URAPLEX 20 MG COATED TABLETS PL 25843/0011 … · the proposed product is manufactured to the same...

UKPAR Uraplex 20mg Coated Tablets PL 25843/0011

URAPLEX 20 MG COATED TABLETS

PL 25843/0011

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment 1

Summary of Product Characteristics Page 12

Product Information Leaflet Labelling

1


URAPLEX 20 MG COATED TABLETS PL 25843/0011

LAY SUMMARY On 14th March 2011, the MHRA granted Tenlec Pharma Ltd a Marketing Authorisation (licence) for the medicinal product Trospium Chloride 20mg Coated Tablets (PL 19053/0096). This medicine is only available on prescription from your doctor. Trospium Chloride is a medicine used for the relaxation of the urinary bladder. It is used for the treatment of symptoms associated with involuntary loss of urine (wetting) and/or increased frequency of urination and imperative urge of urination in patients with hyperactive urinary bladder (involuntary urge of urination and voiding problems of unknown origin or due to nervous system disorder). No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Trospium Chloride 20mg Coated Tablets outweigh the risks; hence a Marketing Authorisation has been granted. A subsequent Change of Ownership (CoA) was granted for this product on 20 July 2011, to change the Marketing Authorisation Holder to Madaus GmbH, Colonia-Allee, 15, Cologne, D-51067, Germany (PL 25843/0011).

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PL 25843/0011

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment (including statistical assessment)

Page 9

Overall conclusions and risk benefit assessment Page 10

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INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA granted a Marketing Authorisation for the medicinal product Trospium Chloride 20mg Coated Tablets (PL 19053/0096) to Tenlec Pharma Ltd on the 14th March 2011. This is a Prescription only medicine used in the treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder (e.g. idiopathic or neurologic detrusor overactivity). This application was submitted as a simple abridged application according to Article 10c of Directive 2001/83/EC, cross-referring to Regurin 20 mg Tablets (PL 25843/0002) held by Madaus GmbH, which was granted a Marketing Authorisation on 14th September 2000. No new data were submitted nor were they necessary for this simple application, as the data are identical to that of the previously granted cross-reference product. As the cross-reference product was granted prior to the introduction of current legislation, no Public Assessment Report (PAR) has been generated. A detailed pharmacovigilance system has been provided with this application and is satisfactory. No environmental risk assessment has been undertaken, as this is not considered necessary. This is justified as it is not anticipated that the grant of this new marketing authorisation will result in an increase in the environmental exposure of the drug. The applicant’s justification for absence of ERA is satisfactory.

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PHARMACEUTICAL ASSESSMENT

PROPRIETARY NAME: Trospium Chloride 20mg Coated Tablets COMPANY NAME: Tenlec Pharma Limited E.C. ARTICLE: Article 10c of Directive 2001/83/EC LEGAL STATUS: POM 1 INTRODUCTION This is a simple, informed consent application for Trospium Chloride 20mg Coated Tablets, submitted under Article 10c of Directive 2001/83/EC. The application cross-refers to Regurin 20 mg Tablets (PL 25843/0002), approved on 14th September 2000 to the Marketing Authorisation holder Madaus GmbH. The current application is considered valid. 2 MARKETING AUTHORISATION APPLICATION (MAA) 2.1 Name(s) The proposed name of the product is Trospium Chloride 20mg Coated Tablets. The product has been named in line with current requirements. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes The product contains the active ingredient trospium chloride. The product is packed in PVC foiled aluminium blister with pack sizes of 2, 20, 28, 30, 40, 50, 56, 60, 90, 100, 120, 150, 200, 500, 600, 1000, 1200 and 2000 tablets. Specifications and Certificates of Analysis for all packaging components used have been provided and are satisfactory. The packaging and pack sizes are the same as those for the reference product. The proposed shelf life is 5 years with no special storage condition. The shelf-life and storage conditions are identical to those for the reference product and are satisfactory. 2.3 Legal status The product is a Prescription only medicine (POM). 2.4 Marketing authorisation holder/Contact Persons/Company The proposed Marketing Authorisation holder is Tenlec Pharma Ltd, Hailsham, East Sussex, UK The Qualified Person (QP) responsible for pharmacovigilance is stated and a Curriculum Vitae (CV) is included. 2.5 Manufacturers The proposed manufacturing sites are the same as those registered for the reference product and evidence of Good Manufacturing Practice compliance has been provided. 2.6 Qualitative and quantitative composition The proposed composition is consistent with the details registered for the reference product.

