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.

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment.

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.

Section 4.5:
Section update from

“The concurrent use of mesalazine with other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reaction (See section 4.4, Special warnings and precautions for use).”

to

“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.”

Section 4.6:

Section update as follows:

“Experience of use during pregnancy is limited. 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

Mesalazine is known to cross the placental barrier, but the limited data available on its use in pregnant women do not allow assessment of possible adverse effects. No teratogenic effects have been observed in animal studies. and its concentration in umbilical cord plasma is one tenth of the concentration in maternal plasma. The metabolite acetyl-mesalazine is found in the same concentration in umbilical cord and maternal plasma. From several observational studies no teratogenic effects are reported and there is no evidence of significant risk of use in humans. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development. 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. No adverse effects in suckling babies of mothers treated with Pentasa have been reported, but the data are very limited. 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.”

Section 4.8
- addition of the subheading: "Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance"

updates to adverse events as follows:
    -Blood and the lymphatic system disorders, Very rare: "eosinophilia (as part of an allergic reaction), altered blood counts (anaemia, aplastic anaemia, leucopenia (incl granulocytopenia and neutropenia)), thrombocytopenia, agranulocytosis, pancytopenia"
    - Immune system disorders, Very rare: "pancolitis, hypersensitivity reactions such as allergic exanthema"
    - Nervous system disorders, Rare: "dizziness"
    - Resiratory, thoracic adn mediastinal disorders, Very rare: "Allergic and fibrotic lung reactions (incl dyspnoea, coughing, bronchospasm, allergic alveolitis, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis)
    - Gastrointestinal disorders, Rare: "Increased amylase, acute pancreatitis*, flatulence"
    - Hepato-biliary disorders, Very rare: "Increased liver enzymes, cholestatis parameters adn bilirubin, hepatotoxicity incl hepatitis*, cholestatic hepatitis, cirrhosis, hepatic failure)
    - Skin and subcutaneous tissue disorders, Very rare: "Reversible alopecis, bullous skin reactions including erythema multidorme adn Stevens Johnson Syndrome"
    - Renal and urinary disorders, Very rare: "Renal function abnormal impairment (incl. acute and chronic interstitial nephritis*, nephrotic syndrome, renal insufficiency), Urine discolouration"

    - Reproductive system disorders, Very rare: "Oligospermia (reversible)"


Section 4.9
'Human experience' section updated from “No cases of overdose have been reported.” to "There is limited clinical experience with overdose of Pentasa which does not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive. There have been reports of patients taking daily doses of 8 grams for a month without any adverse events."

Section 6.4

Following sentence included: “Store in the original package as the product is sensitive to light.”

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.

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment.

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.

Section 4.5:
Section update from

“The concurrent use of mesalazine with other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reaction (See section 4.4, Special warnings and precautions for use).”

to

“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.”

Section 4.6:

Section update as follows:

“Experience of use during pregnancy is limited. 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

Mesalazine is known to cross the placental barrier, but the limited data available on its use in pregnant women do not allow assessment of possible adverse effects. No teratogenic effects have been observed in animal studies. and its concentration in umbilical cord plasma is one tenth of the concentration in maternal plasma. The metabolite acetyl-mesalazine is found in the same concentration in umbilical cord and maternal plasma. From several observational studies no teratogenic effects are reported and there is no evidence of significant risk of use in humans. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development. 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. No adverse effects in suckling babies of mothers treated with Pentasa have been reported, but the data are very limited. 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.”

Section 4.8
- addition of the subheading: "Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance"

updates to adverse events as follows:
    -Blood and the lymphatic system disorders, Very rare: "eosinophilia (as part of an allergic reaction), altered blood counts (anaemia, aplastic anaemia, leucopenia (incl granulocytopenia and neutropenia)), thrombocytopenia, agranulocytosis, pancytopenia"
    - Immune system disorders, Very rare: "pancolitis, hypersensitivity reactions such as allergic exanthema"
    - Nervous system disorders, Rare: "dizziness"
    - Resiratory, thoracic adn mediastinal disorders, Very rare: "Allergic and fibrotic lung reactions (incl dyspnoea, coughing, bronchospasm, allergic alveolitis, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis)
    - Gastrointestinal disorders, Rare: "Increased amylase, acute pancreatitis*, flatulence"
    - Hepato-biliary disorders, Very rare: "Increased liver enzymes, cholestatis parameters adn bilirubin, hepatotoxicity incl hepatitis*, cholestatic hepatitis, cirrhosis, hepatic failure)
    - Skin and subcutaneous tissue disorders, Very rare: "Reversible alopecis, bullous skin reactions including erythema multidorme adn Stevens Johnson Syndrome"
    - Renal and urinary disorders, Very rare: "Renal function abnormal impairment (incl. acute and chronic interstitial nephritis*, nephrotic syndrome, renal insufficiency), Urine discolouration"

    - Reproductive system disorders, Very rare: "Oligospermia (reversible)"


Section 4.9
'Human experience' section updated from “No cases of overdose have been reported.” to "There is limited clinical experience with overdose of Pentasa which does not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive. There have been reports of patients taking daily doses of 8 grams for a month without any adverse events."

Section 6.4

Following sentence included: “Store in the original package as the product is sensitive to light.”