- NAME OF THE MEDICINAL PRODUCT
Mesalazine Pellets Prolonged Release Granules 0.5g Taj Pharma
Mesalazine Pellets Prolonged Release Granules 1g Taj Pharma
Mesalazine Pellets Prolonged Release Granules 2g Taj Pharma
- QUALITATIVE AND QUANTITATIVE COMPOSITION
a) Each sachet contains:
For a full list of excipients, see section 6.1.
- PHARMACEUTICAL FORM
Prolonged release granules
White-grey to pale white-brown granules
- CLINICAL PARTICULARS
4.1 Therapeutic indications
Mild to moderate ulcerative colitis
4.2 Posology and method of administration
Individual dosage, up to 4 g Mesalazine once daily or divided into 2-4 doses.
Individual dosage. Recommended dosage, 2 g Mesalazine once daily.
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.
Method of administration
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.
Hypersensitivity to Mesalazine, any of the excipients listed in section 6.1, or salicylates.
Severe liver and/or renal impairment.
4.4 Special warnings and precautions for use
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, 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 impaired renal function and in patients with haemorrhagic diathesis. The renal function should be regularly monitored (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, such as NSAIDs and azathioprine, may increase the risk of renal reactions.
Caution is recommended in patients with active peptic ulcer.
Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment, please refer to section 4.8.
Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported very rarely with Mesalazine (see section 4.5). Blood tests for differential blood counts is recommended prior to and during treatment, at the discretion of the treating physician. 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.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed. Combination therapy with Pentasa and azathioprine or 6-mercaptopurine or thioguanine have shown a higher frequency of myelosuppressive effects, and an interaction cannot be ruled out, however, the mechanism behind the interaction is not established. Regular monitoring of white blood cells is recommended and the dosage regimen of thiopurine should be adjusted accordingly.
There is weak evidence that Mesalazine might decrease the anticoagulant effect of warfarin.
4.6 Fertility, pregnancy and lactation
Pentasa Sachet should not be used during pregnancy and lactation except when the potential benefits of the treatment 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. 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 (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with Pentasa Sachet.
In one single case after long-term use of a high dose of Mesalazine (2-4g, orally) during pregnancy, renal failure in a neonate was reported.
Breast-feeding: 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 Sachet during breast-feeding have been carried out. Only limited experience during lactation in women after oral application is available to date. Hypersensitivity reactions like diarrhoea 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
4.7 Effects on ability to drive and use machines
Pentasa Sachet has no or negligible influence on the ability to drive or use machines.
4.8 Undesirable effects
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
≥1/100 to <1/10
≥1/10,000 to ≤1/1,000
|Blood and the lymphatic system disorders||Altered blood counts (anaemia, aplastic anaemia, agranulocytosis, neutropenia, leukopenia (incl. granulocytopenia), pancytopenia, thrombocytopenia, and eosinophilia (as part of an allergic reaction).|
|Immune system disorders||Hypersensitivity reaction including anaphylactic reaction, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)|
|Nervous system disorders||Headache||Dizziness||Peripheral neuropathy|
Benign intracranial hypertension in adolescents
|Respiratory, thoracic and mediastinal disorders||Allergic alveolitis, allergic and fibrotic lung reactions (incl. dyspnoea, coughing, bronchospasm, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis)|
Increased amylase (blood and/or urine)
|Hepato-biliary disorders||Increased liver enzymes, cholestasis parameters and bilirubin, hepatotoxicity (incl. hepatitis*, cholestatic hepatitis, cirrhosis, hepatic failure)|
|Skin and subcutaneous tissue disorders||Rash (incl. urticaria, erythematous rash)||Photosensitivity**||(Reversible) alopecia|
Quincke’s oedema, dermatitis allergic,
Erythema multiforme Stevens-Johnson Syndrome (SJS)
|Musculoskeletal and connective tissue disorders||Myalgia|
Lupus erythematosus-like reactions
|Renal and urinary disorders||Renal function impairment|
(incl. interstitial nephritis* (acute and chronic), nephrotic syndrome, renal insufficiency acute/chronic)
|Reproductive system and breast disorders||Oligospermia (reversible)|
|General disorders and administration site conditions||Drug Fever|
(*) The mechanism of Mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of allergic origin.
