Asacolon 800 mg Gastro-Resistant Tablets

4.4 Special warnings and precautions for use

Severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment.

Mesalazine should be discontinued, at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

4.8 Undesirable effects

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).

Table of ADRs
Skin and subcutaneous tissue disorders SOC: Frequency: unknown
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

Warnings and precautions
Talk to your doctor before taking Asacolon if you have any medical conditions or illnesses, particularly if you have:
- any lung disease problems, e.g. asthma.
- liver disease.
- kidney disease.
- suffered an allergy to sulphasalazine in the past.
- ever had allergic reactions of your heart such as inflammation of the heart muscle or heart sac. If you have had previous suspected mesalazine-induced allergic reactions of your heart, then Asacolon must not be taken. Asacolon can be taken with care if you have had a previous allergic reaction of the heart not caused by mesalazine.
- Blood dyscrasia, a condition in which different constituents of blood, such as white blood or red blood cells and platelets, are either high or too low in counts.
- ever developed a severe skin rash or skin peeling, blistering and/or mouth sores after using mesalazine.
Serious skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis have been reported in association with mesalazine treatment. Stop using mesalazine and seek medical attention immediately if you notice any of the symptoms related to these serious skin reactions described in section 4.

4. Possible side-effects

Stop taking Asacolon immediately and seek urgent medical advice
If you develop unexplained bruising (without injury), bleeding under your skin, purple spots or patches under your skin, anaemia (feeling tired, weak and looking pale, especially on lips, nails and inside of eyelids), fever (high temperature), sore throat or unusual bleeding (e.g. nose bleeds), reddish non-elevated, target-like or circular patches on the trunk, often with central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes. These serious skin rashes can be preceded by fever and flu-like symptoms .

4.2       Posology and method of administration

Posology

Adults:

Ulcerative colitis:

Induction of remission:

2.4 g (3 tablets) per day once daily or in divided doses. If required the dose may be increased to 4.8 g (6 tablets) dailyper day in divided doses. Above 2.4 g daily in divided doses only.

The dosage can be adjusted in accordance with the response to the treatment.

under Skin and subcutaneous tissue was added with frequency rare: photosensitivity

c) Description of selected adverse reactions

.... 

Photosensitivity

More severe reactions are reported in patients with pre-existing skin conditions such as atopic

dermatitis and atopic eczema.

4.4       Special warnings and precautions for use

 

Blood tests (differential blood count, liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, follow-up tests are recommended 14 days after commencement of treatment and then every 4 weeks for the following 12 weeks. If the findings are normal, follow-up tests should be carried out every three months. If additional signs appear, these tests should be performed immediately.

 

Renal impairment

Asacolon should not be used in patients with impaired renal function. Urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. Caution should be exercised in patients with raised serum creatinine or proteinuria. The possibility of mesalazine-induced nephrotoxicity should be suspected in patients developing impairment of renal function during treatment.

 

It is recommended that all patients have an evaluation of their renal function prior to initiation of Asacolon therapy and repeatedly whilst on Asacolon therapy. As a guideline, follow-up tests are recommended 14 days after commencement of treatment and then every 4 weeks for the following 12 weeks. Short monitoring intervals early after the start of Asacolon therapy will discover rare acute renal reactions. In the absence of an acute renal reaction monitoring intervals can be extended to every 3 months and then annually after 5 years. If additional laboratory or clinical signs of renal impairment appear, these tests should be performed immediately. Treatment with Asacolon should be stopped immediately if there is evidence of renal impairment and patients should seek immediate medical advice.

 

Blood dyscrasia

Serious blood dyscrasia has very rarely been reported.  Treatment with Asacolon should be stopped immediately if there is a suspicion or evidence of blood dyscrasia (signs of unexplained bleeding, haematoma, purpura, anaemia, persistent fever or sore throat) and patients should seek immediate medical advice. It is recommended that haematological investigations (differential blood count) are performed prior to initiation of Asacolon and whilst on therapy, at the discretion of the treating physician. As a guideline, follow-up tests are recommended 14 days after commencement of therapy and then every 4 weeks for the following 12 weeks. If the findings are normal, follow-up tests should be carried out every 3 months. If additional symptoms occur, these tests should be performed immediately.

 

Hepatic impairment

There have been reports of increased liver enzyme levels in patients taking preparations containing mesalazine. Caution is recommended if Asacolon is administered to patients with liver impairment. Blood tests (liver function parameters such as ALT or AST) should be performed prior to and during treatment, at the discretion of the treating physician. 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 3 months. If additional symptoms occur, these tests should be performed immediately.
...

 

4.8       Undesirable effects

 

a) Summary of the safety profile

Asacolon 800 mg GR Tablets have been evaluated in 140 patients with mild to moderate active ulcerative colitis in one controlled study lasting for 10 weeks comparing safety and efficacy versus another 141 patients treated with placebo. Treatment related undesirable effects in the Asacolon group with the highest reporting rate were worsening of ulcerative colitis (3.6%), haematuria (2.9%), and ketonuria (2.1%). AsacolonAll undesirable effects with Asacolon 800 mg GR Tablets were of mild to moderate severity. Discontinuations due to adverse reactions occurred in 8.6% of patients in the Asacolon group and in 21.3% of patients in the placebo group. Most of the drug related reactions that led to study drug discontinuation were related to worsening of ulcerative colitis.

Organ specific adverse drug reactions affecting the heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue have been reported.

Treatment must be stopped immediately if acute symptoms of intolerance occur such as abdominal cramps, acute abdominal pain, fever, severe headache and rash.

 

b) Tabulated summary of adverse reactions

Undesirable effects reported from clinical studies with patients treated with Asacolon 400 mg GR tablets and other sources are listed below.

Common:  ≥ 1/100 to < 1/10, uncommon:  ≥ 1/1,000 to < 1/100

Rare: ≥ 1/10,000 to < 1/1000, very rare: < 1/10,000  

Not known (cannot be estimated from the available data)

System Organ Class	Common (≥ 1/100 to  < 1/10)	Uncommon  (≥ 1/1,000 to < 1/100)	Rare (≥ 1/10,000 to < 1/1,000)	Very rare (< 1/10,000)	Frequency not known
Blood and lymphatic system disorders	--	eosinophilia (as part of an allergic reaction).	--	altered blood counts (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia).	--
Immune system disorders	--	--	--	hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis.	--
Nervous system disorders	--	paresthesia.	headache, dizziness.	peripheral neuropathy.	--
Cardiac disorders	--	--	myocarditis, pericarditis.	--	--
Respiratory, thoracic and mediastinal disorders	--	--	--	allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), interstitial pneumonia, eosinophilic pneumonia, lung disorder.	pleurisy
Gastrointestinal disorders	dyspepsia.	--	abdominal pain, diarrhoea, flatulence, nausea, vomiting.	acute pancreatitis	--
Hepato-biliary disorders	--	--	--	changes in liver function parameters (increase in transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis.	--
Skin and subcutaneous tissue disorders	rash.	urticaria, pruritus.	--	alopecia.	--
Musculoskeletal, connective tissue and bone disorders	--	--	--	myalgia, arthralgia.	lupus-like syndrome with pericarditis and pleuropericarditis as prominent symptoms as well as rash and arthralgia.
Renal and urinary disorders	--	--	--	impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency, nephrotic syndrome, renal failure which may be reversible on early withdrawal.	--
Reproductive system and breast disorders	--	--	--	oligospermia (reversible).	--
General disorders and administration site conditions	--	pyrexia, chest pain.	--	--	intolerance to mesalazine with C-reactive protein increased and/or exacerbation of symptoms of underlying disease
Investigations	--	--	--	--	blood creatinine increased, weight decreased, creatinine clearance decreased, amylase increased, red blood cell sedimentation rate increased, lipase increased, BUN increased.

