The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC please click here:
https://www.medicines.org.uk/emc/product/144/smpc
https://www.medicines.org.uk/emc/product/6167/smpc
https://www.medicines.org.uk/emc/product/4778/smpc
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/020049Orig1s027.pdf
https://www.medicines.org.uk/emc/product/6154/smpc
https://www.medicines.org.uk/emc/product/3838/smpc

Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11

Introduction and Mechanism of Action

Bowel disease (inflammatory) suppressant: Mechanism of action is uncertain. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with inflammatory bowel disease. Mesalamine appears to diminish inflammation by inhibiting cyclooxygenase and lipoxygenase, thereby decreasing the production of prostaglandins, and leukotrienes and hydroxyeicosatetraenoic acids (HETEs), respectively.

It is also believed that mesalamine acts as a scavenger of oxygen-derived free radicals which are produced in greater numbers in patients with inflammatory bowel disease.

Therapeutic indications

Salofalk

Treatment of mild to moderate acute exacerbations of ulcerative colitis and for the maintenance of remission of ulcerative colitis

Asacol

Ulcerative colitis: For the treatment of mild to moderate acute exacerbations. For the maintenance of remission.
Crohn's ileo-colitis: For the maintenance of remission.

Octasa

Ulcerative Colitis: For the treatment of mild to moderate acute exacerbations. For the maintenance of remission.

Crohn's ileo-colitis: For the maintenance of remission.

Pentasa

For the treatment of mild to moderate exacerbations of ulcerative colitis. For the maintenance of remission of ulcerative colitis.

Mezavant

For the induction of clinical and endoscopic remission in patients with mild to moderate, active ulcerative colitis. For maintenance of remission.

Salazopyrin

Induction and maintenance of remission of ulcerative colitis; treatment of active Crohn's disease.

Dosing, administration, and monitoring

Dosing and administration

Salofalk dosing

Adults and elderly:
Depending upon the clinical requirements in individual cases, the following daily doses are recommended:
For treatment of acute episodes: 1.5g to 3.0g mesalazine daily
For the maintenance of remission: 1.5g mesalazine

 

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: 75mg/kg/day in divided doses. The total dose should not exceed the maximum dose for adults.

Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed the recommended dose for adults.

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.

For maintenance of remission in ulcerative colitis, the dose can usually be reduced to 1.5g mesalazine/day (adults and adolescents with a body weight over 40kg) or 0.75g mesalazine/day (children/adolescents).

 

Method of Administration: Oral

The duration of use is determined by the physician.

Asacol dosing

Adults:

Mild acute exacerbations of ulcerative colitis: Three tablets (2.4g) a day in divided doses.
Moderate acute exacerbations of ulcerative colitis: Six tablets (4.8g) a day in divided doses.
Maintenance of remission of ulcerative colitis: Up to three tablets (2.4g) a day once daily or in divided doses.
Maintenance of remission of Crohn's ileocolitis: Up to three tablets (2.4g) a day in divided doses.

 

Elderly: The normal adult dosage may be used unless renal function is impaired.

 

Children: Not recommended.

Octasa dosing

Mild acute disease: 2.4 g (three tablets) once daily or in divided doses, with concomitant corticosteroid therapy to be taken when clinically indicated.

Moderate acute disease: 2.4 g to 4.8 g (three to six tablets) a day in divided doses, with concomitant corticosteroid therapy where clinically indicated. 2.4 g may be taken once daily or in divided doses. Above 2.4 g should be taken in divided doses.

Maintenance therapy: 1.6 g to 2.4 g (two to three tablets) taken once daily or in divided doses.

The maximum adult dose should not exceed six tablets a day and not exceed 3 tablets taken together at any one time.

Pentasa dosing

Adults:
Acute treatment: Individual dosage of up to 4g mesalazine once daily or in two or three divided doses.
Maintenance treatment: Individual dosage. Recommended dosage, 2g mesalazine once daily.

 

Elderly Patients: The usual adult dose applies.

 

Children: Not recommended.

Mezavant dosing

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:

Mezavant XL is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.

Salazopyrin dosing

The dose is adjusted according to the severity of the disease and the patient's tolerance to the drug, as detailed below.

 

Elderly Patients: No special precautions are necessary.

a) Ulcerative colitis

Adults:
Severe Attacks
Salazopyrin 2-4 tablets four times a day may be given in conjunction with steroids as part of an intensive management regime. Rapid passage of the tablets may reduce effect of the drug.
Night-time interval between doses should not exceed 8 hours.
Moderate Attack
2-4 tablets four times a day may be given in conjunction with steroids.

Maintenance Therapy
With induction of remission reduce the dose gradually to 4 tablets per day. This dosage should be continued indefinitely since discontinuance even several years after an acute attack is associated with a four fold increase in risk of relapse.

 

Children: The dose is reduced in proportion to body weight.

Acute Attack or Relapse
40-60mg/kg per day

Maintenance Dosage
20-30mg/kg per day

Salazopyrin Suspension may provide a more flexible dosage form.

b) Crohn's disease

In active Crohn's disease, Salazopyrin should be administered as in attacks of ulcerative colitis

 

 

Monitoring

Time to peak concentration:

Salofalk —6.5 to 7 hours
Asacol—4 to 12 hours.
Pentasa—3 hours

Elimination:

Faecal:
Asacol: Approximately 80% of an administered dose is recovered in the faeces
Pentasa: Approximately 13% of an administered dose is recovered in the faeces
Salofalk: Partially recovered unchanged in the faeces.

