TAMSULOSIN HYDROCHLORIDE CONSILIENT HEALTH 400 MICROGRAMSPROLONGED-RELEASE HARD CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Risperidone 4mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 4mg of risperidone.

Excipient with known effect:

Lactose monohydrate – 310.2mg

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet.

Green, capsule-shaped tablets with breakline on one side and plain on the other side. The tablet can be divided into equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Risperidone is indicated for the treatment of schizophrenia.

Risperidone is indicated for the treatment of moderate to severe manic episodes associated with bipolar disorders.

Risperidone is indicated for the short-term treatment (up to six weeks) of persistent aggression in patients with moderate to severe Alzheimer’s de­mentia unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others.

Risperidone is indicated for the short-term symptomatic treatment (up to six weeks) of persistent aggression in conduct disorder in children from the age of five years and adolescents with subaverage intellectual functioning or mental retardation diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other disruptive behaviours require pharmacologic treatment. Pharmacological treatment should be an integral part of a more comprehensive treatment programme, including psychosocial and educational intervention. It is recommended that risperidone be prescribed by a specialist in child neurology and child and adolescent psychiatry or physicians well familiar with the treatment of conduct disorder of children and adolescents.

4.2 Posology and method of administration

Posology

Schizophrenia

Adults

Risperidone Tablets may be given once daily or twice daily.

Patients should start with 2 mg/day risperidone. The dosage may be increased on the second day to 4 mg. Subsequently the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6 mg. In some patients, a slower titration phase and a lower starting and maintenance dose may be appropriate.

Doses above 10 mg/day have not demonstrated superior efficacy to lower doses and may cause increased incidence of extrapyramidal symptoms. Safety of doses above 16 mg/day has not been evaluated, and are therefore not recommended.

Elderly

A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 to 2 mg twice daily.

Paediatric population

Risperidone is not recommended for use in children below age 18 with schizophrenia due to a lack of data on efficacy.

Manic episodes in bipolar disorder

Adults

Risperidone should be administered on a once daily schedule, starting with 2 mg risperidone. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. Risperidone can be administered in flexible doses over a range of 1 to 6 mg per day to optimize each patient’s level of efficacy and tolerability. Daily doses over 6mg risperidone have not been investigated in patients with manic episodes.

As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an ongoing basis.

Elderly

A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 to 2 mg twice daily. Since clinical experience in elderly is limited, caution should be exercised.

Paediatric population

Risperidone is not recommended for use in children below age 18 with bipolar mania due to a lack of data on efficacy.

Persistent aggression in patients with moderate to severe Alzheimer’s de­mentia

A starting dose of 0.25mg twice daily is recommended. This dosage can be individually adjusted by increments of 0.25mg twice daily, not more frequently than every other day, if needed. The optimum dose is 0.5mg twice daily for most patients. Some patients, however, may benefit from doses up to 1mg twice daily.

Risperidone should not be used more than 6 weeks in patients with persistent aggression in Alzheimer’s de­mentia. During treatment, patients must be evaluated frequently and regularly, and the need for continuing treatment reassessed.

Conduct disorder

Children and adolescents from 5 to 18 years of age.

For subjects >50 kg, a starting dose of 0.5mg once daily is recommended. This dosage can be individually adjusted by increments of 0.5mg once daily not more frequently than every other day, if needed. The optimum dose is 1mg once daily for most patients. Some patients, however, may benefit from 0.5mg once daily while others may require 1.5mg once daily. For subjects <50kg, a starting dose of 0.25mg once daily is recommended. This dosage can be individually adjusted by increments of 0.25mg once daily not more frequently than every other day, if needed. The optimum dose is 0.5mg once daily for most patients. Some patients, however, may benefit from 0.25mg once daily while others may require 0.75mg once daily.

As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an ongoing basis.

Risperidone is not recommended in children less than 5 years of age, as there is no experience in children less than 5 years of age with this disorder.

Renal and hepatic impairment

Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than in adults with normal renal function. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone.

Irrespective of the indication, starting and consecutive dosing should be halved, and dose titration should be slower for patients with renal or hepatic impairment.