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2.7 Manufacturing process The proposed manufacturing process is consistent with the details registered for the reference product and the maximum batch size is stated. 2.8 Finished product/shelf-life specifications The proposed finished product and shelf-life specifications are in line with the details registered for the reference product. 2.9 Drug substance specification The proposed drug substance specification conforms to the current European Pharmacopoeia monograph for trospium chloride, and is in-line with that for the reference product. European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability for the manufacturer of trospium chloride has been provided. The active substance manufacturer is in line with that for the reference product. 2.10 TSE Compliance No materials of human or animal origin have been used in the manufacture of this product. This is consistent with the reference product. 2.11 Bioequivalence No bioequivalence data are required to support this informed consent application, as the proposed product is manufactured to the same formula utilising the same process as the reference product Regurin 20 mg Tablets (PL 25843/0002). 3 EXPERT REPORT The applicant has included detailed expert reports of the application. Signed declarations and copies of the experts’ CVs are enclosed for the quality, non-clinical and clinical experts. All are considered to have sufficient experience for their responsibilities. 4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product name. The appearance of the product is identical to that of the reference product. 5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The proposed SmPC is consistent with the details registered for the reference product. 6. PATIENT INFORMATION LEAFLET (PIL)/LABELLING The patient information leaflet has been prepared in line with the details registered for the reference product. The Marketing Authorisation Holder has committed to submit a PIL user testing and label mock-ups prior to marketing this product. This is acceptable.

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7. CONCLUSIONS The data submitted with the application is acceptable. The grant of a Marketing Authorisation is recommended.

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PRECLINICAL ASSESSMENT

No new preclinical data have been supplied with this application and none are required for an application of this type.

8


CLINICAL ASSESSMENT

No new clinical data have been supplied with this application and none are required for an application of this type.

9


OVERALL CONCLUSION AND BENEFIT RISK ASSESSMENT QUALITY The data for this application are consistent with those previously assessed for the reference product and, as such, have been judged to be satisfactory. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY This application is identical to the previously granted application for Regurin 20mg Tablets (PL 25843/0002), granted to Madaus GmbH on the 14th September 2000 Pharmaceutical, preclinical and clinical expert statements have been provided, together with CVs showing the experts are appropriately qualified. The experts confirm that the product is identical in composition, manufacture and pharmaceutical characteristics to the respective reference product and that there are no toxicological or clinical issues. No new or unexpected safety concerns arise from this application. The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The applicant’s product is identical to the reference product. Extensive clinical experience with trospium chloride is considered to have demonstrated the therapeutic values of the compounds. The risk benefit is, therefore, considered to be positive.

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PL 25843/0011

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the marketing authorisation application on 16th September

2010

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 4th October 2010

3 Following assessment of the application the MHRA requested further information on 6th January 2010 and 1st February 2011

4 The applicant responded to the MHRA’s request, providing further information on 26th January 2011 and 11th February 2011

5 The application was determined on 14th March 2011

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SUMMARY OF PRODUCT CHARACTERISTICS SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Trospium Chloride 20mg Coated Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient is trospium chloride. Each coated tablet contains 20 mg trospium chloride.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Coated tablet.

Brownish-yellow, glossy coated, biconvex tablets.

4 CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder (e.g. idiopathic or neurologic detrusor overactivity).

4.2 POSOLOGY AND METHOD OF ADMINISTRATION

For oral administration. One coated tablet twice daily (equivalent to 40 mg of trospium chloride per day). In patients with severe renal impairment (creatinine clearance between 10 and 30 mL/min/1.73 m2) the recommended dosage is one coated tablet per day or every second day (equivalent to 20 mg of trospium chloride per day or every second day). The coated tablet should be swallowed whole with a glass of water before meals on an empty stomach. The need for continued treatment should be reassessed at regular intervals of 3-6 months. Since no data are available, the use in children under 12 years of age is contraindicated.

4.3 CONTRAINDICATIONS Trospium chloride is contraindicated in patients with urinary retention, severe gastro-intestinal condition (including toxic megacolon), myasthenia gravis, narrow-angle glaucoma, and tachyarrhythmia.

Trospium chloride is also contraindicated in patients who have demonstrated hypersensitivity to the active substance or to any of the excipients.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Trospium chloride should be used with caution by patients: - with obstructive conditions of the gastrointestinal tract such as pyloric stenosi

- with obstruction of urinary flow with the risk of formation of urinary retention with autonomic neuropathy

- with hiatus hernia associated with reflux oesophagitis

- in whom fast heart rates are undesirable e.g. those with hyperthyroidism, coronary artery disease and congestive heart failure.

As there are no data in patients with severe hepatic impairment, treatment of these patients with trospium chloride is not recommended. In patients with mild to moderate liver impairment caution should be exercised. Trospium chloride is mainly eliminated by renal excretion. Marked elevations in the plasma levels have been observed in patients with severe renal impairment. Therefore in this

