There are rare data on overdosage (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive.
There is no specific antidote.
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.
Acute experience in animals:
Single oral doses of Bufexan of up to 5g/kg in pigs or a single intravenous dose of Bufexan at 920mg/kg in rats were not lethal.
Human experience:
There are rare data on overdosage (e.g. intended suicide with high oral doses of Bufexan), which do not indicate renal or hepatic toxicity.
Management of overdose:
There is no specific antidote and the treatment is symptomatic and supportive. The treatment at hospital includes close monitoring of renal function.
Bufexan 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.
Bufexan granules are contra-indicated in cases of:
-
- Severe impairment of hepatic or renal function.
A history of sensitivity to salicylates or renal sensitivity to sulphasalazine. Confirmed severe renal impairment (GFR <20 ml/min). Children under 2 years of age.
Hypersensitivity to mesalazine, any of the excipients, or salicylates.
Severe liver and/or renal impairment.
Pentasa is contraindicated in:
- patients with known hypersensitivity to salicylates or any of the excipients.
- patients with severe liver and/or renal impairment
History of hypersensitivity to salicylates (including mesalazine) or any of the excipients of Bufexan.
Severe renal impairment (GFR <30ml/min/1.73m2) and/or severe hepatic impairment.
None known.
| Organ Class System | Frequency According to MedDRA Convention | |
| rare (> 1/10,000 to <1/1,000) | very rare (< 1/ 10,000) | |
| Blood and lymphatic system disorders | Altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia) | |
| Nervous system disorders | Headache, dizziness | peripheral neuropathy |
| Cardiac disorders | Myocarditis, pericarditis | |
| Respiratory, thoracic and mediastinal disorders | Allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis) | |
| Gastrointestinal disorders | Abdominal pain, diarrhoea, flatulence, nausea, vomiting | Acute pancreatitis |
| Renal and urinary disorders | Impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency | |
| Skin and subcutaneous tissue disorders | Photosensitivity | Alopecia |
| Musculoskeletal and connective tissue disorders | Myalgia, arthralgia | |
| Immune system disorders | Hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis | |
| Hepatobiliary disorders | Changes in liver function parameters (increase in transaminases and parameters of cholestasis), hepatitis, cholestatic hepatitis | |
| Reproductive system and breast disorders | Oligospermia (reversible) | |
Photosensitivity
More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.
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
United Kingdom
Yellow Card Scheme
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The side effects are predominantly gastrointestinal, including nausea, diarrhoea and abdominal pain. Headache has also been reported.
There have been rare reports of leucopenia, neutropenia, agranulocytosis, aplastic anaemia and thrombocytopenia, alopecia, peripheral neuropathy, pancreatitis, abnormalities of hepatic function and hepatitis, myocarditis and pericarditis, allergic and fibrotic lung reactions, lupus erythematosus-like reactions and rash (including urticaria), interstitial nephritis and nephrotic syndrome with oral mesalazine treatment, usually reversible on withdrawal. Renal failure has been reported. Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.
Mesalazine may very rarely be associated with an exacerbation of the symptoms of colitis, Stevens Johnson syndrome and erythema multiforme.
Other side effects observed with sulphasalazine such as depression of sperm count and function, have not been reported with Bufexan.
Rarely, local irritation may occur after administration of rectal dosage forms containing mesalazine.
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
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.
Table 1: Undesirable effects
Following rectal administration local reactions such as pruritus, rectal discomfort and urge may 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 | Altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia), and eosinophilia (as part of an allergic reaction). | ||
| Nervous system disorders | Headache, dizziness | Peripheral neuropathy | |
| Cardiac disorders | Myocarditis* Pericarditis* | ||
| Respiratory, thoracic and mediastinal disorders | Allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis pulmonary eosinophilia, lung infiltration, pneumonitis) | ||
| Gastrointestinal disorders | Abdominal pain, diarrhoea, flatulence, nausea, vomiting, increased amylase | Acute pancreatitis* | |
| Renal and urinary disorders | Impairment of renal function*** including acute and chronic interstitial nephritis*, nephrotic syndrome, urine discolouration and renal insufficiency | ||
| Skin and subcutaneous tissue disorders | Rash (incl. urticaria, erythematous rash) | Photosensitivity** | Alopecia (reversible) Erythema multiforme, and Stevens-Johnson Syndrome (SJS) |
| Musculoskeletal and connective tissue disorders | Myalgia Arthralgia | ||
| Immune system disorders | Hypersensitivity reaction such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis | ||
| Hepato-biliary disorders | Changes in liver function parameters (increase in transaminases, and cholestasis parameters), hepatitis*, cholestatic hepatitis, cirrhosis, hepatic failure | ||
| Reproductive system and breast disorders | Oligospermia (reversible) |
(*) The mechanism of Bufexan-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.
