Ulcolfree is an aminosalicylate, and signs of salicylate toxicity include tinnitus, vertigo, headache, confusion, drowsiness, pulmonary oedema, dehydration as a result of sweating, diarrhoea and vomiting, hypoglycaemia, hyperventilation, disruption of electrolyte balance and blood-pH and hyperthermia.
Conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. Hypoglycaemia, fluid and electrolyte imbalance should be corrected by the administration of appropriate therapy. Adequate renal function should be maintained.
History of hypersensitivity to salicylates (including mesalazine) or any of the excipients of Ulcolfree.
Severe renal impairment (GFR <30ml/min/1.73m2) and/or severe hepatic impairment.
Not applicable.
The most frequently reported adverse drug reactions (ADRs)within the pooled safety analysis of clinical studies with Ulcolfree, including 3,611 patients, were colitis (including ulcerative colitis) 5.8%, abdominal pain 4.9%, headache 4.5%, liver function test abnormal, 2.1%, diarrhoea 2.0%, and nausea 1.9%.
Adverse reactions are listed by System Organ Class (see table below). Within each system organ class, adverse reactions are listed under headings of frequency using the categories: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); not known (cannot be estimated from the available data).
| Adverse Drug Reactions (ADRs) Associated with Ulcolfree | ||
| System/Organ Class | Incidence Category | Adverse drug reaction |
| Blood and lymphatic system disorders | Uncommon | Thrombocytopenia* |
| Rare | Agranulocytosis* | |
| Not known | Aplastic anaemia*, Leukopenia*, Neutropenia*, Pancytopenia* | |
| Immune system disorders | Rare | Face oedema |
| Not known | Hypersensitivity*, Anaphylactic shock, Angioedema, Stevens-Johnson syndrome, Drug rash with eosinophilia and systemic symptoms (DRESS) | |
| Nervous system disorders | Common | Headache* |
| Uncommon | Dizziness, Somnolence, Tremor | |
| Not known | Intracranial pressure increased, Neuropathy | |
| Ear and labyrinth disorders | Uncommon | Ear pain |
| Cardiac disorders | Uncommon | Tachycardia |
| Not known | Myocarditis*, Pericarditis* | |
| Vascular disorders | Common | Hypertension |
| Uncommon | Hypotension | |
| Respiratory, thoracic and mediastinal disorders | Uncommon | Pharyngolaryngeal pain* |
| Not known | Hypersensitivity pneumonitis (including interstitial Pneumonitis, allergic alveolitis, eosinophilic pneumonitis), Bronchospasm | |
| Gastrointestinal disorders | Common | Abdominal distension, Abdominal pain*, Colitis, Diarrhoea*, Dyspepsia, Vomiting, Flatulence, Nausea |
| Uncommon | Pancreatitis, Rectal polyp | |
| Hepatobiliary disorders | Common | Liver Function Test abnormal* (e.g. ALT; AST, Bilirubin) |
| Not known | Hepatitis, Cholelithiasis | |
| Skin and subcutaneous tissue disorders | Common | Pruritus, Rash* |
| Uncommon | Acne, Alopecia, Urticaria | |
| Musculoskeletal and connective tissue disorders | Common | Arthralgia, Back pain |
| Uncommon | Myalgia | |
| Not known | Systemic-lupus erythematosus-like syndrome, Lupus-like syndrome | |
| Renal and urinary disorders | Rare | Renal failure* |
| Not known | Interstitial nephritis*, Nephrotic syndrome* | |
| General disorders and administration site conditions | Common | Asthenia, Fatigue, Pyrexia* |
*
Description of selected adverse reactions:
Increased intracranial pressure
Cases of increased intracranial pressure with papilledema (pseudotumor cerebri or benign intracranial hypertension) have been reported with the use of mesalamines. If undetected, this condition may result in restriction of the visual field and may progress to permanent loss of vision. Mesalamine should be discontinued, if this syndrome occurs.
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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard
Effects in nonclinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
For the induction of clinical and endoscopic remission in patients with mild to moderate, active ulcerative colitis. For maintenance of remission.
Pharmacotherapeutic group: Aminosalicyclic acid and similar agents
ATC code: A07E C02
Mechanism of action
Mesalazine is an aminosalicylate. The mechanism of action of mesalazine is not fully understood, but appears to have a topical anti-inflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalazine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. Mesalazine has the potential to inhibit the activation of nuclear factor kappa B (NFкB) and consequently the production of key proinflammatory cytokines. More recently, it has been proposed that impairment of PPAR-γ nuclear receptors, (γ-form of the peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. PPAR-γ receptor agonists have shown efficacy in ulcerative colitis and evidence has been accumulating that the mechanism of action of mesalazine may be mediated by PPAR-γ receptors.
