Pentasa Sachet 2g prolonged release granules

To update sections 2 and 4 of the Package Leaflet

Drug reaction with eosinophilia and systemic symptoms (DRESS) is moved from ‘Very rare’ to ‘Not known’ in section 4.8 SmPC in line with the PRAC recommendation. In the ADR table in section 4.8 SmPC a footnote is added to urine discolouration with reference to the new warning re urine discolouration in section 4.4 SmPC. 

Update to Section 4.4, to add sentence 'Cases of nephrolithiases 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.'

Update to Section 4.8, to add column for 'Not known (cannot be estimated from the available data' and include 'Nephrolithiasis' in the Renal and Urinary disorders row.

Update to Section 4.2, to add sentence 'Alternatively the entire content of the sachet can be taken with yogurt and consumed immediately.'

Section 4.8

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

Other minor updates in the table in Section 4.8:

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

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

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

Section 4.2:

Added subheadings:

“Posology”

“Method of administration

Oral use”

New sentence: “The safety and efficacy in children below 6 years of age have not been established.”

Section 4.6:

Sentence update: “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. “

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. “

Section 4.8

Adverse events updated, see SPC for full updated list.

Section 4.9

New sentences:

“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

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. “

“It is currently unknown which, if any, of these mechanisms play a predominant role in the clinical efficacy of mesalazine.”

Sections 5.2 and 5.3

Full updates, see SPC for text.

Section 6.5:

Replaced “Aluminium foil single dose container.” with “Polyester/Aluminium/LD polyethylene sachet”

Section 4.2:

Added subheadings:

“Posology”

“Method of administration

Oral use”

New sentence: “The safety and efficacy in children below 6 years of age have not been established.”

Section 4.6:

Sentence update: “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. “

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. “

Section 4.8

Adverse events updated, see SPC for full updated list.

Section 4.9

New sentences:

“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

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. “

“It is currently unknown which, if any, of these mechanisms play a predominant role in the clinical efficacy of mesalazine.”

Sections 5.2 and 5.3

Full updates, see SPC for text.

Section 6.5:

Replaced “Aluminium foil single dose container.” with “Polyester/Aluminium/LD polyethylene sachet”

Ulcerative colitis

Adults

Active disease

Individual dosage, up to 4 g mesalazine once daily or divided into 2-4 doses.

Ulcerative colitis

Adults

Active disease

Individual dosage, up to 4 g mesalazine once daily or divided into 2-4 doses.

Section 4.3: minor text change, no change to the content

Section 4.4:  full section update

Section 4.5:  updated sentence to: ‘Combination therapy with Pentasa and azathioprine or 6-mercaptopurine or thioguanine have shown a higher frequency of myelosuppressive effects, and an interaction cannot be ruled out, however, the mechanism behind the interaction is not established.’

Section 4.6: 

updated pregnancy section to:

‘Mesalazine is known to cross the placental barrier. Data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the fetus/newborn child. To date no other relevant epidemiologic data are available. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development. Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with Pentasa Sachet.

In one single case after long-term use of a high dose of mesalazine (2-4g, orally) during pregnancy, renal failure in a neonate was reported. .

Lactation section, new sentence: ‘If the infant develops diarrhoea, breast-feeding should be discontinued.’

New Fertility section: ‘Animal data on Mesalazine show no effect on male and female fertility’

Section 4.7:  sentence updated from ‘None known’ to ‘Pentasa Sachet has no or negligible influence on the ability to drive or use machines.’

Section 4.8:
Changes to Rare events:

-         nervous system disorders: ‘dizziness’ added

-         gastrointestinal disorders: ‘flatulence’ added. ‘pancreatitis’ updated to ‘acute pancreatitis’

Changes to Very Rare events:

-         Blood and the lymphatic system disorders: ‘altered blood counts’ and ‘neutropenia’ added.

-         Immune system disorders: ‘hypersensitivity reactions such as allergic exanthema’ and ‘Pancolitis’ added

-         Respiratory, thoracic and mediastinal disorders: ‘bronchospasm’ added

-         Hepato-biliary disorders: ‘cholestasis parameters’ and ‘cholesttic hepatitis’ added

-         Reproductive system disorders: new section. ‘Oligospermia (reversible)’ added.

-         General disorders and administration site conditions: ‘Drug fever’ added

Section 5.1:  Update of Pharmacotherapeutic group to: ‘Pharmacotherapeutic groups: Intestinal anti-inflammatory agents, aminosalicylic acid and similar agents’

Section 4.3: minor text change, no change to the content

Section 4.4:  full section update

Section 4.5:  updated sentence to: ‘Combination therapy with Pentasa and azathioprine or 6-mercaptopurine or thioguanine have shown a higher frequency of myelosuppressive effects, and an interaction cannot be ruled out, however, the mechanism behind the interaction is not established.’

Section 4.6: 

updated pregnancy section to:

‘Mesalazine is known to cross the placental barrier. Data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the fetus/newborn child. To date no other relevant epidemiologic data are available. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development. Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with Pentasa Sachet.

In one single case after long-term use of a high dose of mesalazine (2-4g, orally) during pregnancy, renal failure in a neonate was reported. .

Lactation section, new sentence: ‘If the infant develops diarrhoea, breast-feeding should be discontinued.’

New Fertility section: ‘Animal data on Mesalazine show no effect on male and female fertility’

Section 4.7:  sentence updated from ‘None known’ to ‘Pentasa Sachet has no or negligible influence on the ability to drive or use machines.’

Section 4.8:
Changes to Rare events:

-         nervous system disorders: ‘dizziness’ added

-         gastrointestinal disorders: ‘flatulence’ added. ‘pancreatitis’ updated to ‘acute pancreatitis’

Changes to Very Rare events:

-         Blood and the lymphatic system disorders: ‘altered blood counts’ and ‘neutropenia’ added.

-         Immune system disorders: ‘hypersensitivity reactions such as allergic exanthema’ and ‘Pancolitis’ added

-         Respiratory, thoracic and mediastinal disorders: ‘bronchospasm’ added

-         Hepato-biliary disorders: ‘cholestasis parameters’ and ‘cholesttic hepatitis’ added

-         Reproductive system disorders: new section. ‘Oligospermia (reversible)’ added.

-         General disorders and administration site conditions: ‘Drug fever’ added

Section 5.1:  Update of Pharmacotherapeutic group to: ‘Pharmacotherapeutic groups: Intestinal anti-inflammatory agents, aminosalicylic acid and similar agents’