 

In section 4.1 (therapeutic indications), moderate has been added.

7.         MARKETING AUTHORISATION HOLDER

Tillotts Pharma Limited
United Drug House
Magna Drive
Magna Business Park
Citywest Road
Dublin 24
Tillotts Pharma GmbH

Warmbacher Strasse 80

79618 Rheinfelden

Germany

 

8.         MARKETING AUTHORISATION NUMBER

PA 1204/1/3
PA 2018/1/2

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each suppository contains: Mesalazine 500 mg mesalazine.

 

Excipient(s) with known effect:

Each suppository contains 2.5 g hard fat containing lecithin derived from soya, see section 4.4.

For the full list of excipients, see section 6.1.

4.1       Therapeutic Indications

 

This medication is indicated in adults for:

For the treatment of mild to moderate proctitis and proctosigmoiditis.

 

As an adjunct to oral therapy in severe generalised ulcerative colitis affecting the rectum or rectosigmoid colon.

4.2       Posology and method of administration

 

Rectal administration.

Posology

Adults:

One suppository to be inserted up to three times daily, after defaecation. The dosage is dependent upon the severity of the disease and it may be possible to reduce the dosage as the condition improves. In severe generalised ulcerative colitis affecting the rectum or rectosigmoid, and in cases slow to respond to oral therapy, one suppository may be used morning and evening, as an adjunct to oral therapy.

 

Renal impairment/hepatic impairment:

No data from controlled clinical studies are available warranting a specific dose adjustment in patients with mild to moderate renal or hepatic impairment. The maximum daily adult dose of 1.5 g mesalazine for rectal administration appears to carry little additional risk in these patients considering 4.0 g mesalazine being approved as maximum daily dose for oral administration (Asacolon tablets) to treat mild acute ulcerative colitis, see section 4.4. For severe renal or hepatic impairment, see section 4.3

 

The elderlyOlder people:

As for adults aboveThe normal adult dose can be used unless liver or renal function is severely impaired, (see section 4.3 and 4.4). No studies have been carried out in the elderlyolder people.

 

Paediatric population

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

Method of administration: rectal.

The suppositories are for rectal use and must not be swallowed. If one or more doses have been missed, the next dose is to be taken as usual.

 

4.3       Contraindications

 

Asacolon is contraindicated in cases of:

 

-  History of hypersensitivity to salicylates.

-  Hypersensitivity to mesalazine the active substance or any of the excipients listed in (see section 6.1).

-  Known hypersensitivity to salicylates.

-  Severe renal impairment (GFR less than 30 mL/min/1.73 m²). per minute).

-  Severe liver impairment.

-  Gastric and duodenal ulcers

- Children under 2 years of age.

 

4.4       Special warnings and precautions for use

 

Renal impairment

Asacolon should not be used in patients with impaired renal function.

Urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. Caution should be exercised in patients with raised blood ureaserum creatinine or proteinuria. The possibility of mesalazine-induced nephrotoxicity should be suspected in patients developing impairment of renal function during treatment.

 

It is recommended that all patients have an evaluation of their renal function prior to initiation of Asacolon therapy and periodically while on Asacolonrepeatedly whilst on therapy.  As a guideline, follow-up tests are recommended 14 days after initiation of therapycommencement of treatment and then every 4 weeks for the following 12 weeks. Short monitoring intervals early after the start of Asacolon therapy will discover rare acute allergic impairment of renal functionreactions. In the absence of an acute allergic renal response reaction monitoring intervals can be extended to every 3 months and then annually after 5 years. If additional laboratory or clinical signs of renal impairment appearsymptoms occur, these tests should be performed immediately. Treatment with Asacolon should be stopped immediately if there is evidence of renal impairment and patients should seek immediate medical advice.

 

Blood dyscrasia

Serious blood dyscrasia has very rarely been reported. Asacolon therapy should be stopped immediately if there is a suspicion or evidence of blood dyscrasia (signs of unexplained bleeding, bruising, purpura, anemia, persistent fever or sore throat), and patients should seek immediate medical advice. It is recommended that haematological investigation (differential blood count) are performed prior to initiation of Asacolon and whilst on therapy, at the discretion of the treating physician. As a guideline, follow-up tests are recommended 14 days after initiation of treatment and then two to three tests at intervals of 4 weeks. If the findings are normal, follow-up tests should be carried out every 3 months. If additional symptoms occur, these tests should be performed immediately.

 

Liver Hepatic impairment

There have been reports of increased liver enzyme levels in patients taking preparations containing mesalazine. Caution is recommended if Asacolon is administered to patients with liver impairment. Blood tests (liver function parameters such as ALT or AST) should be determined performed prior to and during treatment, at the discretion of the treating physician. 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 3 months. If additional symptoms occur, these tests should be performed immediately.

 

Cardiac hypersensitivity reactions

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been rarely reported rarely with Asacolon. In case of previous mesalazine-induced cardiac hypersensitivity Asacolon must not be reintroduced. Caution should be used taken in patients with previous myo- and pericarditis of allergic background regardless of its origin.

 

 

Pulmonary disease

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

 

 

Hypersensitivity toAdverse drug reactions to Sulphasalazine

In pPatients with a history of hypersensitivity adverse drug reactions to sulphasalazine, therapy should be initiated onlykept under close medical supervision. Treatment must be stopped immediately if acute symptoms of intolerance occur such as abdominal cramps, acute abdominal pain, fever, severe headache and rash.

 

Hypersensitivity to Soya Oil

Patients with known allergy to peanut or soya oil should not take this medicine.

 

Blood dyscrasia

Very rarely serious blood dyscrasia has been reported with this medicinal product.  Haematological investigations including a complete blood count should be performed prior to initiation and while on therapy at the discretion of the treating physician. As a guideline, follow-up  tests are recommended 14 days after initiation of therapy and then every 4 weeks for the following 12 weeks. If the results are normal, follow-up tests are recommended should be carried out every 3 months. If additional symptoms occur, these tests should be performed immediately.. This procedure is to be followed especially, if a patient develops signs and symptoms suggestive of blood dyscrasia during treatment, such as unexplained bleeding, haematoma, purpura, anaemia, persistent fever or sore throat. Treatment with Asacolon should be stopped immediately if there is a suspicion or evidence of blood dyscrasia and patients should seek immediate medical advice.