(**) Photosensitivity: More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.
It is important to note that several of these disorders can also be attributed to the inflammatory bowel disease itself.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
Acute experience in animals: A single intravenous dose of Mesalazine in rats of 920 mg/kg and single oral doses of Mesalazine in pigs up to 5 g/kg were not lethal.
Human experience: There is limited clinical experience with overdose of Pentasa sachet 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 oral daily doses of 8 grams for a month without any adverse events
There is no specific antidote and treatment is symptomatic and supportive. The treatment at hospital includes close monitoring of renal function.
- PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic groups: Intestinal anti-inflammatory agents, aminosalicylic acid and similar agents
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. 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 leukocyte 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. 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 have been implicated. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leukocyte chemotaxis, decrease cytokine and leukotriene 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.
5.2 Pharmacokinetic properties
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.
Pentasa Sachet prolonged release granules consist of ethylcellulose coated microgranules of Mesalazine. The coated microgranules 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 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.
|Single dose||Steady state|
|Cmax (ng/mL)||AUC 0-24 (h·ng/mL)||Cmax (ng/mL)||AUC 0-24 (h·ng/mL)|
|2 g BID||5103.51||36,456||6803.70||57,519|
|4 g OD||8561.36||35,657||9742.51||50,742|
|Molecular weight of Mesalazine: 153.13 g/moL; Ac-Mesalazine: 195.17 g/moL.|
The transit and release of Mesalazine after oral administration are independent of food co-administration, whereas the systemic exposure may be increased.
Distribution: Mesalazine and acetyl-Mesalazine do not cross the blood-brain barrier. 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 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 have 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 patients with accelerated intestinal transit. Likewise, a corresponding increase in faecal excretion has been seen.
5.3 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.
In vitro test systems and in-vivo studies showed no evidence of mutagenic effects. Studies on the tumourigenic potential carried out in 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.
- PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.3 Shelf life
The granules should be used immediately after first opening of the sachet.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Polyester/Aluminium/LD polyethylene sachet.
1 x 50 sachets
2 x 50 or 100 sachets
3 x 50 or 150 sachets
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
- MANUFACTURED IN INDIA BY:
TAJ PHARMACEUTICALS LTD;
Plot No. 220, Mahagujarat Industrial Estate,
Moraiyya, Tal-Sanand, Dist-Ahmedabad, Gujarat.
PACKAGE LEAFLET: INFORMATION FOR THE USER
0.5G / 1G / 2G
Read all of this leaflet carefully before you start taking this medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
IN THIS LEAFLET:
- What Mesalazine Prolonged Release Granules 500mg Taj Pharma are and what they are used for
- Before you take Mesalazine Prolonged Release Granules 500mg Taj Pharma
- How to take Mesalazine Prolonged Release Granules 500mg Taj Pharma
- Possible side effects
- How to store Mesalazine Prolonged Release Granules 500mg Taj Pharma
- Further information1. WHAT MESALAZINE PROLONGED RELEASE GRANULES 500MG TAJ PHARMA ARE AND WHAT THEY ARE USED FOR
Mesalazine Prolonged Release Granules 500mg Taj Pharma contain the active substance mesalazine (also known as 5-aminosalicylic acid) which is an anti-inflammatory drug used in the treatment of:
- Ulcerative colitis– a disease of the large bowel (colon) and back passage (rectum) in which the lining of the bowel becomes inflamed (red and swollen). Symptoms can include rectal bleeding, frequent diarrhoea and abdominal pain. Mesalazine Prolonged Release Granules 500mg Taj Pharma act locally in the colon to reduce inflammation and can also prevent further episodes (flares) of ulcerative colitis.
