Pentasa 10 mg/ml Rectal Suspension

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.

- “anal discomfort and irritation at the application site, pruritus tenesmus” updated to “anal discomfort and irritation at the application site, pruritus (anal), rectal tenesmus”

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.

- “anal discomfort and irritation at the application site, pruritus tenesmus” updated to “anal discomfort and irritation at the application site, pruritus (anal), rectal tenesmus”

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 6.6:

New sentence: “The rectal suspension may colour the linen and toilet.”

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 6.6:

New sentence: “The rectal suspension may colour the linen and toilet.”

.

for 2  3 weeksan effect in children.

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, 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.

Combination therapy with Pentasa and azathioprine, 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.

Mesalazine is known to cross the placental barrier 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. 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.

No adverse 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. 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

Single oral doses of mesalazine of up to 5gkg in pigs or a single intravenous dose of mesalazine at 920mgkg in rats were not lethal.

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.

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

The absorption following rectal administration is low, and 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 - 2), about 15-20% of the dose is absorbed after administration of Rectal Suspensions.

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%.

Elimination:

The plasma half-life of mesalazine following i.v. administration is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

The systematic absorption following administration of Pentasa Rectal Suspension 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 mesalazine may constitute an increased risk of nephrotoxic adverse reactions.

Definitive nephrotoxicity and possible gastrointestinal toxicity is demonstrated in all species examined, and nephrotoxicity is evident with doses 5-10 times those used in humans.

In-vitro test systems and in-vivo studies showed no evidence of mutagenic effects. Studies on the tumorigenic potential carried out in rats showed no evidence of any substance-related increase in the incidence of tumours.

Disodium edetate.

Sodium metabisulfite (E223)

Sodium acetate.

Hydrochloric acid (for pH adjustment)

Purified water.

Not applicable.

Before opening individual foil pack: 3 years

After opening individual foil pack: Use immediately

.

nd February 1989

Date of last renewal: 2

nd February 2009

.

for 2  3 weeksan effect in children.

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, 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.

Combination therapy with Pentasa and azathioprine, 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.

Mesalazine is known to cross the placental barrier 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. 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.

No adverse 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. 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

Single oral doses of mesalazine of up to 5gkg in pigs or a single intravenous dose of mesalazine at 920mgkg in rats were not lethal.

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.

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

The absorption following rectal administration is low, and 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 - 2), about 15-20% of the dose is absorbed after administration of Rectal Suspensions.

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%.

Elimination:

The plasma half-life of mesalazine following i.v. administration is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

The systematic absorption following administration of Pentasa Rectal Suspension 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 mesalazine may constitute an increased risk of nephrotoxic adverse reactions.

Definitive nephrotoxicity and possible gastrointestinal toxicity is demonstrated in all species examined, and nephrotoxicity is evident with doses 5-10 times those used in humans.

In-vitro test systems and in-vivo studies showed no evidence of mutagenic effects. Studies on the tumorigenic potential carried out in rats showed no evidence of any substance-related increase in the incidence of tumours.

Disodium edetate.

Sodium metabisulfite (E223)

Sodium acetate.

Hydrochloric acid (for pH adjustment)

Purified water.

Not applicable.

Before opening individual foil pack: 3 years

After opening individual foil pack: Use immediately

.

nd February 1989

Date of last renewal: 2

nd February 2009

Section 6.4: Storage conditions updated from

"Do not store above 25°C. Store in the original package to protect from light." to: "Store below 25C. Do not freeze. Store in the original package in order t protect from light."

Section 6.4: Storage conditions updated from

"Do not store above 25°C. Store in the original package to protect from light." to: "Store below 25C. Do not freeze. Store in the original package in order t protect from light."

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."

- addition of the sentence: “Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment.”
- 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 the 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, 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 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 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."

- addition of the sentence: “Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment.”
- 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 the 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, 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 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 4.5:  Updated to: 'Combination therapy with PENTASA and azathioprine or 6-mercaptopurine have in several studies shown a higher frequency of leucopenia, 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.'

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 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 umbilican 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.  In animal studies no teratogenic or mutagenic effects have been observed. 

Blood disorders (pancytopenia, leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA.

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.'

Section 4.8:  Addition of undesirable effect: very rare - interstitial lung disease

Section 4.9: Updated 'Human experience' section to: 'There is limited clinical experience with overdose of PENTASA. There have been reports of patients taking daily doses of 8 grams for a month without any adverse events.'

Section 4.5:  Updated to: 'Combination therapy with PENTASA and azathioprine or 6-mercaptopurine have in several studies shown a higher frequency of leucopenia, 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.'

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 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 umbilican 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.  In animal studies no teratogenic or mutagenic effects have been observed. 

Blood disorders (pancytopenia, leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA.

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.'

Section 4.8:  Addition of undesirable effect: very rare - interstitial lung disease

Section 4.9: Updated 'Human experience' section to: 'There is limited clinical experience with overdose of PENTASA. There have been reports of patients taking daily doses of 8 grams for a month without any adverse events.'