Gastric and duodenal ulcers

In case of existing gastric or duodenal ulcers treatment should begin with caution based on theoretical grounds.

 

The elderlyOlder people

Use in the elderlyolder people should be handled with caution and the product should only be prescribed to patients having a normal or non-severely impaired liver and renal function, see section 4.3.

 

Paediatric population

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

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Specific No interaction studies have not been performed.

There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

 

In patients who are concomitantly treated with azathioprine, or 6-mercaptopurine or thioguanine a possible increase in the myelosuppressive effects of Mesalazine can increase the myelosuppressive effects of azathioprine and or 6-mercapto-purine, or thioguanine should be taken into account. As a result, Llife-threatening infection can occur. Patients should be closely observed for signs of infection and myelosuppression. Haematological parameters, such asespecially the leukocyte, thrombocyte and lymphocyte cell counts should be monitored regularly (weekly), especially at initiation of such combination therapy (see section 4.4). If white blood cells are stable after 1 month, testing every 4 weeks for the following 12 weeks followed by 3 monthly monitoring intervals appears to be justified.

 

Concurrent use of known nephrotoxic agents, such as NSAIDs, azathioprine, or methotrexate, may increase the risk of renal reactions. However, no adverse events proving such interactions have been reported (see section 4.4).

 

There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

 

Apart from purine antimetabolites interaction studies in adults and children, no other interaction studies in adults or paediatric patients have been performed.

 

4.6       PFertility, pregnancy and lactation

 

Pregnancy

There are no adequate data on the use of Asacolon in pregnant women. However, data from a limited number (627) of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the foetus/newborn child., but more frequent pre-term births cannot be excluded. To date no other relevant epidemiologic data are available.

 

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.

 

Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/feoetal development, parturition or postnatal development.

 

Mesalazine crosses the placental barrier. Asacolon should only be used during pregnancy if the potential benefit outweighs the possible risk. Caution should be exercised when using high doses of mesalazine.

 

Breast-feeding

N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. The clinical significance of this has not been determined. Only limited experience during lactation in women is available to date. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Asacolon should only be used during breast-feeding, if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, breast-feeding should be discontinued.

 

Fertility

No effects on fertility have been observed.

 

4.7       Effects on ability to drive and use machines

 

No effects on the ability to drive and use machines have been observed.Asacolon has no or negligible influence on the ability to drive and use machines.

4.8       Undesirable effects

 

a)      Summary of the safety profile

The Asacolon clinical trial database includes 246 patients treated with Asacolon 500 mg Suppositories. The mesalazine doses were in the range of 1.0 g/day to 1.5 g/day, the treatment duration varied between four weeks and twelve months.

Undesirable effects relevant for the labelling reported from four double-blind and one open clinical study and information from spontaneous reporting and the literature is listed below. The latter was reported from a population of unknown size. Their frequency is not known.

Organ specific adverse drug reactions affecting the heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue have been reported in association with oral or combined oral and rectal mesalazine administration. Most of these undesirable effects have not been reported following Asacolon 500 mg Suppositories monotherapy, but were observed with oral mesalazine administration. However, it cannot be excluded that these events can also occur with rectal mesalazine use alone.

Treatment must be stopped immediately if acute symptoms of intolerance occur such as abdominal cramps, acute abdominal pain, fever, severe headache and rash.

 

b)      Tabulated summary of adverse reactions

Undesirable effects relevant for the labelling reported from four double-blind clinical studies and one open label clinical trial, from spontaneous reporting, the literature and the EU Mesalazine Core Safety Profile of 07 April 2011 is listed below. The frequency of some reactions cannot be reliably estimated due to the limitation of the reporting sources.

Common:  ≥ 1/100 and < 1/10, uncommon:  ≥ 1/1,000 and < 1/100

Rare: ≥ 1/10,000 to < 1/1000, very rare: < 1/10,000  

 

	Rare (≥ 1/10,000 to < 1/1,000)	Very rare (< 1/10,000)
Blood and lymphatic system disorders	--	altered blood counts (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia).
Immune system disorders	--	hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis.
Nervous system disorders	headache, dizziness.	peripheral neuropathy.
Cardiac disorders	myocarditis, pericarditis.	--
Respiratory, thoracic and mediastinal disorders	--	allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis).
Gastrointestinal disorders	abdominal pain, diarrhoea, flatulence, nausea, vomiting.	acute pancreatitis
Hepato-biliary disorders	--	changes in liver function parameters (increase in transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis.
Skin and subcutaneous tissue disorders	--	alopecia.
Musculoskeletal, connective tissue and bone disorders	--	myalgia, arthralgia.
Renal and urinary disorders	--	impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency.
Reproductive system and breast disorders	--	oligospermia (reversible).

 

Blood and lymphatic system disorders
Very rare:          altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia)., bone marrow depression, eosinophilia, blood disorder.   Immune system disorders Very rare:          hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis.   Nervous system disorders Rare:                  headache, dizziness. Very rare:          peripheral neuropathy.
Cardiac disorders
Rare	myocarditis, pericarditis.
Respiratory, thoracic and mediastinal disorders
Very rare:          allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis)., pneumonia, interstitial pneumonia, eosinophilic pneumonia, lung disorder.
Gastrointestinal disorders
Rare:	abdominal pain, diarrhoea, flatulence, nausea, vomiting.
Very rare: Not known:	acute pancreatitis. exacerbation of the symptoms of colitis.
Hepato-biliary disorders
Very rare:          changes in liver function parameters (increase in transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis., blood bilirubin increased.
Skin and subcutaneous tissue disorders
Very rare:	alopecia.
Musculoskeletal, connective tissue and bone disorders
Very rare: Not known:	myalgia, arthralgia. lupus-like syndrome with pericarditis and pleuropericarditis as prominent symptoms as well as rash and arthralgia.
Renal and urinary disorders
Very rare:          impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency., nephrotic syndrome, renal failure which may reversible on withdrawal.   Reproductive system and breast disorders Very rare:             oligospermia (reversible).
General disorders and administration site conditions
Uncommon:	drug ineffective.

Very rare:          chest pain.

 

Very common: ≥ 1/10, common: ≥ 1/100 and < 1/10,

uncommon: ≥ 1/1,000 and < 1/100, rare: ≥ 1/10,000 and < 1/1,000,

very rare: < 1/10,000, not known (cannot be estimated from the available data)

 

c)      Description of selected adverse reactions

An unknown number of the above undesirable effects are probably associated to the underlying IBD rather than Asacolon/mesalazine medication. This holds true especially for gastrointestinal undesirable effects.

 

Mesalazine-induced nephrotoxicity, which may be reversible on withdrawal, should be suspected in patients developing renal dysfunction during treatment (see section 4.4).