- Crohn’s ileo-colitis– a disease affecting the small bowel (terminal ileum) and colon in which the lining of the bowel becomes swollen and sore. This may lead to the development of ulcers, abscesses and narrowing (strictures) in the bowel. Mesalazine Prolonged Release Granules 500mg Taj Pharmaact locally in the terminal ileum and colon to control the disease and prevent further flares of Crohn’s ileocolitis.
- BEFORE YOU TAKE MESALAZINE PROLONGED RELEASE GRANULES 500MG TAJ PHARMA
Do not take Mesalazine Prolonged Release Granules 500mg Taj Pharma if you:
- are allergic (hypersensitive) to any of the ingredients in the product (see Section 6 on ‘What Mesalazine Prolonged Release Granules 500mg Taj Pharma contain’)
- are allergic to aspirin or any other salicylate
- have had kidney problems or blood abnormalities while taking other medicines such as sulphasalazine
- have severe kidney impairment.
DO NOT give the tablets to children under 2 years of age.
Take special care with Mesalazine Prolonged Release Granules 500mg Taj Pharma
- Mesalazine Prolonged Release Granules 500mg Taj Pharma should be used with extreme caution in patients with confirmed mild to moderate kidney impairment.
- Mesalazine Prolonged Release Granules 500mg Taj Pharma should be used with caution in the elderly.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including those obtained without a prescription. Mesalazine Prolonged Release Granules 500mg Taj Pharma should NOT be taken with Lactulose (a medicine for constipation).
Use of non-steroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, aspirin, Cox-II inhibitors) and azathioprine in particular may increase the risk of kidney reactions.
Pregnancy and breast-feeding
Women who are pregnant or breast-feeding should not take Mesalazine Prolonged Release Granules 500mg Taj Pharma unless advised otherwise by their doctor.
Ask your doctor or pharmacist for advice before taking any medicine.
Tests on your liver, kidney and blood
Before you start treatment with Mesalazine Prolonged Release Granules 500mg Taj Pharma you will have a blood and urine test to check how well your kidneys are working and what your blood is doing. During treatment your doctor will check how well your liver, kidney and blood is working by taking blood and urine sample periodically during your treatment.
Driving and using machines
Mesalazine Prolonged Release Granules 500mg Taj Pharma are not expected to affect your ability to drive or operate machinery.
Important information about some of the ingredients of Mesalazine Prolonged Release Granules 500mg Taj Pharma
Lactose – if you know you have an intolerance to some sugars, contact your doctor before taking this medicine.
- HOW TO TAKE MESALAZINE PROLONGED RELEASE GRANULES 500MG TAJ PHARMA
Always take Mesalazine Prolonged Release Granules 500mg Taj Pharma exactly as your doctor has told you. You should check with your doctor if you are not sure.
The tablets should be swallowed whole with water; do not break, crush or chew them.
Whilst taking this medicine ensure you drink adequate fluids to remain well hydrated, especially after severe or prolonged episodes of vomiting and /or diarrhoea, high fever or heavy sweating. This is to avoid problems with your kidneys.
The usual dose is:
- Treating ulcerative colitis– 6 tablets each day divided throughout the day. For example:
- 2 tablets 3 times a day OR
- 3 tablets twice a day.
- Preventingfurther episodes of ulcerative colitis
- between 3 and 6 tablets once daily or divided throughout the day. For example:
- a daily dosage of 3 tablets may be taken as 3 tablets once a day or 1 tablet 3 times a day
- a daily dosage of 6 tablets may be taken as 6 tablets once a day or 3 tablets twice a day.
- Preventingfurther episodes of Crohn’s ileo-colitis – between 3 and 6 tablets divided throughout the day. For example:
- a daily dosage of 3 tablets may be taken as 1 tablet 3 times a day
- a daily dosage of 6 tablets may be taken as 3 tablets twice a day.
DO NOT take more than 6 tablets a day.
Mesalazine Prolonged Release Granules 500mg Taj Pharma are not recommended for use in children.
If you stop taking Ascol 400mg MR tablets
Keep taking the tablets for as long as your doctor tells you. Your symptoms may come back if you stop treatment too early. Remember to get a repeat prescription at the right time so that you do not miss a day of treatment.