Risperidone should be used with caution in these groups of patients.

Method of administration

Risperidone is for oral use. Food does not affect the absorption of risperidone.

Upon discontinuation, gradual withdrawal is advised. Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic medicines (see section 4.8). Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported.

Switching from other antipsychotics

When medically appropriate, gradual discontinuation of the previous treatment while risperidone therapy is initiated is recommended. Also, if medically appropriate, when switching patients from depot antipsychotics, initiate risperidone therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medicines should be reevaluated periodically.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

As with other a 1-adrenoceptors antagonists, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin, as a result of which, rarely, syncope can occur. At the first signs of orthostatic hypotension (dizziness, weakness), the patient should sit or lie down until the symptoms have disappeared.

Before therapy with tamsulosin is initiated, the patient should be examined in order to exclude the presence of other conditions, which can cause the same symptoms as benign prostatic hyperplasia. Digital rectal examination and, when necessary, determination of prostate specific antigen (PSA) should be performed before treatment and at regular intervals afterwards.

The treatment patients with severe renal impairment (creatinine clearance of < 10 ml/min) should be approached with caution as these patients have not been studied.

The ‘Intraoperative Floppy Iris Syndrome’ (IFIS, a variant of small pupil syndrome) has been observed during cataract and glaucoma surgery in some patients on or previously treated with tamsulosin. IFIS may increase the risk of eye complications during and after the operation. Discontinuing tamsulosin 1–2 weeks prior to cataract or glaucoma surgery is anecdotally considered helpful, but the benefit of treatment discontinuation has not yet been established. IFIS has also been reported in patients who had discontinued tamsulosin for a longer period prior to cataract surgery.

The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery is scheduled is not recommended.

During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with tamsulosin in order to ensure that appropriate measures will be in place to manage the IFIS during surgery.

Tamsulosin should not be given in combination with strong inhibitors of CYP3A4 in patients with poor metaboliser CYP2D6 phenotype.

Tamsulosin should be used with caution in combination with strong and moderate inhibitors of CYP3A4 (see section 4.5).

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Paediatric population

Interaction studies have only been performed in adults.

No interactions have been seen when tamsulosin hydrochloride was given concomitantly with either atenolol, enalapril, or theophylline.

Concomitant cimetidine brings about a rise in plasma levels of tamsulosin, whereas furosemide a fall, but as levels remain within the normal range posology need not be adjusted.

In vitro, neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitriptyline, diclofenac, glibenclamide, simvastatin and warfarin change the free fraction of tamsulosin in human plasma. Neither does tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide and chlormadinon.

Diclofenac and warfarin, however, may increase the elimination rate of tamsulosin. Concomitant administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 may lead to increased exposure to tamsulosin hydrochloride. Concomitant administration with ketoconazole (a known strong CYP3A4 inhibitor) resulted in an increase in AUC and Cmax of tamsulosin hydrochloride by a factor of 2.8 and 2.2, respectively.

Tamsulosin hydrochloride should not be given in combination with strong inhibitors of CYP3A4 in patients with poor metaboliser CYP2D6 phenotype.

Tamsulosin hydrochloride should be used with caution in combination with strong and moderate inhibitors of CYP3A4.

Concomitant administration of tamsulosin hydrochloride with paroxetine, a strong inhibitor of CYP2D6, resulted in a Cmax and AUC of tamsulosin that had increased by a factor of 1.3 and 1.6, respectively, but these increases are not considered clinically relevant.

Concurrent administration of other al-adrenoreceptor antagonists could lead to hypotensive effects.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of risperidone in pregnant women. Risperidone was not teratogenic in animal studies but other types of reproductive toxicity were seen (see section 5.3). The potential risk for humans is unknown.

Neonates exposed to antipsychotics (including Risperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Risperidone should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.

Breast-feeding

In animal studies, risperidone and 9-hydroxyrisperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxyrisperidone are also excreted in human breast milk in small quantities. There are no data available on adverse reactions in breast-feeding infants. Therefore, the advantage of breast-feeding should be weighed against the potential risks for the child.

