Asacolon 500 mg Suppositories

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 using Asacolon if you have any medical conditions or illnesses, particularly if you have:
- any lung 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 using 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 .

update the product information on the risk of ‘nephrolithiasis’ in line with the recent recommendation issued by the Pharmacovigilance Risk Assessment Committee (PRAC)

update the product information on the risk of ‘nephrolithiasis’ in line with the recent recommendation issued by the Pharmacovigilance Risk Assessment Committee (PRAC)

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.

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 1204/1/1
PA 2018/1/3

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  

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.

6.1       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

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. 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 after 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 symptoms 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.

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.  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.

The elderly

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

Children

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

4.5       Interaction with other medicinal products and other forms of interaction

Specific interaction studies have not been performed.

Mesalazine can increase the myelosuppressive effects of azathioprine and 6-mercapto-purine, 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.

4.2       Posology and method of administration

new: 

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 elderly: only the word severely has been added

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

Section 4.4 (Special warnings and precautions for use):

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

Section 4.5 (Interaction with other medicinal products and other forms of interaction):

Removed paragraph ‘Mesalazine decreases the absorption of digoxin’.

Added paragraph ‘Concurrent use of known nephrotoxic agents including non steroidal anti-inflammatory drugs and azathioprine may increase the risk of renal impairment’.

Added ‘Haematological parameters, especially the white cell and lymphocyte cell counts should be monitored…’.

Replaced ‘Haematological parameters … should be monitored repeatedly …’ by ‘Haematological parameters … should be monitored regularly …’.

Removed ‘The uricosuric activity of probenecid and the activity of spironolactone may be reduced’.

Removed paragraph ‘Gastrointestinal side effects of glucocorticoids may be increased’.

Removed paragraph ‘Mesalazine may affect the action of antineoplastics by inhibition of thiopurine methyltransferase’.

Removed paragraph ‘Mesalazine may inhibit the action of warfarin; prothrombin time should be closely monitored if this combination is essential’.

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

Section 4.8 (Undesirable effects):

This section has been widely amended according to the EC SPC guideline of October 2005. All undesirable effects are now grouped according to system organ classes and the frequency of occurrence has been added.

Section 4.9 (Overdose):

Removed ‘Gastric lavage’.

Section 5.1 (Pharmacodynamic properties):

Paragraph one: Replacement of  ‘… active component which is delivered directly to the distal colon by  the suppositories’ by ‘… active component which is delivered directly to the rectum and sigmoid colon by the suppositories’.