If you take more Mesalazine Prolonged Release Granules 500mg Taj Pharma than you should
Do not exceed the recommended dose. You should only take as many tablets as your doctor has instructed on the pharmacist’s label. If you take too much medicine, tell your doctor immediately or go to your nearest Accident & Emergency Department. Take the tablet pack with you if possible.
If you forget to take Mesalazine Prolonged Release Granules 500mg Taj Pharma
If you forget to take a dose at the required time, take it as soon as you remember and continue taking your tablets as before. DO NOT take more than two doses in one hour. If it is almost time for your next dose, wait until then and carry on as before.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
- POSSIBLE SIDE EFFECTS
Like all medicines, Mesalazine Prolonged Release Granules 500mg Taj Pharma can cause side effects, although not everybody gets them.
Allergic reactions can occur. Tell your doctor if you get:
- a rash with or without itching, any shortness of breath, palpitations (rapid heartbeat) or chest pain. These effects will usually disappear when you stop taking the medicine.
Tell your doctor immediately
if you experience any of the following symptoms:
- fever, sore throat, mouth or lip ulcers, spots underneath your skin anywhere on your body, including the genital and anal regions, become very pale, swollen ankles or have unusual bleeding (e.g. unexpected nosebleeds or bleeding gums)
- skin rash with flaking, boils or sore lips or mouth
- bruising more easily or sIPect blood abnormalities
- problems with kidney function
Common side effects (in more than 1 in 100 people but less than 1 in 10 people):
- abdominal pain
- nausea (feeling sick)
Rare side effects (in less than 1 in 1000 people):
- problems with heart, lung, liver or kidney function
- inflammation of the pancreas
- blood abnormalities
- numbness and tingling of the fingers and toes due to damaged nerves
- hair loss
- skin rash.
Very rare side effects (in less than 1 in 10,000 people):
- worsening of symptoms of colitis
- Erythema multiforme and Stevens-Johnson syndrome (skin and mucous membrane disease).
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
- HOW TO STORE Mesalazine PROLONGED RELEASE GRANULES 500MG TAJ PHARMA
Keep out of the sight and reach of children.
Store Mesalazine Prolonged Release Granules 500mg Taj Pharma in their original pack below 25°C (77°F) in a dry place, protected from direct sunlight.
Do not remove the moisture absorbing pouch from the bottle. The pouch is not part of your medicine and is marked DO NOT EAT. Keep the bottle tightly closed.
Do not use Mesalazine Prolonged Release Granules 500mg Taj Pharma after the expiry date which is stated on the pack after ‘Exp’. The expiry date refers to the last day of that month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
- FURTHER INFORMATION
What Mesalazine Prolonged Release Granules 500mg Taj Pharma contain
The active substance is mesalazine (also known as 5-aminosalicylic acid). Each tablet contains 400mg mesalazine.
The other ingredients are
Core: lactose monohydrate, sodium starch glycollate, magnesium stearate, talc, povidone.
Coating: methacrylic acid-methyl methacrylate copolymer (1:2), dibutyl sebacate, ferric oxide yellow, ferric oxide red and macrogol 6000.
See also Section 2 on ‘Important information about some of the ingredients of Mesalazine Prolonged Release Granules 500mg Taj Pharma
What Mesalazine Prolonged Release Granules 500mg Taj Pharma look like and contents of the pack
Mesalazine Prolonged Release Granules 500mg Taj Pharma are red-brown, coated and oblong shaped. They are packed in a plastic bottle with a child-resistant closure that contains a cotton/silica gel moisture absorbing pouch. Mesalazine Prolonged Release Granules 500mg Taj Pharma are available in packs of 84, 90, 120 or 168 tablets (not all pack sizes may be marketed).
- MANUFACTURED IN INDIA BY:
TAJ PHARMACEUTICALS LTD;
Plot No. 220, Mahagujarat Industrial Estate,
Moraiyya, Tal-Sanand, Dist-Ahmedabad, Gujarat.