Fertility

As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin level. Hyperprolactinaemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

There were no relevant effects observed in the non-clinical studies.

4.7 Effects on ability to drive and use machines

Risperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see section 4.8). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

4.8 Undesirable effects

During cataract and glaucoma surgery a small pupil situation, known as Intraoperative Floppy Iris Syndrome (IFIS), has been associated with therapy of tamsulosin during post-marketing surveillance (See also section 4.4).

Post-marketing experience: In addition to the adverse events listed above, atrial fibrillation, arrhythmia, tachycardia and dyspnoea have been reported in association with tamsulosin use. Because these spontaneously reported events are from the worldwide post marketing experience, the frequency of events and the role of tamsulosin in their causation cannot be reliably determined.

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 the Yellow Card Scheme Website via: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

In general, reported signs and symptoms have been those resulting from an exaggeration of the known pharmacological effects of risperidone. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In overdose, QT-prolongation and convulsions have been reported. Torsades de Pointes has been reported in association with combined overdose of risperidone and paroxetine.

In case of acute overdose, the possibility of multiple drug involvement should be considered.

Treatment

Establish and maintain a clear airway, and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered only when drug intake was less than one hour before. Cardiovascular monitoring should commence immediately and should include continuous electrocardio­graphic monitoring to detect possible arrhythmias.

There is no specific antidote to risperidone. Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, an anticholinergic medicinal product should be administered.

Close medical supervision and monitoring should continue until the patient recovers.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antipsychotics, ATC code: N05AX08

Mechanism of action

Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for both serotonergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors and, with lower affinity, to H1-histaminergic and alpha2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical antipsychotics. Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.

Pharmacodynamic effects

Clinical e fficacy

Schizophrenia

The efficacy of risperidone in the short-term treatment of schizophrenia was established in four studies, 4– to 8-weeks in duration, which enrolled over 2500 patients who met DSM-IV criteria for schizophrenia. In a 6-week, placebo-controlled trial involving titration of risperidone in doses up to 10 mg/day administered twice daily, risperidone was superior to placebo on the Brief Psychiatric Rating Scale (BPRS) total score. In an 8-week, placebo-controlled trial involving four fixed doses of risperidone (2, 6, 10, and 16 mg/day, administered twice daily), all four risperidone groups were superior to placebo on the Positive and Negative Syndrome Scale (PANSS) total score. In an 8-week, dose comparison trial involving five fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day administered twice-daily), the 4, 8, and 16 mg/day risperidone dose groups were superior to the 1 mg risperidone dose group on PANSS total score. In a 4-week, placebo-controlled dose comparison trial involving two fixed doses of risperidone (4 and 8 mg/day administered once daily), both risperidone dose groups were superior to placebo on several PANSS measures, including total PANSS and a response measure (>20% reduction in PANSS total score). In a longer-term trial, adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medicinal product were randomised to risperidone 2 to 8 mg/day or to haloperidol for 1 to 2 years of observation for relapse. Patients receiving risperidone experienced a significantly longer time to relapse over this time period compared to those receiving haloperidol.

Manic episodes in bipolar disorder

The efficacy of risperidone monotherapy in the acute treatment of manic episodes associated with bipolar I disorder was demonstrated in three double-blind, placebo-controlled monotherapy studies in approximately 820 patients who had bipolar I disorder, based on DSM-IV criteria. In the three studies, risperidone 1 to 6 mg/day (starting dose 3 mg in two studies and 2 mg in one study) was shown to be significantly superior to placebo on the prespecified primary endpoint, i.e., the change from baseline in total Young Mania Rating Scale (YMRS) score at Week 3. Secondary efficacy outcomes were generally consistent with the primary outcome. The percentage of patients with a decrease of > 50% in total YMRS score from baseline to the 3-week endpoint was significantly higher for risperidone than for placebo. One of the three studies included a haloperidol arm and a 9-week double-blind maintenance phase. Efficacy was maintained throughout the 9-week maintenance treatment period. Change from baseline in total YMRS showed continued improvement and was comparable between risperidone and haloperidol at Week 12.

