Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Ferring Ireland Ltd, United Drug House, Magna Drive, Magna Business Park, Citywest Road, Dublin 24, Ireland
Hypersensitivity to mesalazine, any of the excipients listed in section 6.1, or salicylates.
Severe liver and/or renal impairment.
Most patients who are intolerant or hypersensitive to sulphasalazine are able to take Pentasa without risk of similar reactions. However, caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates). In case of acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy 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 renal impairment. The renal function should be monitored regularly (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 should increase monitoring frequency of renal function.
Cases of nephrolithiasis have been reported with the use of mesalazine including stones with a 100% mesalazine content. It is recommended to ensure adequate fluid intake during treatment.
Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment; please refer to section 4.8.
Mesalazine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported very rarely with mesalazine. Blood test for differential blood count is recommended prior to and during treatment, at the discretion of the treating physician. As stated in the interaction section 4.5, concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine, or 6- mercaptopurine or thioguanine. 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.
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment. Pentasa should be discontinued, at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.
Combination therapy with Pentasa and azathioprine, or 6-mercaptopurine or thioguanine have in several studies shown a higher frequency of myelosuppressive effects, and an interaction seems to exist, however, the mechanism behind the interaction is not fully established. Regular monitoring of white blood cells is recommended and dosage regime of thiopurines should be adjusted accordingly.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.
Pentasa should be used with caution during pregnancy and lactation and only if the potential benefit outweighs the possible hazards in the opinion of the physician. The underlying condition itself (Inflammatory bowel disease (IBD) may increase risks for adverse pregnancy outcome.
Mesalazine is known to cross the placental barrier and its concentration in umbilical cord plasma is lower than the concentration in maternal plasma. The metabolite acetyl-mesalazine is found at similar concentrations in umbilical cord and maternal plasma. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetal development, parturition or postnatal development.
There are no adequate and well controlled studies of Pentasa use in pregnant women. Limited published human data on mesalazine show no increase in the overall rate of congenital malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease.
Blood disorders (pancytopenia, leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with Pentasa.
In one single case after long-term use of a high dose of mesalazine (2-4 g, orally) during pregnancy, renal failure in a neonate was reported.
Mesalazine is excreted in breast milk. The mesalazine concentration in breast milk is lower than in maternal blood, whereas the metabolite, acetyl mesalazine, appears in similar or increased concentrations. There is limited experience of the use of oral mesalazine in lactating women. No controlled studies with Pentasa during breast-feeding have been carried out. Hypersensitivity reactions like diarrhoea in the infant can not be excluded. If the infant develops diarrhoea, breast-feeding should be discontinued
Animal data on mesalazine show no effect on male and female fertility. Oligospermia (reversible) has been reported after use of mesalazine, see section 4.8.
Treatment with Pentasa is unlikely to affect the ability to drive and/or use machines.
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.
Following rectal administration, local reactions such as pruritus, rectal discomfort and urge may occur.
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).
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 | Not known (cannot be estimated from the available data) |
|---|---|---|---|---|
| Blood and the lymphatic system disorders | Altered blood counts (anaemia, aplastic anaemia, agranulocytosis, neutropenia, leukopenia (including granulocytopenia), pancytopenia, thrombocytopenia and eosinophilia (as part of an allergic reaction)) | |||
| Immune system disorders | Hypersensitivity reaction including anaphylactic reaction, Drug Reaction with Eosinophilia and Systemic Symptoms(DRESS) | |||
| Nervous System Disorders | Headache | Dizziness | Peripheral neuropathy | |
| Cardiac disorders | Myocarditis*, Pericarditis* | |||
| Respiratory, thoracic and mediastinal disorders | Allergic and fibrotic lung reactions (incl. dyspnoea, coughing, bronchospasm, allergic alveolitis), pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis | |||
| Gastrointestinal disorders | Diarrhoea, Abdominal pain, Nausea Vomiting, Flatulence | Increased amylase, acute pancreatitis* | Pancolitis |
| Hepato-biliary
disorders | Increase in
transaminases,
increase in
cholestasis
parameters (e.g.
alkaline
phosphatase,
gamma-glutamyltra
nsferase and
bilirubin),
hepatotoxicity (incl.
hepatitis*,
cholestatic hepatitis,
cirrhosis, hepatic
failure) |
| Skin and subcutaneous tissue disorders | Rash (incl. urticaria, erythematous rash) | Photosensitivity** | Alopecia reversible, dermatitis allergic, erythema multiform | Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) |
| Musculoskeletal, connective tissue and bone disorders | Myalgia, Arthralgia, Lupus erythematosus-like syndrome (systemic lupus erythematosus) | |||
| Renal and urinary disorders | Renal function impairment (incl. acute and chronic interstitial nephritis*, nephrotic syndrome, renal insufficiency), Urine discolouration | Nephrolithiasis§ | ||
| Reproductive system disorders | Oligospermia (reversible) | |||
| General disorders and administration site conditions | Anal discomfort and irritation at the application site, pruritus (anal), rectal tenesmus | Drug Fever |
* The mechanism of mesalazine induced myocarditis, 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.
§ See Section 4.4 for further information.
It is important to note that several of these disorders can also be attributed to be the inflammatory bowel disease itself.
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 HPRA Pharmacovigilance, Website: www.hpra.ie.
Not applicable.
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