Pentasa 1 g Suppositories

  • Name:

    Pentasa 1 g Suppositories

  • Company:
    info
  • Active Ingredients:

    Mesalazine

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Summary of Product Characteristics last updated on medicines.ie: 12/11/2019

Click on this link to Download PDF directly

Ferring Ireland Limited

Ferring Ireland Limited

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Medicine Name Pentasa 1 g Prolonged-release Tablets Active Ingredients Mesalazine
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1 - 0 of 35 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 12 November 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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.

Updated on 29 January 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 29 January 2018 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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”

Updated on 29 January 2018 PIL

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose

Free text change information supplied by the pharmaceutical company

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”

Updated on 24 June 2016 SmPC

Reasons for updating

  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 4.6 - Pregnancy and lactation

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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.

Updated on 24 June 2016 PIL

Reasons for updating

  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 4.6 - Pregnancy and lactation

Free text change information supplied by the pharmaceutical company

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.

Updated on 26 May 2015 PIL

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Free text change information supplied by the pharmaceutical company

Update to include new HPRA contact information

Updated on 26 May 2015 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Update to include new HPRA contact information

Updated on 17 July 2014 PIL

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

1. NAME OF THE MEDICINAL PRODUCT

 

Pentasa 1g Suppositories

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each suppository contains mesalazine 1g.

For full list of excipients, see section 6.1.

 

 

3. PHARMACEUTICAL FORM:

 

Suppository

White to tan, spotted, oblong suppository.

 

 

4. CLINICAL PARTICULARS:

4.1 Therapeutic indications:

For the treatment of

Ulcerativeulcerative proctitis.

 

4.2 Posology and method of administration

 

Adults:

 

 

Acute

 

Active treatment:

 

 

 

The recommended dosage is one suppository1 g mesalazine

 

twice daily for two to four weeks...

 

 

 

 

Maintenance treatment:

 

 

1000-2000mg1-2 g

 

mesalazine daily.

 

 

 

Children:

20-30mg mesalazine per kilogram body weight daily, divided into several doses when possible.

Paediatric population:

There is little experience with only limited documentation for an effect in children.

 

 

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.

4.4 Special warnings and precautions for use:

 

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.

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.

4.5 Interaction with other medicinal products and other forms of interaction:

 

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.

4.6 Fertility, pregnancy and lactation

 

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.

4.7 Effects on ability to drive and use machines:

 

No adverse effects.

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.

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

<No changes made to AER table>

 

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

 

 

 4.9 Overdose
Acute experience in animals:
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.

Human experience:
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.

Management of overdose in man:
Symptomatic treatment at hospital. Close monitoring of renal function. Intravenous infusion of electrolytes may be used to promote diuresis.

 

 

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.

5.2 Pharmacokinetic properties:

 

General characteristics of the active substance:

 

Disposition and local availability:

Pentasa suppositories are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. They are used to treat the rectum.

Biotransformation: Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl mesalazine). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.

Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.

Absorption: The absorption following rectal administration is low, but 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 x 2), approximately 10% of the dose is adsorbed after administration of suppositories.

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 pure mesalazine 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:

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.

5.3 Pre-clinical safety data

 

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS:

6.1 List of excipients

 

Povidone

Macrogol 6000

Magnesium Stearate

Talc

6.2 Incompatibilities:

 

Not applicable

6.3 Shelf-life:

3 years

6.4 Special precautions for storage:

Do not store above 25ºC. Store in the original package in order to protect from light.

6.5 Nature and contents of container:

 

Each suppository is individually packed in double aluminium foil and presented in cartons of 28 suppositories.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product.

 

No special requirements.

7. MARKETING AUTHORISATION HOLDER:

 

Ferring Ireland Ltd

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

Ireland

8. MARKETING AUTHORISATION NUMBER:

 

PA 1009/6/2

9. DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION:

 

Date of first authorisation: 21 December 1992

Date of last renewal: 21 December 2007

 

 

10. DATE OF (PARTIAL) REVISION OF THE TEXT:

 

June

20122014

 

 

 

Updated on 17 July 2014 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

1. NAME OF THE MEDICINAL PRODUCT

 

Pentasa 1g Suppositories

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each suppository contains mesalazine 1g.

For full list of excipients, see section 6.1.

 

 

3. PHARMACEUTICAL FORM:

 

Suppository

White to tan, spotted, oblong suppository.

 

 

4. CLINICAL PARTICULARS:

4.1 Therapeutic indications:

For the treatment of

Ulcerativeulcerative proctitis.

 

4.2 Posology and method of administration

 

Adults:

 

 

Acute

 

Active treatment:

 

 

 

The recommended dosage is one suppository1 g mesalazine

 

twice daily for two to four weeks...

 

 

 

 

Maintenance treatment:

 

 

1000-2000mg1-2 g

 

mesalazine daily.

 

 

 

Children:

20-30mg mesalazine per kilogram body weight daily, divided into several doses when possible.

Paediatric population:

There is little experience with only limited documentation for an effect in children.

 

 

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.

4.4 Special warnings and precautions for use:

 

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.

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.

4.5 Interaction with other medicinal products and other forms of interaction:

 

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.

4.6 Fertility, pregnancy and lactation

 

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.

4.7 Effects on ability to drive and use machines:

 

No adverse effects.

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.

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

<No changes made to AER table>

 

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

 

 

 4.9 Overdose
Acute experience in animals:
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.

Human experience:
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.

Management of overdose in man:
Symptomatic treatment at hospital. Close monitoring of renal function. Intravenous infusion of electrolytes may be used to promote diuresis.

 

 

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.

5.2 Pharmacokinetic properties:

 

General characteristics of the active substance:

 

Disposition and local availability:

Pentasa suppositories are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. They are used to treat the rectum.