 

To avoid blood dyscrasia resulting from developing bone marrow depression patients should be monitored with care, (see section 4.4).

 

Under Cco-administration of myelosuppressive immunosuppressive drugs such as azathioprine, or 6-MP or thioguanine can precipitate leucopenialife-threatening infection can occur, (see section 4.5).

 

Concurrent use of NSAIDs, azathioprine, or methotrexate, may increase the risk of renal reactions (see section 4.5).

 

d) Paediatric population

There is only limited safety experience with the use of Asacolon Suppositories in the paediatric population. It is expected that the target organs of possible adverse reactions in the paediatric population are the same as for adults (heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue).

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Reporting suspected adverse reactions after authorization 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 Irish Medicines Board, Pharmacovigilance Section, Fax: +353 1 6767836; e-mail: imbpharmacovigilance@imb.ie; www.imb.ie.

 

4.9       Overdose

 

There is littleare rare data on overdose (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive.

 

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agents, ATC code: A07EC02

 

Mechanism of action

Asacolon 500 mg Suppositories contains mesalazine [ATC A07EC02], also known as 5-aminosalicylic acid, which has an anti-inflammatory effect through a mechanism that has not yet been fully clarified. Mesalazine has been shown to inhibit LTB4-stimulated migration of intestinal macrophages and thus may reduce intestinal inflammation by restricting migration of macrophages to inflamed areas. Mesalazine inhibits migration of polymorph nuclear leucocytes and lipoxygenase of cells at concentrations reached in the large intestine during treatment. The production of pro-inflammatory leukotrienes (LTB4 and 5-HETE) in macrophages of the intestinal wall is then inhibited. Under trial conditions mesalazine has also inhibited the cyclooxygenase and thus, the release of thromboxane B2 and prostaglandin E2, but the clinical meaning of this effect is still unclear. Mesalazine inhibits the formation of platelet activating factor (PAF). Recently mMesalazine has been shown to activate PPAR-γ receptors which counteract nuclear activation of intestinal inflammatory responses.

 

Pharmacodynamic effects

Under trial conditions mesalazine inhibited the cyclooxygenase and thus, the release of thromboxane B₂ and prostaglandin E₂, but the clinical meaning of this effect is still unclear. Mesalazine inhibits the formation of platelet activating factor (PAF). Mesalazine is also an antioxidant; it has been shown to decrease formation of reactive oxygen products and to capture free radicals.

 

Epidemiological data indicate that continued long-term mesalazine maintenance treatment may reduce the risk of colon cancer.

 

Clinical efficacy and safety

Clinical studies in patients with mild to moderate proctitis and proctosigmoiditis.

Induction of remission of mild to moderate proctitis and proctosigmoiditis.

Two prospective, double-blind, placebo controlled studies including 156 patients provided evidence of clinical efficacy for Asacolon 500 mg Suppositories for the induction of remission of mild to moderate proctitis and proctosigmoiditis.

In one study, 94 patients with mild to moderate distal proctosigmoiditis (<20 cm) were enrolled. The primary endpoint included clinical, endoscopic and histologic remission rates at one month. Clinical remission was achieved in 22 of 32 (69%) in the 1 g Asacolon group, in 23 of 31 (74%) in the 1.5 g Asacolon group versus 7 of 31 (39%) with placebo.

 

A second study included 62 patients with mild to moderate ulcerative colitis localized at the distal rectosigmoid region. The primary endpoint included clinical, endoscopic and histologic remission rates at one month. The clinical outcome of either remission or improvement was achieved in 28 of 32 (88%) in the 500 mg t.i.d Asacolon group versus 10 of 30 (33%) with placebo.

 

Maintenance of remission of mild to moderate proctitis.

The clinical development of Asacolon 500 mg Suppositories included one comparative bioavailability study, one small scale tolerability and four double-blind clinical studies. The bioavailability study showed an acceptable profile in comparison to another licensed mesalazine suppository. The tolerability and clinical studies provided data supporting the safe and efficacious use. Evidence of clinical efficacy showed a statistically significant improvement in clinical, sigmoidoscopic and histological indices of disease.

Clinical study in patients with quiescent ulcerative proctitis.

A prospective, double-blind, multicentre trial studied the efficacy and tolerability of Asacolon 500 mg Suppositories in 111 patients with quiescent ulcerative proctitis limited to the rectum (≤ 15 cm from anus) for one year. Clinical outcome assessment was based on cumulative relapse rates at 12 months which were: 3 of 32 (10%) in the 1.0 g/day Asacolon group, 11 of 35 (32%) in the 0.5 g/day Asacolon group and 14 of 29 (47%) in the placebo group.

 

 

5.2       Pharmacokinetic properties

 

Absorption

As with the tablets, oOnly a proportion of mesalazine contained in the suppositories is absorbed and available to the systemic circulation. The mode of action of mesalazine is local rather than systemic. Acetylation of mesalazine to N-acetyl mesalazine occurs in the gastrointestinal wall and in the liver. N-acetyl mesalazine is predominantly excreted in the urine. After a single dose of Asacolon 500 mg Suppositories in healthy volunteers the mean Cmax and Tmax were 211 ng/mL and 2.0 hours for mesalazine and 443 ng/mL and 3.0 hours for N-acetyl mesalazine, respectively. Mesalazine and the main metabolite N-acetyl mesalazine were reported to have biological half-lives of 4.97 hours and 8.32 hours, respectively. About 43% of mesalazine and about 78% of N-acetyl mesalazine are bound to plasma proteins.

 

Distribution

Low concentrations of mesalazine and its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined.

 

Biotransformation

Mesalazine is metabolised both by the intestinal mucosa and the liver to the inactive metabolite N-acetyl mesalazine.

 

Elimination

The elimination of mesalazine is essentially faecal and urinary in the form of mesalazine and its N-acetyl metabolite. Mesalazine and the main metabolite N-acetyl mesalazine were reported to have biological half-lives of 4.97 hours and 8.32 hours, respectively, following the use of Asacolon 500 mg Suppositories in healthy volunteers.

 

Linearity/non-linearity

No specific studies have been performed.

 

Pharmacokinetic/pharmacodynamic relationship(s)

No specific studies have been performed.

 

5.3       Preclinical safety data

 

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.Toxicity of mesalazine after oral administration has been investigated in several studies with both single and repeated doses. When a dose of 1g/kg body weight/day was administered repeatedly to rats, it caused damage in kidneys and the gastro-intestinal tract.

 

 

6.         PHARMACEUTICAL PARTICULARS

 

6.1       List of excipients

Hard Fat.

Lecithin, derived from soya oil.

6.4       Special precautions for storage

Do not store above 25 °C. Do not refrigerate or freeze. Store in a dry place protected from direct heat. Store in the original package in order to protect from light.

