Update to section 2.0 & section 4.0

Updates:

Section 4.4, to add sentence ‘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.’.

Section 4.8, to add column ‘Not known (cannot be estimated from the available data)’ and ‘Nephrolitiasis’ in Renal and urinary disorders section.

Section 4.4:

Sentence update: “Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment; please refer to section 4.8.”

Section 4.8

“Photosensitivity” added as a rare side effect with the note “More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.”

Other minor updates:

-          “blood disorders” updated to “altered blood counts”

-          “allergic exanthema” reworded to “dermatitis allergic” and relocated to section for skin and subcutaneous tissue disorders

-          “increased liver enzymens, cholestasis parameters and bilirublin” reworded for clarification to “Increase in transaminases, increase in cholestasis parameters (e.g. alkaline phosphatase, gamma-glutamyltransferase and bilirubin),”

-          “lupus erythematosus-like reactions” reworded to “lupus erythematosus-like syndrome (systemic lupus erythematosus)”

-          “drug fever” moved to section for general disorders and administration site conditions.

Section 4.9

Most common symptoms of salicylate toxicity added for clarification as follows:

“But since PENTASA is an amino salicylate, symptoms of salicylate toxicity such as acid-base balance disorder, hyperventilation, pulmonary oedema, vomiting, dehydration and hypoglycaemia may occur. Symptoms of salicylate over dosage are well described in the literature”

Section 4.4:

Sentence update: “Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment; please refer to section 4.8.”

Section 4.8

“Photosensitivity” added as a rare side effect with the note “More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.”

Other minor updates:

-          “blood disorders” updated to “altered blood counts”

-          “allergic exanthema” reworded to “dermatitis allergic” and relocated to section for skin and subcutaneous tissue disorders

-          “increased liver enzymens, cholestasis parameters and bilirublin” reworded for clarification to “Increase in transaminases, increase in cholestasis parameters (e.g. alkaline phosphatase, gamma-glutamyltransferase and bilirubin),”

-          “lupus erythematosus-like reactions” reworded to “lupus erythematosus-like syndrome (systemic lupus erythematosus)”

-          “drug fever” moved to section for general disorders and administration site conditions.

Section 4.9

Most common symptoms of salicylate toxicity added for clarification as follows:

“But since PENTASA is an amino salicylate, symptoms of salicylate toxicity such as acid-base balance disorder, hyperventilation, pulmonary oedema, vomiting, dehydration and hypoglycaemia may occur. Symptoms of salicylate over dosage are well described in the literature”

Section 4.6:

New sentence: “The underlying condition itself (Inflammatory bowel disease (IBD) may increase risks for adverse pregnancy outcome.”

New text:  “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. “

Deleted: “From several observational studies no teratogenic effects are reported and there is no evidence of significant risk of use in humans.”

Section 4.7:

Text updated from “No adverse effects” to “Treatment with Pentasa is unlikely to affect the ability to drive and/or use machines.”

Section 4.8

Adverse events updated, see SPC for full updated list.

Section 4.9

New sentences:

“But since Pentasa is an amino salicylate, symptoms of salicylate toxicity may occur.  Symptoms of salicylate over dosage are well described in the literature.  “

“There is no specific antidote and the management of overdose is supportive and symptomatic. The treatment at hospital includes close monitoring of renal function.”

Deleted text:

“There is no specific antidote and treatment is symptomatic and supportive.”

“Management of overdose in man:

Symptomatic treatment at hospital. Close monitoring of renal function. Intravenous infusion of electrolytes may be used to promote diuresis.”

Section 5.1

Deleted: “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.”

New sections:

“It has been established that mesalazine is the active component of sulphasalazine which is used for the treatment of ulcerative colitis and Crohn’s disease.  Based on clinical results, the therapeutic value of mesalazine after oral as well as rectal administration 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. “

“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 has been implicated.  “

Sections 5.2 and 5.3

Full updates, see SPC for text.

Section 4.6:

New sentence: “The underlying condition itself (Inflammatory bowel disease (IBD) may increase risks for adverse pregnancy outcome.”

New text:  “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. “

Deleted: “From several observational studies no teratogenic effects are reported and there is no evidence of significant risk of use in humans.”

Section 4.7:

Text updated from “No adverse effects” to “Treatment with Pentasa is unlikely to affect the ability to drive and/or use machines.”