Pharmacodynamic effects
The Ulcolfree tablet contains a core of mesalazine (5-aminosalicylic acid) 1.2g formulated in a multi-matrix system. This system is coated with methacrylic acid - methyl methacrylate copolymer (1:1) and methacrylic acid - methyl methacrylate copolymer (1:2), which are designed to delay release of mesalazine until exposure to approximately pH 7.
Clinical efficacy and safety
Ulcolfree was investigated in two similarly designed, Phase 3, placebo controlled studies (SPD476-301 and SPD476-302) in 623 randomised patients with mild to moderate, active Ulcerative Colitis. Ulcolfree 2.4g/day and 4.8g/day administered with food achieved statistical superiority over placebo in terms of the number of patients achieving remission from Ulcerative Colitis after 8 weeks treatment. Using the Ulcerative Colitis Disease Activity Index (UC-DAI), remission was defined as a UC-DAI score of ≤1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in sigmoidoscopy score from baseline. Study SPD476-302, included a comparator, mesalazine pH 7-dependent modified release 2.4g/day (0.8g administered in 3 divided doses), as an internal reference arm. On the primary variable of remission, the following results were achieved:
| Study SPD476-301 (n=262#) | |||||
| Placebo | Ulcolfree 2.4g/day in two divided doses | Ulcolfree 4.8g/day once daily | |||
| % patients in remission | 12.9 | 34.1* | 29.2* | ||
| Study SPD476-302 (n=341#) | |||||
| Placebo | Ulcolfree 2.4g/day once daily | Ulcolfree 4.8g/day once daily | Mesalazine pH 7-dependent modified release 2.4g/day in three divided doses | ||
| % patients in remission | 22.1 | 40.5* | 41.2* | 32.6NS | |
#Based on the ITT Population; * Statistically different from placebo (p<0.025); NSNot significant (p>0.05)
The mechanism of action of mesalazine (5-ASA) is not fully understood but appears to be topical, and therefore the clinical efficacy of Ulcolfree does not correlate with the pharmacokinetic profile. A major pathway of clearance of mesalazine is via metabolism to N-acetyl-5-aminosalicylic acid (Ac-5-ASA), which is pharmacologically inactive.
Absorption:
Gamma-scintigraphy studies have shown that a single dose of Ulcolfree 1.2g passed rapidly and intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labelled tracer through the colon, indicating that mesalazine had spread throughout this region of the gastrointestinal tract. Complete disintegration of Ulcolfree and complete release of mesalazine occurred after approximately 17.4 hours.
The total absorption of mesalazine from Ulcolfree 2.4g or 4.8g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose.
In a single dose study, Ulcolfree 1.2g, 2.4g and 4.8g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalazine were detectable after 2 hours (median) and reached a maximum by 9-12 hours (median) on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects. Mesalazine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was dose proportional between 1.2g and 4.8g Ulcolfree. Maximum plasma concentrations (Cmax) of mesalazine increased approximately dose proportionately between 1.2g and 2.4g and less than dose proportional between 2.4g and 4.8g Ulcolfree, with the dose normalised value at 4.8g representing, on average, 74% of that at 2.4g based on geometric means.
In a single and multiple dose pharmacokinetic study of Ulcolfree 2.4 and 4.8g administered with standard meals in 56 healthy volunteers plasma concentrations of mesalazine were detectable after 4 hours and were maximal by 8 hours after the single dose. At steady state (achieved generally by 2 days after dosing), 5-ASA accumulation was 1.1- to 1.4- fold for the 2.4g and 4.8g dose, respectively, above that expected on the basis of single dose pharmacokinetics.
Administration of a single dose of Ulcolfree 4.8g with a high fat meal resulted in further delay in absorption and mesalazine plasma levels were detectable after approximately 4 hours following dosing. However, a high fat meal increased systemic exposure of mesalazine (mean Cmax by 91%; mean AUC 16%) compared to results in the fasted state. Ulcolfree was administered with food in the Phase 3 trials.