(***) Renal failure has been reported. Bufexan-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.
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, or search for MHRA Yellow Card in the Google Play or Apple App Store.
The most frequently reported adverse drug reactions (ADRs)within the pooled safety analysis of clinical studies with Bufexan, 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 Bufexan | ||
| 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
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenicity (rat) or toxicity to reproduction.
Kidney toxicity (renal papillary necrosis and epithelial damage in the proximal convoluted tubule or the whole nephron) has been seen in repeat-dose toxicity studies with high oral doses of mesalazine. The clinical relevance of this finding is unknown.
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
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.
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
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 treatment of acute episodes and the maintenance of remission of ulcerative colitis.
For the treatment of mild to moderate acute exacerbations of ulcerative colitis.
The suppositories are particularly appropriate in patients with distal disease.
For the maintenance of remission of ulcerative colitis.
Mild to moderate ulcerative colitis
PENTASA Bufexan Enema is indicated for the treatment of ulcerative colitis affecting the distal colon and rectum.
For the induction of clinical and endoscopic remission in patients with mild to moderate, active ulcerative colitis. For maintenance of remission.
Pharmacotherapeutic group: Intestinal anti-inflammatory agents; aminosalicylic acid and similar agents.
ATC code: A07EC02
Mechanism of action
The mechanism of the anti-inflammatory action is unknown. The results of in vitro studies indicate that inhibition of lipoxygenase may play a role.
Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated. Mesalazine (5-aminosalicylic acid / 5-ASA) may also function as a radical scavenger of reactive oxygen compounds.
Pharmacodynamic effects
Mesalazine, orally administered, acts predominantly locally at the gut mucosa and in the submucous tissue from the luminal side of the intestine. It is important, therefore, that mesalazine is available at the regions of inflammation. Systemic bioavailability/plasma concentrations of mesalazine therefore are of no relevance for therapeutic efficacy, but rather a factor for safety. In order to realise this, Bufexan granules are gastric juice resistant and release mesalazine in a pH dependent manner due to an Eudragit L coating, and prolonged manner due to the matrix granule structure.
Mesalazine is one of the two components of sulphasalazine, the other being sulphapyridine. It is the latter which is responsible for the majority of the side effects associated with sulphasalazine therapy whilst mesalazine is known to be the active moiety in the treatment of ulcerative colitis. Bufexan consists only of this active component which is delivered directly by the suppositories.
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.
Pharmacotherapeutic group: Intestinal anti-inflammatory agents.
Mechanism of action and pharmacodynamic effects:
Bufexan is recognised as the active moiety of sulphasalazine in the treatment of ulcerative colitis. It is thought to act locally on the gut wall in inflammatory bowel disease, although its precise mechanism of action has not been fully elucidated.
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. Bufexan has in-vitro and in-vivo pharmacological effects that inhibit leucocyte 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 Bufexan.
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 Bufexan 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
Bufexan 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. Bufexan 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 | Bufexan 2.4g/day in two divided doses | Bufexan 4.8g/day once daily | |||
| % patients in remission | 12.9 | 34.1* | 29.2* | ||
| Study SPD476-302 (n=341#) | |||||
| Placebo | Bufexan 2.4g/day once daily | Bufexan 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)
General considerations of mesalazine:
Absorption:
Mesalazine absorption is highest in proximal gut regions and lowest in distal gut areas.