6.6              Special precautions for disposal and other handling

No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

10.       DATE OF REVISION OF THE TEXT

October 2013September 2014

 

 

OLD	CURRENTLY APPROVED
4.2       Posology and Method of Administration	4.2       Posology and Method of Administration
Children There is no dose recommendation for children (see 4.3 and 4.4).	Paediatric population There is only limited documentation for an effect in children (age 6-18 years).   Children 6 years of age and older ·        Active disease: To be determined individually, starting with 30-50 mg/kg/day in divided doses. Maximum dose: 75 mg/kg/day in divided doses. The total dose should not exceed 4.0 g/day. ·        Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 2.0 g/day.   It is generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult dose to those above 40 kg.
4.4       Special warnings and precautions for use	4.4       Special warnings and precautions for use
Children Safety and effectiveness of Asacolon tablets in children have not been established.	Paediatric population There is only limited documentation for an effect in children (age 6-18 years), see section 4.2.
10.       DATE OF REVISION OF THE TEXT	10.       DATE OF REVISION OF THE TEXT
August 2012	October 2013

 

Section 4.2

 

Adults:

Ulcerative colitis:

Induction of remission:

2.4 g (3 tablets) per day in divided doses. If required the dose may be increased to 4 g (5 tablets) 4.8 g (6 tablets) daily.

The dosage can be adjusted in accordance with the response to the treatment.

 

Maintenance of remission:

1.6  to 2.4 g per day once daily or in divided doses.

 

 

 

Crohn’s disease :

Maintenance of remission:

2.4 g (3 tablets) per day once daily or in divided doses.

 

Section 10

November 2011

August 2012

 

 

 

4.3       Contraindications

 

Asacolon is contraindicated in cases of:

 

-  History of hypersensitivity to salicylates.

-  Hypersensitivity to mesalazine or any of the excipients (see section 6.1).

-  Severe renal impairment (GFR less than 30 mL per minute).

-  Severe liver impairment.

-  Gastric and duodenal ulcers.

-  Children under 2 years of age.

 

4.4       Special warnings and precautions for use

Renal impairment

Urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. Not recommended for use in patients with renal impairment. Caution should be exercised in patients with raised blood urea or proteinuria. The possibility of mesalazine-induced nephrotoxicity should be suspected in patients developing impairment of renal function during treatment.

 

It is recommended that all patients have an evaluation of their renal function prior to initiation of Asacolon therapy and periodically while on Asacolon therapy. As a guideline, follow-up tests are recommended 14 days of initiation of therapy and then every 4 weeks for the following 12 weeks. Short monitoring intervals early after the start of Asacolon therapy will discover rare acute allergic impairment of renal function. In the absence of an acute allergic renal response monitoring intervals can be extended to every 3 months and then annually after 5 years. If additional signs of illness appear, these tests should be performed immediately. Treatment with Asacolon should be stopped immediately if there is evidence of renal impairment and patients should seek immediate medical advice.

 

Liver impairment

There have been reports of increased liver enzyme levels in patients taking preparations containing mesalazine. Caution is recommended if Asacolon is administered to patients with liver impairment. Blood tests (liver function parameters such as ALT or AST) should be determined prior to and during treatment, at the discretion of the treating physician. 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 3 months. If additional symptoms occur, these tests should be performed immediately.

 

 

 

Cardiac hypersensitivity reactions

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely with Asacolon. In case of previous mesalazine-induced cardiac hypersensitivity Asacolon must not be reintroduced. Caution should be used in patients with previous myo- and pericarditis of allergic background regardless of its origin.

 

Pulmonary disease

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

 

Hypersensitivity to Sulphasalazine

In patients with a history of hypersensitivity to sulphasalazine, therapy should be initiated only under close medical supervision. Treatment must be stopped immediately if acute symptoms of intolerance occur such as abdominal cramps, acute abdominal pain, fever, severe headache and rash.

 

Blood dyscrasia

Very rarely serious blood dyscrasia has been reported with this medicinal product.  Treatment with Asacolon should be stopped immediately if there is a suspicion or evidence of blood dyscrasia, such as unexplained bleeding, haematoma, purpura, anaemia, persistent fever or sore throat, and patients should seek immediate medical advice. Haematological investigations including a complete blood count should be performed prior to initiation and while on therapy, at the discretion of the treating physician. As a guideline, follow-up  tests are generally recommended 14 days after initiation of therapy and then every 4 weeks for the following 12 weeks. If the results are normal, follow-up tests should be carried out every 3 months. If additional symptoms occur, these tests should be performed immediately.

 

Tablets in stool

A limited number of reports of intact tablets in stool have been received. What appear to be intact tablets may in some cases represent largely empty shells of the tablet coating. Asacolon 800 mg Gastro-resistant Tablets release their content in the lower gut even if the coating does not dissolve entirely. Once pH 7.0 is reached, cracks in the coating are sufficient for the release of mesalazine from the tablets. This process is irreversible from here on and mesalazine will therefore be released continuously, independent of intestinal pH. If tablets are observed in the stool repeatedly, the patient should consult his/her physician.

 

Intolerance to carbohydrates

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

 

 

The elderly

Use in the elderly should be handled with caution and the product should only be prescribed to patients having a normal renal function.

 

Children

Safety and effectiveness of Asacolon tablets in children have not been established.

 

4.5       Interactions with other medicinal products and other forms of interactions

 

Specific interaction studies have not been performed.

 

Sulphasalazine decreases the absorption of digoxin. There are no data on interaction of digoxin with mesalazine.

 

Mesalazine can increase the myelosuppressive effects of azathioprine, or 6-mercaptopurine, or thioguanine. Life-threatening infection can occur. Patients should be closely observed for signs of infection and myelosuppression. Haematological parameters, such as leukocyte and lymphocyte cell counts should be monitored regularly (weekly), especially at initiation of such combination therapy (see section 4.4). If white blood cells are stable after 1 month, testing every 4 weeks for the following 12 weeks followed by 3 monthly monitoring intervals appears to be justified.

 

The concurrent use of known nephrotoxic agents, such as NSAIDs, azathioprine, or methotrexate, may increase the risk of renal reactions. However, no adverse events proving such interactions have been reported (see section 4.4).

 

There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

 

Apart from purine antimetabolites interaction studies in adults and children, no other interaction studies in adults or paediatric patients have been performed.

 

4.6       Pregnancy and lactation

There are no adequate data on the use of Asacolon in pregnant women. However, data from a limited number (627) of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the fetus/newborn child, but more frequent pre-term births cannot be excluded. To date no other relevant epidemiologic data are available.

 

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.

 

Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development.

Mesalazine crosses the placental barrier. Asacolon should only be used during pregnancy if the potential benefit outweighs the possible risk.

Caution should be exercised when using high doses of mesalazine.

 

N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. The clinical significance of this has not been determined. Only limited experience during lactation in women is available to date. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Asacolon should only be used during breast-feeding, if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, breast-feeding should be discontinued.

 

4.7       Effects on ability to drive and use machines

No effects on the ability to drive and use machines

4.8       Undesirable effects

The Asacolon clinical trial database includes 651 patients treated with Asacolon 400 mg GR Tablets. The mesalazine doses were in the range of 0.8 to 4.8 g/day, the average treatment duration varied between four weeks and four years.

