalline cellulose.
PR granules: Ethylcellulose, povidone.
Enema: disodium edetate, sodium metabisulphite, sodium acetate, purified water and hydrochloric acid for pH adjustment.
Suppository: magnesium stearate, talc, povidone, macrogol 6000.
Action
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 Mesalamine.
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 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.
SR tab, PR tab, 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 downregulation 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.
SR tab, PR tab, PR granules: PENTASA prolonged release tablets/granules consist of ethylcellulose-coated microgranules of mesalazine.
The tablet disintegrate upon administration to coated microgranules (for SR tab and PR tab only) and microgranules (for PR granules only) 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.
Enema & Suppository: PENTASA enemas/suppositories 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 (for Enema only) and suppositories cover the rectum (for Suppository only).
Absorption: SR tab, PR tab, 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 (1 x 4 g/d) and a twice-daily dosage (2 x 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.
Enema & Suppository: 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 2g (1g x 2), about 15-20% is absorbed after administration of enemas (for Enema only) and approximately 10% of the dose is absorbed after administration of suppositories (for Suppository only).
Distribution: Protein binding of mesalazine is approximately 50% and of acetylmesalazine 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.
SR tab, PR tab, PR 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 x 3 and 2 g x 3, respectively, implying a dose dependent acetylation which may be subject to saturation.
Elimination: SR tab, PR tab, 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. 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.
Enema: The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes. 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.
Suppository: The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes.
Characteristics in patients: SR tab, PR tab, 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 tab: In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.
Indications/Uses
SR tab, PR tab, PR granules: Treatment of mild to moderate ulcerative colitis and Crohn's disease.
Enema: Treatment of ulcerative proctosigmoiditis and left-sided colitis.
Suppository: Treatment of ulcerative proctitis.
Dosage/Direction for Use
SR tab, PR tab, 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, 2 g mesalazine once daily. 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).
Enema: 1 enema at bedtime.
Suppository: 1 suppository 1 - 2 times daily.
SR tab/PR tab/PR granules: Note for paediatric population: 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.
There is only limited documentation for an effect in children (age 6 -18 years).
SR tab/PR tab/PR granules: PENTASA tablets/sachet must not be chewed. To facilitate swallowing, the tablets may be dispersed in 50 ml of cold water. Stir and drink immediately (for SR tab/PR tab only). The contents of the sachet should be emptied onto the tongue and washed down with some water or juice (for PR granules only).
Enema/Suppository: There is little experience and only limited documentation for an effect in children.
Overdosage
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 may occur. Symptoms of salicylate over dosage 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.
Management of overdose in man: 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.
Contraindications
Hypersensitivity to mesalazine, any of the excipients, or salicylates.
Severe liver or renal impairment.
Special Precautions
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). In case of acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, 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.
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.
Use In Pregnancy & Lactation
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. 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.
SR tab, PR tab, 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.
SR tab, PR tab, 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.
Adverse Reactions
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.
Following rectal administration local reactions such as pruritus, rectal discomfort and urge may occur (for Enema and Suppository only).
Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance. (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.
Drug Interactions
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.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.
Caution For Usage
Instructions for Use and Handling: 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 the 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.
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.
Incompatibilities: None known.
Storage
Store below 30°C. Store in the original package, as the product is sensitive to light.
Shelf-life: SR tab, PR tab, Suppository: 3 years.
PR granules, Enema: 2 years.
ATC Classification
A07EC02 - mesalazine ; Belongs to the class of aminosalicylic acid and similar antiinflammatory. Used in the treatment of intestinal inflammation.
Presentation/Packing
SR tab 500 mg (white grey to pale brown, speckled round, breakmark and embossing: 500 mg on one side, PENTASA on the other side) x 10 x 10's. PR tab 1 g (white-grey to pale brown, speckled, oval, embossing on both sides: PENTASA) x 6 x 10's. PR granules (sachet) (white grey to pale white brown cylindrical shaped granules) 1 g x 50's. 2 g x 60's. Enema (white to slightly yellow suspension) 1 g/100 mL x 7's. Supp (white to tan, spotted, oblong, suppositories) 1 g x 4 x 7's.
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