Section 4.8

Adverse events updated, see SPC for full updated list.

Section 4.9

New sentences:

“But since Pentasa is an amino salicylate, symptoms of salicylate toxicity may occur.  Symptoms of salicylate over dosage are well described in the literature.  “

“There is no specific antidote and the management of overdose is supportive and symptomatic. The treatment at hospital includes close monitoring of renal function.”

Deleted text:

“There is no specific antidote and treatment is symptomatic and supportive.”

“Management of overdose in man:

Symptomatic treatment at hospital. Close monitoring of renal function. Intravenous infusion of electrolytes may be used to promote diuresis.”

Section 5.1

Deleted: “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.”

New sections:

“It has been established that mesalazine is the active component of sulphasalazine which is used for the treatment of ulcerative colitis and Crohn’s disease.  Based on clinical results, the therapeutic value of mesalazine after oral as well as rectal administration 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. “

“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 has been implicated.  “

Sections 5.2 and 5.3

Full updates, see SPC for text.

1.         TRADE NAME OF MEDICINAL PRODUCT

Pentasa 1 g prolongedProlonged-release tabletsTablets

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION     

Each tablet contains mesalazine 1 g.

For a full list of excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

Prolonged-release tablet.

White-grey to pale brown, speckled, oval tablet. Embossing on both sides: PENTASA.

4.         CLINICAL  PARTICULARS

4.1       Therapeutic indications

For the treatment of mild to moderate ulcerative colitis and Crohn's disease.

4.2              Posology and method of administration

Ulcerative Colitis

Adults:

Acute TreatmentActive treatment:  Individual dosage, up to 4 g mesalazine once daily or in two or three divided doses.

Maintenance treatment:  Recommended dosage, 2 g mesalazine once daily.

Children:

Individual dosage, recommended starting dose is 20-30 mg/kg bodyweight daily in two or three divided doses.

Crohn’s Disease

Adults:

Acute TreatmentActive treatment:  Individual dosage, up to 4 g mesalazine daily in two or three divided doses.

Maintenance treatment:  Individual dosage, up to 4 g mesalazine daily in two or three divided doses.

Paediatric population

There is only limited documentation for an effect in children (age 6-18 years)

Ulcerative colitis

Treatment of active disease:

Children:

Individual dosage, recommended  6 years of age and older:  To be determined individually, starting dose is 20-with 30-50 mg/kg bodyweight daily in two or three/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:

Children 6 years of age and older:  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.

Crohn’s disease

Treatment of active disease:

Children 6 years of age and older:  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:

Children 6 years of age and older:  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.

Method of Administration

Pentasa tablets must not be chewed.  To facilitate swallowing the tablets may be dispersed in 50 ml of cold water. Stir and drink immediately.

4.3       CONTRAINDICATIONS

Hypersensitivity to mesalazine, any of the excipients, or salicylates

Severe liver and/or renal impairment

Children under the age of 2 years

4.8       Undesirable effects

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. 

            <No changes were made to the ADR table>

* The mechanism of mesalazine induced myocarditis, 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 be 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 IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517.

Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic Properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agents.

ATC Code:  A07 EC02

Mechanism of action and pharmacodynamic effects:

Mesalazine 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. Mesalazine 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 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.

10.       DATE OF REVISION OF THE TEXT

September 2013

June 2014

1.         TRADE NAME OF MEDICINAL PRODUCT

Pentasa 1 g prolongedProlonged-release tabletsTablets

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION     

Each tablet contains mesalazine 1 g.

For a full list of excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

Prolonged-release tablet.

White-grey to pale brown, speckled, oval tablet. Embossing on both sides: PENTASA.

4.         CLINICAL  PARTICULARS

4.1       Therapeutic indications

For the treatment of mild to moderate ulcerative colitis and Crohn's disease.

4.2              Posology and method of administration

Ulcerative Colitis

Adults:

Acute TreatmentActive treatment:  Individual dosage, up to 4 g mesalazine once daily or in two or three divided doses.

Maintenance treatment:  Recommended dosage, 2 g mesalazine once daily.

Children:

Individual dosage, recommended starting dose is 20-30 mg/kg bodyweight daily in two or three divided doses.

