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.
Hypersensitivity to mesalazine, any of the excipients, or salicylates.
Severe liver and/or renal impairment.
Not applicable
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
| SOC | Common >1/100 to <1/10 | Rare >1/10,000 to ≤1/1,000 | Very rare ≤1/10,000 |
| Blood and the lymphatic system disorders | Blood disorders such as: Anaemia, aplastic anaemia, agranulocytosis, neutropenia, leukopenia (incl. granulocytopenia), pancytopenia, thrombocytopenia, and eosinophilia (as part of an allergic reaction. | ||
| Immune system disorders | Hypersensitivity reaction including allergic exanthema, anaphylactic reaction, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Drug Fever | ||
| Nervous system disorders | Headache | Dizziness | Peripheral neuropathy Benign intracranial hypertension in adolescents |
| Cardiac disorders | Myocarditis* Pericarditis* | Pericardial effusion | |
| Respiratory, thoracic and mediastinal disorders | Allergic alveolitis, allergic and fibrotic lung reactions (incl. dyspnoea, coughing, bronchospasm), pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis) | ||
| Gastrointestinal disorders | Diarrhoea Abdominal pain Nausea Vomiting Flatulence | Acute pancreatitis* Increased amylase (blood and/or urine) | Pancolitis |
| 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) | (Reversible) alopecia Quincke's oedema Erythema multiform, and Stevens-Johnson Syndrome (SJS) | |
| Musculoskeletal and connective tissue disorders | Myalgia Arthralgia Lupus erythematosus-like reactions | ||
| Renal and urinary disorders | Renal function impairment (incl. interstitial nephritis* (acute and chronic), nephrotic syndrome, renal insufficiency acute/chronic) Urine discolouration. | ||
| Reproductive system and breast disorders | Oligospermia (reversible) |
(*) The mechanism of mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of allergic origin.
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. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.
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.
Mild to moderate ulcerative colitis
Pharmacotherapeutic groups: Intestinal anti-inflammatory agents, aminosalicylic acid and similar agents
ATC code: A07E C02
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.
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) |
| Mesalazine |
|
|
|
|
| 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.
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.
Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported very rarely with mesalazine. 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.
Pentasa Sachet has no or negligible influence on the ability to drive or use machines.
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.
Paediatric population:
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.
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.
Any unused product or waste material should be disposed of in accordance with local requirements.