In a single dose pharmacokinetic study of Ulcolfree, 4.8g was administered in the fasted state to 71 healthy male and female volunteers (28 young (18-35yrs); 28 elderly (65-75yrs); 15 elderly (>75yrs)). Increased age resulted in increased systemic exposure (up to approximately 2-fold, based on AUC0-t, AUC0-∞ and Cmax) to mesalazine and its metabolite N-acetyl-5-aminosalicylic acid but did not affect the percentage of mesalazine absorbed. Increased age resulted in a slower apparent elimination of mesalazine, though there was high between-subject variability. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
Distribution:
Following dosing of Ulcolfree the distribution profile of mesalazine is presumed to be the same as that of other mesalazine containing products. Mesalazine has a relatively small volume of distribution of approximately 18L confirming minimal extravascular penetration of systemically available drug. Mesalazine is 43% bound and N-acetyl-5-aminosalicylic 78 - 83% bound to plasma proteins when in vitro plasma concentrations are up to 2.5μg/mL and up to 10μg/mL respectively.
Biotransformation:
The only major metabolite of mesalazine is N-acetyl-5-aminosalicylic acid, which is pharmacologically inactive. Its formation is brought about by N-acetyltransferase-1 (NAT-1) activity in the liver and in the cytosol of intestinal mucosal cells.
Elimination:
Elimination of absorbed mesalazine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation). However, there is also limited excretion of the parent drug in urine. Of the approximately 21-22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine at steady state after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. The apparent terminal half-lives for mesalazine and its major metabolite after administration of Ulcolfree 2.4g and 4.8g were, on average, 7-9 hours and 8-12 hours, respectively.
Hepatic Impairment
There are no data in patients with hepatic impairment taking Ulcolfree. Systemic exposure to mesalazine increased by up to 2-fold in elderly subjects (>65 years, with a mean creatinine clearance of 68 - 76 ml/min) compared with younger adult subjects (18-35 years, mean creatinine clearance 124 ml/min) after a 4.8g single dose of Ulcolfree.
Renal impairment
Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
Elderly
The potential impact on the safe use of Ulcolfree in the elderly population in clinical practice should be considered. Furthermore, in patients with renal impairment, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.
In different clinical studies with Ulcolfree, mesalazine plasma AUC in females appeared up to 2-fold higher than in males.
Based on limited pharmacokinetic data, 5-ASA and Ac-5-ASA pharmacokinetics appear comparable between Caucasian and Hispanic subjects.
Pharmacokinetics data have not been investigated in elderly people.
Reports of renal impairment, including minimal change nephropathy, acute / chronic interstitial nephritis and renal failure have been associated with preparations containing mesalazine and pro-drugs of mesalazine. Ulcolfree should be used with caution in patients with confirmed mild to moderate renal impairment. It is recommended that all patients have an evaluation of renal function prior to initiation of therapy and at least twice a year, while on treatment.
Patients with chronic lung function impairment, especially asthma, are at risk of hypersensitivity reactions and should be closely monitored.
Following mesalazine treatment, serious blood dyscrasias have been reported rarely. If the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat, haematological investigations should be performed. If there is suspicion of blood dyscrasia, treatment should be terminated..
Mesalazine induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely with Ulcolfree and with other mesalazine containing preparations. Caution should be used in prescribing this medication to patients with conditions predisposing to the development of myo- or pericarditis. If such hypersensitivity reaction is suspected, products containing mesalazine must not be reintroduced.
Mesalazine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalazine or sulphasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhoea, sometimes fever, headache and rash. If acute intolerance syndrome is suspected, prompt withdrawal is required and products containing mesalazine must not be reintroduced.
There have been reports of increased liver enzyme levels in patients taking preparations containing mesalazine. Caution is recommended if Ulcolfree is administered to patients with hepatic impairment.
Caution should be exercised when treating patients allergic to sulphasalazine due to the potential risk of cross sensitivity reactions between sulphasalazine and mesalazine.
Organic or functional obstruction in the upper gastrointestinal tract may delay onset of action of the product.
Interference with Laboratory Tests
Use of mesalazine may lead to falsely elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection, because of the similarity in the chromatograms of normetanephrine and mesalazine's main metabolite, N-acetylaminosalicylic acid (N-Ac-5-ASA). An alternative, selective assay for normetanephrine should be considered.
No studies on the effects on the ability to drive and use machines have been performed. Ulcolfree is considered to have negligible influence on these abilities.
Ulcolfree is intended for once daily, oral administration. The tablets must not be crushed or chewed and should be taken with food.
Adults, including the elderly (>65 years)
For induction of remission: 2.4 to 4.8g (two to four tablets) should be taken once daily. The highest dose of 4.8g/day is recommended for patients not responding to lower doses of mesalazine. When using the highest dose (4.8g/day), the effect of the treatment should be evaluated at 8 weeks.
For maintenance of remission: 2.4g (two tablets) should be taken once daily.
Children and adolescents:
Ulcolfree is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
Specific studies have not been performed to investigate Ulcolfree in patients with hepatic or renal impairment.
No special requirements.