 

Undesirable effects relevant for the labelling reported from nine double-blind and six open clinical studies and information from spontaneous reporting or the literature is listed below. The latter was reported from a population of unknown size. Their frequency is not known.

 

Blood and lymphatic system disorders
Uncommon:	anaemia.

Very rare:        altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia), bone marrow depression, eosinophilia, blood disorder.

 

Immune system disorders

Very rare:        hypersensitivity reactions such as allergic exanthema, drug fever, lupus

erythematosus syndrome, pancolitis.

 

Nervous system disorders
Uncommon:	tinnitus, paresthesia.

Rare:                             headache, dizziness.

Very rare:          peripheral neuropathy.

 

Cardiac disorders
Rare:	myocarditis, pericarditis.

 

Respiratory, thoracic and mediastinal disorders

Very rare:        allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), pneumonia, interstitial pneumonia, eosinophilic pneumonia, lung disorder.

 

Gastrointestinal disorders

Rare:                             abdominal pain, diarrhoea flatulence, nausea,, vomiting, dyspepsia.

Very rare:          acute pancreatitis.

Not known:

exacerbation of the symptoms of colitis.

 

Hepato-biliary disorders

Very rare:        changes in liver function parameters (increase in transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis.

 

Skin and subcutaneous tissue disorders
Common:	Rash.
Uncommon:	pruritus, urticaria.
Very rare:	alopecia.

 

Musculoskeletal and connective tissue disorders
Very rare: Not known:	myalgia, arthralgia. lupus-like syndrome with pericarditis and pleuropericarditis as prominent symptoms as well as rash and arthralgia.

 

Renal and urinary disorders

Very rare:        impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency, nephrotic syndrome, renal failure which may be reversible on withdrawal.

 

Reproductive system and breast disorders

Very rare:        oligospermia (reversible).

 

General disorders and administration site conditions
Uncommon:	drug ineffective.

Very rare:            chest pain.

 

Investigations
Not known:	blood bilirubin increased, liver function test abnormal.

 

Very common:  ≥ 1/10, common:  ≥ 1/100 and < 1/10, uncommon:  ≥  0.1/1,000 and < 1/100,

rare:  ≥  1/10,000 and < 1/1,000, very rare:  < 1/10,000, not known (cannot be estimated from the available data)

 

An unknown number of the above undesirable effects are probably associated to the underlying IBD rather than Asacolon/mesalazine medication. This holds true especially for gastrointestinal undesirable effects and arthralgia.

 

Mesalazine‑induced nephrotoxicity, which may be reversible on withdrawal, should be suspected in patients developing renal dysfunction during treatment (see section 4.4).

 

To avoid blood dyscrasia resulting from developing bone marrow depression patients should be monitored with care (see section 4.4).

 

Co-administration of myelosuppressive drugs such as azathioprine, or 6-MP, or thioguanine can precipitate leucopenia (see section 4.5).

 

Concurrent use of NSAIDs and azathioprine may increase the risk of renal reactions (see section 4.5).

 

4.9       Overdose

There are rare data on overdose (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive.

 

 

10.       DATE OF REVISION OF THE TEXT

November 2011

6. PHARMACEUTICAL PARTICULARS

 

6.1. List of Excipients

 

Lactose, granular

Sodium starch glycollate

Magnesium stearate (E572)

Talc (E553b)

Povidone

 

Film Coating

Methacrylic acid-methyl methacrylate copolymer (1:2)

Talc

Dibutyl phthalate Triethyl citrate
Yellow pigment (ferric oxide) (E172)

Macrogol 6000

Red pigment (ferric oxide) (E172)

 

 

10. DATE OF REVISION OF THE TEXT

 

        October 2009     February 2011

2.         Qualitative and Quantitative Composition

Excipients: contains 152.8 mg of lactose monohydrate.

For full list of excipients see 6.1.

4.2. Posology and Method of Administration

The tablets should be swallowed whole and not chewed with a glass of water one hour before food intake.  They must not be chewed, crushed or broken before swallowing. If one or more doses have been missed, the next dose is to be taken as usual. 

Adults:

Ulcerative colitis:

Induction of remission:

2.4g (3 tablets) per day in divided doses in divided doses per day.  If required the dose may be increased to 4g daily.

The dosage can be adjusted in accordance with the response to the treatment.

Crohn’s disease :

Maintenance of remission:

2.4g (3 tablets) per day in divided doses.

 

Paediatric patients Children: There is no dose recommendation for children (see section 4.3 and 4.4).

Geriatric patients Elderly: As for adults above unless renal function is impaired (see 4.3 and 4.4). No studies have been carried out in the elderly.

4.3. Contraindications

 

Use in patients with a – h History of allergy to salicylates.

Use in patients with a known sensitivity to any excipient.

- Hypersensitivity to mesalazine or to any other ingredient (see section 6.1).

Use in patients with - sSevere renal impairment (GFR less than 30ml per minute).

Use in patients with - sSevere liver impairment.

Use in children under the age of 2 years.

Use in patients with – g Gastric or duodenal ulcers.

Use in patients with haemorrhagic tendency.

-  Children under 2 years of age.

 

 

4.4.  Special Warnings and Special Precautions for Use

Renal impairment

Not recommended for use in patients with renal impairment, and . Ccaution should be exercised in patients with a raised blood urea or proteinuria. The possibility of mMesalazine induced nephrotoxicity should be suspected in patients developing renal failure during treatment.

 

It is recommended that all patients have an evaluation of their renal function prior to initiation of Asacolon therapy and periodically while on Asacolon therapy. While on Asacolon therapy S such a test is generally recommended within 14 days of initiation of therapy with 2-3 repeat evaluations each after a further four weeks and then every 4 weeks for the following 12 weeks. If the results are normal, tests are recommended quarterly. Short monitoring intervals early after the start of Asacolon therapy will discover rare acute allergic impairment of renal function. In the absence of an acute allergic renal response monitoring intervals can be extended to every 6 months and then annually after 5 years. If additional signs of illness appear, further tests are necessary. Asacolon should be stopped immediately if there is evidence of renal impairment and patients should seek immediate medical advice.

 

Liver impairment

There have been reports of increased liver enzyme levels in patients taking preparations containing mesalazine. Caution is recommended if Asacolon is administered to patients with liver impairment.

 

Patients with lung function impairment, especially asthma, should be very closely monitored.

Cardiac hypersensitivity reactions

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely with Asacolon. In case of previous mesalazine-induced cardiac hypersensitivity Asacolon must not be reintroduced. Caution should be used in patients with previous myo- and pericarditis of allergic background regardless of its origin.

 

Hypersensitivity to Sulphasalazine

In patients with a history of sensitivity to sulphasalazine, therapy should be initiated only under close medical supervision. Treatment must be stopped immediately immediately if acute symptoms of intolerance occur such as cramps, abdominal pain, fever, severe headache, or rash.