Biotransformation: Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl mesalazine). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.

Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.

Absorption: The absorption following rectal administration is low, but 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 x 2), approximately 10% of the dose is adsorbed after administration of suppositories.

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 pure mesalazine 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:

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.

5.3 Pre-clinical safety data

 

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS:

6.1 List of excipients

 

Povidone

Macrogol 6000

Magnesium Stearate

Talc

6.2 Incompatibilities:

 

Not applicable

6.3 Shelf-life:

3 years

6.4 Special precautions for storage:

Do not store above 25ºC. Store in the original package in order to protect from light.

6.5 Nature and contents of container:

 

Each suppository is individually packed in double aluminium foil and presented in cartons of 28 suppositories.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product.

 

No special requirements.

7. MARKETING AUTHORISATION HOLDER:

 

Ferring Ireland Ltd

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

Ireland

8. MARKETING AUTHORISATION NUMBER:

 

PA 1009/6/2

9. DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION:

 

Date of first authorisation: 21 December 1992

Date of last renewal: 21 December 2007

 

 

10. DATE OF (PARTIAL) REVISION OF THE TEXT:

 

June

20122014

 

 

 

Updated on 15 August 2012 PIL

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.3 - Contraindications
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 6.4 - Special precautions for storage

Free text change information supplied by the pharmaceutical company

 

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

 

Section 4.4:

Serious blood dyscrasias have been reported rarely with mesalazine. 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). Haematological investigations should be performed if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Treatment should be stopped if there is suspicion or evidence of blood dyscrasia.   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.

 

It is recommended that mesalazine be used with extreme caution in patients with mild to moderate renal impairment. (See section 4.3, Contraindications).

   

If a patient develops dehydration while on treatment with mesalazine, normal electrolyte levels and fluid balance should be restored as soon as possible.

 

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 reactions (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 updated to:

“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.

 

Mesalazine is excreted in breast milk. The concentration 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.”

 


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 and 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 alopecia, bullous skin reactions including erythema multidorme and Stevens Johnson Syndrome"
    - Renal and urinary disorders, Very rare: "Abnormal renal function (incl. acute and chronic interstitial nephritis*, nephrotic syndrome, renal insufficiency), Urine discolouration"

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

-          General disorders and administration, Very rare: “drug fever”

 

 

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 6.4

Updated storage conditions to “ Store in the original package in order to protect from light.”

Updated on 15 August 2012 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.3 - Contraindications
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 6.4 - Special precautions for storage

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

 

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

 

Section 4.4:

Serious blood dyscrasias have been reported rarely with mesalazine. 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). Haematological investigations should be performed if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Treatment should be stopped if there is suspicion or evidence of blood dyscrasia.   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.

 

It is recommended that mesalazine be used with extreme caution in patients with mild to moderate renal impairment. (See section 4.3, Contraindications).

   

If a patient develops dehydration while on treatment with mesalazine, normal electrolyte levels and fluid balance should be restored as soon as possible.

 

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 reactions (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 updated to:

“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.

 

Mesalazine is excreted in breast milk. The concentration 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.”

 


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 and 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 alopecia, bullous skin reactions including erythema multidorme and Stevens Johnson Syndrome"
    - Renal and urinary disorders, Very rare: "Abnormal renal function (incl. acute and chronic interstitial nephritis*, nephrotic syndrome, renal insufficiency), Urine discolouration"

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

-          General disorders and administration, Very rare: “drug fever”

 

 

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 6.4

Updated storage conditions to “ Store in the original package in order to protect from light.”

Updated on 22 June 2009 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company



Section 4.8:  Addition of undesirable effects: peripheral neuropathy, pneumonitis and urine discolouration.  Table updated to MedDRA format.

Updated on 22 June 2009 PIL

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Free text change information supplied by the pharmaceutical company



Section 4.8:  Addition of undesirable effects: peripheral neuropathy, pneumonitis and urine discolouration.  Table updated to MedDRA format.

Updated on 11 August 2008 PIL

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation

Free text change information supplied by the pharmaceutical company

Section 3  Change description of the product to 'White to tan, spotted, oblong suppository'
Section 6.4  Added: 'Store in the original package'.
Section 6.6 Changed 'No special precaution required' to 'No special requirements'
Section 9  Renewal of authorisation changed to '21st December 2007'

Updated on 11 August 2008 SmPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 3  Change description of the product to 'White to tan, spotted, oblong suppository'
Section 6.4  Added: 'Store in the original package'.
Section 6.6 Changed 'No special precaution required' to 'No special requirements'
Section 9  Renewal of authorisation changed to '21st December 2007'

Updated on 27 August 2007 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 27 August 2007 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 16 August 2007 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration

Free text change information supplied by the pharmaceutical company

 Error in SPC section 4.2 dose for children incorrectly recorded as /Kg updated to mg/Kg

Updated on 16 August 2007 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration

Free text change information supplied by the pharmaceutical company

Change to section 4.2 due to error on SPC-dose for children recorded as /Kg changed to mg/KG.

Updated on 16 August 2007 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Change to section 4.2 due to error on SPC-dose for children recorded as /Kg changed to mg/KG.

Updated on 16 August 2007 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

 Error in SPC section 4.2 dose for children incorrectly recorded as /Kg updated to mg/Kg

Updated on 4 April 2007 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Change to section 6.5  Nature and Contents of Container. Wording has been modified.

Updated on 4 April 2007 PIL

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

Free text change information supplied by the pharmaceutical company

Change to section 6.5  Nature and Contents of Container. Wording has been modified.

Updated on 27 June 2005 PIL

Reasons for updating

  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Updated on 27 June 2005 SmPC

Reasons for updating

  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 26 June 2003 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 26 June 2003 PIL

Reasons for updating

  • New SPC for medicines.ie