The efficacy of risperidone in addition to mood stabilisers in the treatment of acute mania was demonstrated in one of two 3-week double-blind studies in approximately 300 patients who met the DSM-IV criteria for bipolar I disorder. In one 3-week study, risperidone 1 to 6 mg/day starting at 2 mg/day in addition to lithium or valproate was superior to lithium or valproate alone on the pre-specified primary endpoint, i.e., the change from baseline in YMRS total score at Week 3. In a second 3-week study, risperidone 1 to 6 mg/day starting at 2 mg/day, combined with lithium, valproate, or carbamazepine was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this study was induction of risperidone and 9-hydroxy-risperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxy-risperidone. When the carbamazepine group was excluded in a post-hoc analysis, risperidone combined with lithium or valproate was superior to lithium or valproate alone in the reduction of YMRS total score.

Persistent aggression in dementia

The efficacy of risperidone in the treatment of Behavioural and Psychological Symptoms of Dementia (BPSD), which includes behavioural disturbances, such as aggressiveness, agitation, psychosis, activity, and affective disturbances was demonstrated in three doubleblind, placebo-controlled studies in 1150 elderly patients with moderate to severe dementia. One study included fixed risperidone doses of 0.5, 1, and 2 mg/day. Two flexible-dose studies included risperidone dose groups in the range of 0.5 to 4 mg/day and 0.5 to 2 mg/day, respectively. Risperidone showed statistically significant and clinically important effectiveness in treating aggression and less consistently in treating agitation and psychosis in elderly dementia patients (as measured by the Behavioural Pathology in Alzheimer’s Disease Rating Scale [BEHAVE-AD] and the Cohen-Mansfield Agitation Inventory [CMAI]). The treatment effect of risperidone was independent of Mini-Mental State Examination (MMSE) score (and consequently of the severity of dementia); of sedative properties of risperidone; of the presence or absence of psychosis; and of the type of dementia, Alzheimer’s, vascular, or mixed. (See also section 4.4)

Paediatric population

Conduct disorder

The efficacy of risperidone in the short-term treatment of disruptive behaviours was demonstrated in two double-blind placebo-controlled studies in approximately 240 patients 5 to 12 years of age with a DSM-IV diagnosis of disruptive behaviour disorders (DBD) and borderline intellectual functioning or mild or moderate mental retardation/le­arning disorder. In the two studies, risperidone 0.02 to 0.06 mg/kg/day was significantly superior to placebo on the pre-specified primary endpoint, i.e., the change from baseline in the Conduct Problem subscale of the Nisonger-Child Behaviour Rating Form (N-CBRF) at Week 6.

5.2 Pharmacokinetic properties

Risperidone is metabolised to 9-hydroxy-risperidone, which has a similar pharmacological activity to risperidone (see Biotransformation and Elimination).

Absorption

Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) compared with a solution. The absorption is not affected by food and thus risperidone can be given with or without meals. Steady-state of risperidone is reached within 1 day in most patients. Steady-state of 9-hydroxy-risperidone is reached within 4–5 days of dosing.

Distribution

Risperidone is rapidly distributed. The volume of distribution is 1–2 l/kg. In plasma, risperidone is bound to albumin and alpha1-acid glycoprotein. The plasma protein binding of risperidone is 90%, that of 9-hydroxy-risperidone is 77%.

Biotransformation and elimination

Risperidone is metabolised by CYP 2D6 to 9-hydroxy-risperidone, which has a similar pharmacological activity as risperidone. Risperidone plus 9-hydroxy-risperidone form the active antipsychotic fraction. CYP 2D6 is subject to genetic polymorphism. Extensive CYP 2D6 metabolisers convert risperidone rapidly into 9-hydroxy-risperidone, whereas poor CYP 2D6 metabolisers convert it much more slowly. Although extensive metabolisers have lower risperidone and higher 9-hydroxy-risperidone concentrations than poor metabolisers, the pharmacokinetics of risperidone and 9-hydroxy-risperidone combined (i.e., the active antipsychotic fraction), after single and multiple doses, are similar in extensive and poor metabolisers of CYP 2D6.