 

Organic or functional obstruction in the upper gastrointestinal tract will delay onset of action of the product.

 

Blood dyscrasia

Very rarely serious blood dyscrasia has been reported Serious blood dyscrasias have been reported very rarely with this medicinal product. Haematological investigations including a complete blood count should be performed prior to initiation and while on therapy. While on therapy such tests are generally recommended within 14 days of initiation of therapy and then every 4 weeks for the following 12 weeks. If the results are normal, tests are recommended quarterly. In case additional signs of illness appear, further control tests are necessary. This procedure is to be followed especially, if the a patient develops signs and symptoms suggestive of blood dyscrasia during treatment, such as unexplained bleeding, haematoma, purpura, anaemia, persistent fever or sore throat.  Treatment with Asacolon should be stopped immediately immediately if there is a suspicion or evidence of blood dyscrasia and patients should seek immediate medical advice.

 

The product should be used under the direction of a specialist with appropriate facilities for monitoring.

 

Tablets in stool

A limited number of reports of intact tablets in stool have been received. What appear to be intact tablets may in some cases represent largely empty shells of the tablet coating. Asacolon 800 mg Gastro-resistant Tablets release their content in the lower gut even if the coating does not dissolve entirely. Once pH 7.0 is reached, cracks in the coating are sufficient for the release of mesalazine from the tablets. This process is irreversible from here on and mesalazine will therefore be released continuously, independent of intestinal pH. If tablets are observed in the stool repeatedly, the patient should consult his/her physician.

 

Intolerance to carbohydrates

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

 

The elderly

Use in the elderly should be handled with caution and the product should only be prescribed to patients having a normal renal function.

 

Children

Safety and effectiveness of Asacolon tablets in children have not been established.

 

4.5. Interactions with other Medicaments and other forms of Interaction

 

 

Mesalazine Sulphasalazine decreases the absorption of digoxin. There are no data on interaction of digoxin with mesalazine.

 

Mesalazine can increase the immunosuppressive effects of azathioprine and 6-mercaptopurine. Life-threatening infection can occur. Patients should be closely observed for signs of infection and immunosuppression.

Haematological parameters, especially the white cell count such as leukocyte and lymphocyte cell counts should be monitored regularly, especially at initiation of such combination therapy (see section 4.4). If white blood cells are stable after 1 month, testing every 4 weeks for the following 12 weeks followed by 3 monthly monitoring intervals appears to be justified.

 

The uricosuric activity of probenecid and sulfinpyrazone, the diuretic effect of furosemide and the activity of spironolactone may be reduced.

 

Gastrointestinal side effects of glucocorticoids may be increased.

 

Mesalazine may affect the action of antineoplastics by inhibition of thiopurine methyltransferase. Mesalazine may inhibit the action of warfarin; prothrombin time should be closely monitored if this combination is essential.

 

In theory, interaction with antacids may occur due to pH imbalance, but this has not been shown experimentally.

 

The concurrent use of known nephrotoxic agents, such as NSAIDs, azathioprine, or methotrexate, may increase the risk of renal reactions. However, no adverse events proving such interactions have been reported (see section 4.4).

 

 

There have been isolated reports of supposedly altered INR when taken with warfarin.

 

Apart from purine antimetabolites interaction studies in adults and children, no other interaction studies in adults or paediatric patients have been performed.

 

4.6.  Pregnancy and Lactation

 

The use of mesalazine during pregnancy and lactation should be restricted to those cases where in the physician’s opinion potential benefits from this therapy outweigh potential risks.

 

Animal studies have revealed no evidence of teratogenic effects or foetal toxicity due to mesalazine. Limited use of mesalazine in pregnancy has shown no untoward effect on the foetus.

 

Pregnancy

Data from a limited number (627) of pregnant women exposed to mesalazine do not indicate an increased risk of congenital malformations, but more frequent pre-term births cannot be excluded. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, foetal development, parturition or postnatal development (see section 5.3).

Mesalazine crosses the placental barrier. Mesalazine should be used during pregnancy only when clearly indicated. Caution should be exercised when using high doses of mesalazine.

 

Lactation

Low concentrations of mesalazine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. Whilst Tthe clinical significance of this has not been determined,. Ccaution should be exercised mesalazine is administered to a nursing mother when using Mesalazine while breast-feeding and only if the benefit outweighs the risks. Sporadically acute diarrhoea has been reported in breast fed infants.

 

 

4.7. Effects on Ability to Drive and Use Machines

 

No known effect. Asacolon tablets have no influence on the ability to drive and use machines.

 

4.8. Undesirable Effects

 

Adverse reactions occur in a small proportion of patients and are predominantly gastrointestinal. Nausea, vomiting, diarrhoea, abdominal pain, fever, alopecia, vertigo, headache and dose-independent hypersensitivity reactions such as bronchospasm have been reported.

 

Reversible peripheral neuropathy has been associated with mesalazine treatment and paraesthesia has been reported.

 

Asacolon has been associated with the exacerbation of the symptoms of colitis.

Blood dyscrasias have been reported in a few patients:  leucopenia, neutropenia, aplastic anaemia, pancytopenia, thrombocytopenia, anaemia and haemolytic anaemia. Agranulocytosis has been reported.

 

There have been reports of pancreatitis, hepatitis, myocarditis, pericarditis, interstitial nephritis, nephrotic syndrome and renal failure with oral treatment, usually reversible on withdrawal.

 

Drug induced lupus may be a rare complication of mesalazine therapy, with pericarditis and pleuropericarditis prominent symptoms, and also rashes, myalgia and arthralgia. There have been rare reports of allergic lung reactions, eosinophilic pneumonia, and symptomatic sinus bradycardia.

 

A limited number of reports of intact tablets in stools have been received.

 

The Asacolon clinical trial database includes 651 patients treated with Asacolon 400 mg GR Tablets. The mesalazine doses were in the range of 0.8 to 4.8 g/day, the average treatment duration varied between four weeks and four years.

 

Undesirable effects reported from nine double-blind and six open clinical studies for which an association with mesalazine use is suspected and/ or cannot be ruled out, are presented by organ system class. Adverse reactions reported only from worldwide post-marketing experience or the literature are shown in italics. The reporting rate is not known.

 

The only very common undesirable effect is headache, which is occurring in approximately 17.8% of patients. The following common undesirable effects were reported: nausea (8.4%), dyspepsia (7.5%), abdominal pain (4.3%), dizziness (4.0%), rash (2.8%), vomiting (2.5%), arthralgia (2.3%), diarrhoea (1.8%) and drug fever (1.7%).

 

Blood and lymphatic system disorders
Uncommon:	anaemia
Not known:	aplastic anaemia, agranulocytosis, pancytopenia, bone marrow depression, leucopenia, neutropenia, thrombocytopenia, eosinophilia, blood disorder.

 

Nervous system disorders
Very common:	headache
Common:	dizziness
Uncommon:	tinnitus, paresthesia
Not known:	peripheral neuropathy.