 

Renal:
Excreted in the urine as the Ac-5-ASA metabolite.

Adverse effects

Mesalazine in general is contraindicated in cases of:

• Hypersensitivity to the active substance, salicylates or to any of the excipients listed in each specific mesalazine product.
• Severe impairment of hepatic or renal function.

Sulfasalazine is contraindicated in:

• Infants under the age of 2 years.
• Patients with a known hypersensitivity to sulfasalazine, its metabolites or any of the excipients as well as sufonamides or salicylates.
• Patients with porphyria.

Special warnings and precautions for use

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.

Mesalazine 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 mesalazine tablets.

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 mesalazine tablets. Should mesalazine tablets cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.

Mesalazine Undesirable effects

Organ Class System	Frequency According to MedDRA convention
	Rare (≥1/10,000; <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 cholestasis parameters), hepatitis, cholestatic hepatitis
Reproductive system disorders		Oligospermia (reversible)

Photosensitivity

More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.

Overdose

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.

Salazopyrin undesirable effects

Overall, about 75% of ADRs occur within 3 months of starting therapy, and over 90% by 6 months. Some undesirable effects are dose-dependent and symptoms can often be alleviated by reduction of the dose.

General
Sulfasalazine is split by intestinal bacteria to sulfapyridine and 5-amino salicylate so ADRs to either sulfonamide or salicylate are possible. Patients with slow acetylator status are more likely to experience ADRs related to sulfapyridine. The most commonly encountered ADRs are nausea, headache, rash, loss of appetite and raised temperature.

Specific
The adverse reactions observed during clinical studies conducted with Sulfasalazine have been provided in a single list below by class and frequency (very common (≥1/10); common (≥1/100 to< 1/10); uncommon (≥1/1000 to < 1/100). Where an adverse reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.

Additional reactions reported from post-marketing experience are included as frequency Not known (cannot be estimated from the available data) in the list below.

Body System	Adverse drug reactions
Infections and infestations
Not known	Pseudomembranous colitis
Blood and Lymphatic System Disorders
Common	Leukopenia
Uncommon	Thrombocytopenia
Not known	Agranulocytosis, aplastic anaemia, haemolytic anaemia, Heinz body anaemia, hypoprothrombinaemia, lymphadenopathy, macrocytosis, megaloblastic anaemia, methaemoglobinaemina, neutropenia, pancytopenia
Immune System Disorders
Not known	Anaphylaxis, polyarteritis nodosa, serum sickness
Metabolism and Nutrition Disorders
Not known	Loss of appetite
Psychiatric Disorders
Common	Insomnia
Uncommon	Depression
Not known	Hallucinations
Nervous System Disorders
Common	Dizziness, headache, taste disorders
Uncommon	Convulsions
Not known	Aseptic meningitis, ataxia, encephalopathy, peripheral neuropathy, smell disorders
Ear and Labyrinth Disorders
Common	Tinnitus
Uncommon	Vertigo
Eye Disorders
Common	Conjunctival and scleral injection
Cardiac Disorders
Not known	Allergic myocarditis, cyanosis, pericarditis
Vascular Disorders
Uncommon	Vasculitis
Respiratory, Thoracic and Mediastinal Disorders
Common	Cough
Uncommon	Dyspnoea
Not known	Fibrosing alveolitis, eosinophilic infiltration, interstitial lung disease
Gastrointestinal Disorders
Very Common	Gastric distress, nausea
Common	Abdominal pain, diarrhoea, vomiting, stomatitis
Not known	Aggravation of ulcerative colitis, pancreatitis, parotitis
Hepato-biliary Disorders
Not known	Hepatic failure, fulminant hepatitis, hepatitis
Skin and Subcutaneous Tissue Disorders
Common	Pruritus
Uncommon	Alopecia, urticaria
Not known	Epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), toxic pustuloderma, erythema, exanthema, exfoliative dermatitis, periorbital oedema, lichen planus, photosensitivity
Musculoskeletal and Connective Tissue Disorders
Common	Arthralgia
Not known	Systemic lupus erythematosus
Renal and Urinary Disorders
Common	Proteinuria
Not known	Nephrotic syndrome, interstitial nephritis, crystalluria, haematuria
Reproductive System and Breast Disorders
Not known	Reversible oligospermia
General Disorders and Administration Site Conditions
Common	Fever
Uncommon	Facial oedema
Not known	Yellow discoloration of skin and body fluids
Investigations
Uncommon	Elevation of liver enzymes
Not known	Induction of autoantibodies

Special situations (e.g. pregnancy)

Pregnancy

There are no adequate data from the use of mesalazine tablets in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the foetus/newborn child. To date no other relevant epidemiologic data are available. In one single case after long-term use of a high dose mesalazine (2-4g, orally) during pregnancy, renal failure in a neonate was reported. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development. Mesalazine tablets should only be used during pregnancy if the potential benefit outweighs the possible risk.

Breastfeeding / Lactation

N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. Only limited experience during lactation in women is available to date. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Mesalazine tablets should only be used during breast-feeding if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, breast-feeding should be discontinued.

Sulfasalazine and sulfapyridine are found in low levels in breast milk. Patients should avoid breastfeeding while taking this medicine. There have been reports of bloody stools or diarrhoea in infants who were breastfeeding from mothers on sulfasalazine. In cases where the outcome was reported, bloody stools or diarrhoea resolved in the infant after discontinuation of sulfasalazine in the mother.