Crohn’s Disease

Adults:

Acute TreatmentActive treatment:  Individual dosage, up to 4 g mesalazine daily in two or three divided doses.

Maintenance treatment:  Individual dosage, up to 4 g mesalazine daily in two or three divided doses.

Paediatric population

There is only limited documentation for an effect in children (age 6-18 years)

Ulcerative colitis

Treatment of active disease:

Children:

Individual dosage, recommended  6 years of age and older:  To be determined individually, starting dose is 20-with 30-50 mg/kg bodyweight daily in two or three/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:

Children 6 years of age and older:  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.

Crohn’s disease

Treatment of active disease:

Children 6 years of age and older:  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:

Children 6 years of age and older:  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.

Method of Administration

Pentasa tablets must not be chewed.  To facilitate swallowing the tablets may be dispersed in 50 ml of cold water. Stir and drink immediately.

4.3       CONTRAINDICATIONS

Hypersensitivity to mesalazine, any of the excipients, or salicylates

Severe liver and/or renal impairment

Children under the age of 2 years

4.8       Undesirable effects

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. 

            <No changes were made to the ADR table>

* The mechanism of mesalazine induced myocarditis, 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 be 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 IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517.

Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic Properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agents.

ATC Code:  A07 EC02

Mechanism of action and pharmacodynamic effects:

Mesalazine 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. Mesalazine 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 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.

10.       DATE OF REVISION OF THE TEXT

September 2013

June 2014

"Ulcerative Colitis

Adults:

Acute Treatment:  Individual dosage, up to 4 g mesalazine once daily or in two or three divided doses."

"Ulcerative Colitis

Adults:

Acute Treatment:  Individual dosage, up to 4 g mesalazine once daily or in two or three divided doses."

Section 4.3:
Removed two contraindications: active peptic ulcer and coagulopathy.

Section 4.4:
- addition of the sentence: "In case of acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately."
- addition of the sentence: "Urinary status (dip sticks) should be determined prior to and during treatment at the discretion of the treating physician."
- inclusion of 'thioguanine' in the sentence "As stated in the interaction section 4.5, concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine, 6-mercaptopurine or thioguanine."
- addition of hte following sentences: "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:
- sentence update: "Combination therapy with Pentasa and azathioprine, or  6-mercaptopurine or thioguanine, have in several studies shown a higher frequency of leucopenia myelosuppressive effects, and an interaction seems to exist, however, the mechanism behind the interaction is not fully established."
- addition of the sentence: "There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin."

Section 4.6:

- addition of the sentence: "Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development."

- deletion of the sentence: "In animal studies no teratogenic or mutagenic effects have been observed".
- addition of the sentences:
"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."
"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:
    - Deletion of the column 'Not known'. The two 'Not known' events of hypersensitivity reaction and drug fever were changed to 'Very rare' frequency, as described below.

    -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...)
    - Gastrointestinal disorders, Rare: "Increased amylast, 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 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 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 sympotmatic and supportive. There have been reports of patients taking daily doses of 8 grams for a month without any adverse events."

Section 4.3:
Removed two contraindications: active peptic ulcer and coagulopathy.

Section 4.4:
- addition of the sentence: "In case of acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately."
- addition of the sentence: "Urinary status (dip sticks) should be determined prior to and during treatment at the discretion of the treating physician."
- inclusion of 'thioguanine' in the sentence "As stated in the interaction section 4.5, concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine, 6-mercaptopurine or thioguanine."
- addition of hte following sentences: "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:
- sentence update: "Combination therapy with Pentasa and azathioprine, or  6-mercaptopurine or thioguanine, have in several studies shown a higher frequency of leucopenia myelosuppressive effects, and an interaction seems to exist, however, the mechanism behind the interaction is not fully established."
- addition of the sentence: "There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin."

Section 4.6:

- addition of the sentence: "Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development."

- deletion of the sentence: "In animal studies no teratogenic or mutagenic effects have been observed".
- addition of the sentences:
"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."
"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:
    - Deletion of the column 'Not known'. The two 'Not known' events of hypersensitivity reaction and drug fever were changed to 'Very rare' frequency, as described below.

    -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...)
    - Gastrointestinal disorders, Rare: "Increased amylast, 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 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 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 sympotmatic and supportive. There have been reports of patients taking daily doses of 8 grams for a month without any adverse events."