 

Cardiac disorders
Not known:	myocarditis, pericarditis.

 

Respiratory, thoracic and mediastinal disorders
Not known:	dyspnoea, pneumonia, interstitial pneumonia, eosinophilic pneumonia, lung disorder, chest pain, cough.

 

Gastrointestinal disorders
Common:	vomiting, nausea, dyspepsia, abdominal pain, diarrhoea
Uncommon:	flatulence
Not known:	exacerbation of the symptoms of colitis, pancreatitis.

 

Hepato-biliary disorders
Not known:	hepatitis.

 

Skin and subcutaneous tissue disorders
Common:	rash
Uncommon:	pruritus, urticaria
Not known:	alopecia.

 

Musculoskeletal and connective tissue disorders
Common:	arthralgia
Uncommon:	myalgia
Not known:	lupus-like syndrome with pericarditis and pleuropericarditis as prominent symptoms as well as rash and arthralgia.

 

Renal and urinary disorders
Not known:	interstitial nephritis, nephrotic syndrome, renal failure which may be reversible on withdrawal.

 

General disorders and administration site conditions
Common:	drug fever
Uncommon:	drug ineffective.

 

Investigations
Not known:	blood bilirubin increased, liver function test abnormal.

 

Very common:  ≥ 1/10, common:  ≥ 1/100 and < 1/10,

uncommon:  ≥  0.1/1,000 and < 1/100, rare:  ≥  1/10,000 and < 1/1,000,

very rare:  < 1/10,000, not known (cannot be estimated from the available data)

 

An unknown number of the above undesirable effects are probably associated to the underlying IBD rather than Asacolon/mesalazine medication. This holds true especially for gastrointestinal undesirable effects and arthralgia.

 

Mesalazine‑induced nephrotoxicity, which may be reversible on withdrawal, should be suspected in patients developing renal dysfunction during treatment (see section 4.4).

 

To avoid blood dyscrasia resulting from developing bone marrow depression patients should be monitored with care (see section 4.4).

 

Co-administration of immunosuppressive drugs such as azathioprine and 6-MP can precipitate leucopenia (see section 4.5).

 

Concurrent use of NSAIDs and azathioprine may increase the risk of renal reactions (see section 4.5).

 

4.9. Overdose

 

In principle, the signs and symptoms would be expected to be similar to those observed in cases of salicylate intoxication: mixed acidosis-alkalosis, hyperventilation, pulmonary edema, dehydration as a result of sweating and vomiting, and hypoglycemia.

 

Treatment: For mixed acidosis-alkalosis: restoration of the acid-base balance in line with the specific situation and replacement of electrolytes.

 

For dehydration due to sweating and vomiting: administration of fluids.

 

For hypoglycemia: glucose administration.

 

Gastric lavage and intravenous transfusion of electrolytes to promote diuresis. 

 

There is no clinical experience with overdose of Asacolon tablets. Mesalazine is not metabolized to salicylate. There is no specific antidote for mesalazine overdose and treatment is symptomatic and supportive. It may include intravenous infusion of appropriate electrolytes.

 

 

5. PHARMACOLOGICAL PROPERTIES

 

5.1. Pharmacodynamic Properties

 

Mesalazine is one of the two components of sulphasalazine, the other being sulphapyridine. It is the latter which is responsible for the majority of side-effects associated with sulphasalazine therapy whilst mesalazine is known to be the active moiety in the treatment of ulcerative colitis.

 

Asacolon 800 mg Gastro-resistant Tablets contain mesalazine [ATC A07EC02], or 5-aminosalicylic acid, which has an anti-inflammatory effect through a mechanism that has not yet been fully clarified. Mesalazine inhibits migration of polymorph nuclear leukocytes and lipooxygenase of cells at concentrations reached in the large intestine during treatment. The production of pro-inflammatory leukotrienes (LTB4 and 5-HETE) in macrophages of the intestinal wall is then inhibited. In trial conditions mesalazine has also inhibited cyclo-oxygenase and thus, the release of thromboxane B2 and prostaglandin E2, but the clinical meaning of this effect is still unclear. Mesalazine inhibits formation of platelet activating factor (PAF). Mesalazine is also an antioxidant; it has been shown to decrease formation of reactive oxygen products and to capture free radicals. Furthermore, mesalazine inhibits secretion of water and chloride and increases the re-absorption of sodium in the intestine in experimental colitis in test animals.

 

 

5.2. Pharmacokinetic Properties

 

Mesalazine is partially absorbed in the colon.  Since plasma concentrations at steady- state are relatively low, it is considered that only a proportion of mesalazine is absorbed and available to the systemic circulation and that the mode of action of mesalazine is local rather than systemic. 

 

Acetylation, which is not subject to genetic control and is not reversible, occurs in the gastrointestinal wall during absorption and also in the liver.  The acetylated metabolite, which has been reported by some, but not all, workers to be active, is predominately excreted in the urine.  Although mesalazine itself is reported to have a short half-life (about 1 hour) and to be slightly bound to plasma proteins (about 40%) the acetylated metabolite is reported to have a much longer half-life (about 5 to 10 hours) and to be more extensively bound (about 80%).

 

Asacolon 800 mg Gastro-resistant Tablets are coated with a polymer [Eudragit™ S] which allows the active principle to be released when the intraluminal pH is above 7, that is within the terminal ileum and colon, which are the main sites of inflammation. Asacolon tablets have been designed to minimise absorption of mesalazine in the digestive tract. Absorption by the oral route is approximately 26 %. Consequently, 74 % of the administered dose remain within the terminal ileum, colon, and rectum, being available to exert a topical anti-inflammatory effect. Mesalazine is metabolised both by the liver and the intestinal mucosa to an inactive derivative, N-acetyl-5-aminosalicylic acid. Mesalazine has an elimination half-life between 9 hours (single dose) and 11 hours (steady state). The elimination of mesalazine is essentially faecal and urinary, in the form of mesalazine and its N-acetyl metabolite.

 

5.3. Preclinical safety data

 

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

Toxicity of mesalazine after oral administration has been investigated in several studies with both single and repeated doses. When a dose of 1g/kg per day was administered repeatedly to rats, it caused damage in kidneys and gastro-intestinal tract.

 

6. PHARMACEUTICAL PARTICULARS

 

6.1. List of Excipients

 

Lactose, granular

Sodium starch glycollate

Magnesium stearate (E572)

Talc (E553b)

Povidone

 

Film Coating

Methacrylic acid-methyl methacrylate copolymer (1:2)

Talc

Dibutyl phthalate

Yellow pigment (ferric oxide) (E172)

Macrogol 6000

Red pigment (ferric oxide) (E172)

6.4. Special Precautions for Storage

 

Do not store above 25°C. Store in a dry place. Store in the original container in order to protect from moisture.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

 

Date of first authorisation: 07 February 2003

 

Date of last renewal: 07 February 2008

 

 

10. DATE OF REVISION OF THE TEXT

 

April 2005  October 2009