Another metabolic pathway of risperidone is N-dealkylation. In vitro studies in human liver microsomes showed that risperidone at clinically relevant concentration does not substantially inhibit the metabolism of medicines metabolised by cytochrome P450 isozymes, including CYP 1A2, CYP 2A6, CYP 2C8/9/10, CYP 2D6, CYP 2E1, CYP 3A4, and CYP 3A5. One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxy-risperidone represent 35–45% of the dose. The remainder is inactive metabolites. After oral administration to psychotic patients, risperidone is eliminated with a half-life of about 3 hours. The elimination half-life of 9-hydroxy-risperidone and of the active antipsychotic fraction is 24 hours.

Linearity/non-linearity

Risperidone plasma concentrations are dose-proportional within the therapeutic dose-range.

Elderly, hepatic and renal impairment

A single-dose PK-study with oral risperidone showed on average a 43% higher active antipsychotic fraction plasma concentrations, a 38% longer half-life and a reduced clearance of the active antipsychotic fraction by 30% in the elderly. In adults with moderate renal disease the clearance of the active moiety was ~48% of the clearance in young healthy adults. In adults with severe renal disease the clearance of the active moiety was ~31% of the clearance in young healthy adults. The half-life of the active moiety was 16.7 h in young adults, 24.9 h in adults with moderate renal disease (or ~1.5 times as long as in young adults), and 28.8 h in those with severe renal disease (or ~1.7 times as long as in young adults).Risperidone plasma concentrations were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by 37.1 %.

The oral clearance and the elimination half-life of risperidone and of the active moiety in adults with moderate and severe liver impairment were not significantly different from those parameters in young healthy adults.

Paediatric population

The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active antipsychotic fraction in children are similar to those in adults.

Gender, race and smoking habits

A population pharmacokinetic analysis revealed no apparent effect of gender, race or smoking habits on the pharmacokinetics of risperidone or the active antipsychotic fraction.

5.3 Preclinical safety data

In (sub)chronic toxicity studies, in which dosing was started in sexually immature rats and dogs, dose- dependent effects were present in male and female genital tract and mammary gland. These effects were related to the increased serum prolactin levels, resulting from the dopamine D2-receptor blocking activity of risperidone. In addition, tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Risperidone was not teratogenic in rat and rabbit. In rat reproduction studies with risperidone, adverse effects were seen on mating behaviour of the parents, and on the birth weight and survival of the offspring. In rats, intrauterine exposure to risperidone was associated with cognitive deficits in adulthood. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring. In a toxicity study in juvenile rats, increased pup mortality and a delay in physical development was observed. In a 40-week study with juvenile dogs, sexual maturation was delayed. Based on AUC, long bone growth was not affected in dogs at 3.6-times the maximum human exposure in adolescents (1.5 mg/day); while effects on long bones and sexual maturation were observed at 15 times the maximum human exposure in adolescents. Risperidone was not genotoxic in a battery of tests. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. These tumours can be related to prolonged dopamine D2 antagonism and hyperprolacti­naemia. The relevance of these tumour findings in rodents in terms of human risk is unknown. In vitro and in vivo, animal models show that at high doses risperidone may cause QT interval prolongation, which has been associated with a theoretically increased risk of torsade de pointes in patients.

6.1 List of excipients

Content of capsule

Microcrystalline cellulose

Methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30 per cent

Polysorbate 80

Sodium laurilsulfate

Triethyl citrate

Talc

Capsule body

Gelatine

Indigo carmine(E 132)

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Black iron oxide (E 172)

6.2

Not applicable.

6.3

36 months.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

The tablets are packed in PVC/PVdC blister strips consisting of 200^m polyvinyl chloride/25|jm low density polyethylene/po­lyvinylidene chloride and 20^m aluminium foil.

The strips are packed in a cardboard carton containing 60 tablets.

6.6 Special precautions for disposal

No special requirements.