Biotransformation:
Mesalazine is metabolised both pre-systemically by the intestinal mucosa and the liver to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria. Protein binding of mesalazine and N-Ac-5-ASA is 43 % and 78 %, respectively.
Elimination:
Mesalazine and its metabolite N-Ac-5-ASA are eliminated via the faeces (major part), renally (varies between 20 and 50 %, dependent on kind of application, pharmaceutical preparation and route of mesalazine release, respectively), and biliary (minor part). Renal excretion predominantly occurs as N-Ac-5-ASA. About 1 % of total orally administered mesalazine dose is excreted into the breast milk mainly as N-Ac-5-ASA.
Bufexan Granules specific:
Distribution:
Owing to the granule size of about 1 mm, transit from the stomach to the small intestine is fast.
A combined pharmacoscintigraphic/pharmacokinetic study showed that the compound reaches the ileocaecal region within approx. 3 hours and the ascending colon within approx. 4 hours. The total transit time in the colon amounts to about 20 hours. Approximately 80 % of an administered oral dose is estimated to be available in the colon, sigmoid and rectum.
Absorption:
Mesalazine release from Bufexan granules starts after a lag phase of about 2-3 hours, peak plasma concentrations are reached at about 4-5 hours. The systemic bioavailability of mesalazine after oral administration is estimated to be approximately 15-25 %.
Food intake delays absorption for 1 to 2 hours but does not change the rate and extent of absorption.
Elimination:
From a 3 x 500 mg daily mesalazine dose, a total renal elimination of mesalazine and N-Ac-5-ASA under steady state condition was calculated to be about 25 %. The un-metabolised excreted mesalazine part was less than 1 % of the oral dose. The elimination half-life in this study was 4.4 hours.
The suppository is designed to deliver mesalazine directly to the proposed site of action in the distal bowel.
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.
General characteristics of the active substance
Disposition and local availability:
PENTASA enemas are designed to provide the distal part of the intestinal tract with high concentrations of Bufexan and a low systemic absorption. The enemas have been shown to reach and cover the descending colon.
Biotransformation:
Bufexan is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl Bufexan (acetyl Bufexan). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.
Acetyl Bufexan is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.
Absorption:
The absorption following rectal administration is low, but 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% of the dose is absorbed after administration of enemas.
Distribution:
Bufexan and acetyl Bufexan do not cross the blood brain barrier. Protein binding of Bufexan is approximately 50% and of acetyl Bufexan about 80%.
Elimination:
The plasma half-life of pure Bufexan is approximately 40 minutes and for acetyl Bufexan approximately 70 minutes. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl Bufexan.
Characteristics in patients:
The systematic absorption following administration of PENTASA enemas has been shown to be significantly decreased in patients with active ulcerative colitis compared to those in remission.
In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination and increased systemic concentration of Bufexan may constitute an increased risk of nephrotoxic adverse reactions.
The mechanism of action of mesalazine (5-ASA) is not fully understood but appears to be topical, and therefore the clinical efficacy of Bufexan 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 Bufexan 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 Bufexan and complete release of mesalazine occurred after approximately 17.4 hours.
The total absorption of mesalazine from Bufexan 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, Bufexan 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 Bufexan. 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 Bufexan, 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 Bufexan 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 Bufexan 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. Bufexan was administered with food in the Phase 3 trials.
In a single dose pharmacokinetic study of Bufexan, 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 Bufexan 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 Bufexan 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 Bufexan. 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 Bufexan.
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 Bufexan 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 Bufexan, 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.
Blood tests (differential blood count; liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. 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 3 months. If additional symptoms occur, these tests should be performed immediately.
Caution is recommended in patients with impaired hepatic function.
Bufexan granules should not be used in patients with impaired renal function.
Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment.
Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with Bufexan granules.
Patients with a history of adverse drug reactions to preparations containing sulphasalazine should be kept under close medical surveillance on commencement of a course of treatment with Bufexan granules. Should Bufexan granules cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.
In patients with phenylketonuria it should be kept in mind that Bufexan 1000mg granules contain aspartame as a sweetening agent, equivalent to 1.12mg phenylalanine.
Bufexan granules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
Use in the elderly should be cautious and subject to patients having normal renal function.
Renal disorder: Mesalazine is excreted rapidly by the kidney, mainly as its metabolite, N-acetyl-5-aminosalicylic acid. In rats, large doses of mesalazine injected intravenously produce tubular and glomerular toxicity. Bufexan should be used with extreme caution in patients with confirmed mild to moderate renal impairment. Treatment with mesalazine should be discontinued if renal function deteriorates. If dehydration develops, normal electrolyte and fluid balance should be restored as soon as possible.
Serious blood dyscrasias have been reported very rarely with mesalazine. Haematological investigations should be performed if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Treatment should be stopped if there is suspicion or evidence of blood dyscrasia.
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.
Blood tests (differential blood count; liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. 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.
Caution is recommended in patients with impaired hepatic function.
PENTASA should not be used in patients with impaired renal function. Bufexan-induced renal toxicity should be considered, if renal function deteriorates during treatment.
Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with PENTASA.
Patients with a history of adverse drug reactions to preparations containing sulphasalazine (risk of allergy to salicylates), should be kept under close medical surveillance on commencement of a course of treatment with PENTASA. Should PENTASA cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, the treatment should be discontinued immediately.
If a patient develops dehydration while on treatment with meclizine, normal electrolyte levels and fluid balance should be restored as soon as possible.
Bufexan-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely. Treatment should be discontinued on suspicion or evidence of these reactions.
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. Bufexan 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 Bufexan 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 Bufexan 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.
Bufexan granules have no, or negligible, influence on the ability to drive or use machines.
Not applicable.
Pentasa Sachet has no or negligible influence on the ability to drive or use machines.
No effects on the ability to drive and use machines have been observed.
No studies on the effects on the ability to drive and use machines have been performed. Bufexan is considered to have negligible influence on these abilities.
Posology
Adults and elderly:
For the treatment of acute episodes of ulcerative colitis:
Once daily 1 sachet of Bufexan 3g granules, 1 or 2 sachets of Bufexan 1.5g granules, 3 sachets of Bufexan 1000mg granules or 3 sachets of Bufexan 500mg granules (equivalent to 1.5 - 3.0g mesalazine daily) preferably to be taken in the morning according to the individual clinical requirement.
It is also possible to take the prescribed daily dose in three divided doses (1 sachet of Bufexan 500mg granules three times daily or 1 sachet of Bufexan 1000mg granules three times daily) if this is more convenient to the patient.
For the maintenance of remission of ulcerative colitis:
The standard treatment is 0.5g mesalazine three times daily (in the morning, at midday and in the evening) corresponding to a total dose of 1.5g mesalazine per day.
For patients known to be at increased risk for relapse for medical reasons or due to difficulties to adhere to application of three daily doses the dosing schedule can be adapted to 3.0g mesalazine given as a single daily dose preferably in the morning.
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 30-50mg/kg/day once daily preferably in the morning or in divided doses. Maximum dose: 75mg/kg/day. The total dose should not exceed the 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 the recommended adult dose.
It is generally recommended that half the adult dose may be given to children up to a body weight of 40kg and the normal adult dose to those above 40kg.
Method of administration:
The contents of the sachets of Bufexan granules should not be chewed. The granules should be taken on the tongue and swallowed, without chewing, with plenty of liquid.
Both in the treatment of acute inflammatory episodes and during long term treatment, Bufexan granules should be used on a regular basis and consistently in order to achieve the desired therapeutic effects.
The duration of use is determined by the physician.
ADULTS:
Suppositories 250 mg: Three to six suppositories a day in divided doses, with the last dose at bedtime.
Suppositories 500 mg: A maximum of three suppositories a day in divided doses, with the last dose at bedtime.
ELDERLY: The normal adult dosage may be used unless renal function is impaired.
CHILDREN: There is no dosage recommendation.
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.
Adults: The recommended dosage is one enema at bedtime.
Children: Not recommended.
PENTASA Bufexan Enemas are for rectal administration
Bufexan 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:
Bufexan 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 Bufexan in patients with hepatic or renal impairment.
None.