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population and also in patients with mild to moderate renal impairment caution should be exercised (see section 4.2). Before commencing therapy organic causes of urinary frequency, urgency, and urge incontinence, such as heart diseases, diseases of the kidneys, polydipsia, or infections, or tumours of urinary organs should be excluded. Trospium chloride 20mg Coated Tablets contain lactose-monohydrate, sucrose and wheat starch. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Patients with rare hereditary problems of fructose intolerance or sucrase-isomaltase insufficiency should not take this medicine. Patients with wheat allergy (different from coeliac disease) should not take this medicine. Apart from that, trospium chloride is suitable for people with coeliac disease.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION Pharmacodynamic interactions: The following potential pharmacodynamic interactions may occur: potentiation of the effect of drugs with anticholinergic action (such as amantadine, tricyclic antidepressants), enhancement of the tachycardic action of ß-sympathomimetics, decrease in efficacy of pro-kinetic agents (e.g. metoclopramide). Since trospium chloride may influence gastro-intestinal motility and secretion, the possibility cannot be excluded that the absorption of other concurrently administered drugs may be altered. Pharmacokinetic interactions: An inhibition of the absorption of trospium chloride with drugs like guar, colestyramine and colestipol cannot be excluded. Therefore the simultaneous administration of these drugs with trospium chloride is not recommended. Metabolic interactions of trospium chloride have been investigated in vitro on cytochrome P450 enzymes involved in drug metabolism (P450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). No influence on their metabolic activities was observed. Since trospium chloride is metabolised only to a low extent and since ester hydrolysis is the only relevant metabolic pathway, no metabolic interactions are expected.

4.6 PREGNANCY AND LACTATION

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). In rats, placental transfer and passage into the maternal milk of trospium chloride occurs. There are no clinical data on exposed pregnancies available. Caution should be exercised when prescribing to pregnant or breastfeeding women.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Principally, disorders of accommodation can lower the ability to drive and to use machines. However, examinations of parameters characterising the ability to drive (visual orientation, general ability to react, reaction under stress, concentration and motor coordination) have not revealed any effects of trospium chloride.

4.8 UNDESIRABLE EFFECTS

Undesirable effects observed with trospium chloride such as dry mouth, dyspepsia and constipation mainly reflect the typical anticholinergic properties of the active ingredient. In clinical studies, dry mouth was very common and occurred in approximately 18% of patients treated with trospium chloride and in approximately 6% treated with placebo (total of 1931 patients of which 911 received placebo). The following table lists possibly related drug reactions reported for patients treated with trospium chloride:

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Very common (>1/10)

Common (≥1/100,<1/10)

Uncommon (≥1/1000, <1/100)

Rare (≥1/10.000, <1/1000)

Very Rare (<1/10.000)

Not known (cannot be estimated from the available data)

Cardiac disorders

Tachycardia Tachyarrhythmia

Nervous system disorders

Headache

Dizziness

Eye disorders Vision disorders

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Dry mouth Dyspepsia Constipation Abdominal pain Nausea

Flatulence Diarrhoea

Renal and urinary disorders

Micturition disorders Urinary retention

Skin and subcutaneous disorders

Rash Angio-oedema Pruritus Urticaria Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)

Muscoskeletal and connective tissue disorders

Myalgia Arthralgia

General disorders and administration site conditions

Chest pain Asthenia

Immune system disorders

Anaphylaxis

Investigations Mild to moderate increase in serum transaminase levels

4.9 OVERDOSE

After the administration of a maximum single dose of 360 mg trospium chloride to healthy volunteers, dryness of the mouth, tachycardia and disorders of micturition were observed to an increased extent. No manifestations of severe overdosage or intoxication in humans have been reported to date. Increased anticholinergic symptoms are to be expected as signs of intoxication. In the case of intoxication the following measures should be taken: - gastric lavage and reduction of absorption (e.g. activated charcoal) - local administration of pilocarpine to glaucoma patients - catheterisation in patients with urinary retention - treatment with a parasympathomimetic agent (e.g. neostigmine) in the case of severe

symptoms

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- administration of beta blockers in the case of insufficient response, pronounced tachycardia and/or circulatory instability (e.g. initially 1 mg propranolol intravenously along with monitoring of ECG and blood pressure).

5 PHARMACOLOGICAL PROPERTIES 5.1 PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Urinary Antispasmodic, ATC code G04BD09 Trospium chloride is a quaternary derivative of nortropane and therefore belongs to the class of parasympatholytic or anticholinergic drugs, as it competes concentration-dependently with acetylcholine, the body's endogenous transmitter at postsynaptic, parasympathic binding sites. Trospium chloride binds with high affinity to muscarinic receptors of the so called M1-, M2- and M3- subtypes and demonstrates negligible affinity to nicotinic receptors. Consequently, the anticholinercic effect of trospium chloride exerts a relaxing action on smooth muscle tissue and organ functions mediated by muscarinic receptors. Both in preclinical as well as in clinical experiments, trospium chloride diminishes the contractile tone of smooth muscle in the gastrointestinal and genito-urinary tract. Furthermore, it can inhibit the secretion of bronchial mucus, saliva, sweat and the occular accommodation. No effects on the central nervous system have so far been observed. In two specific safety studies in healthy volunteers trospium chloride has been proven not to affect cardiac repolarisation, but has been shown to have a consistent and dose dependant heart rate accelerating effect. A long term clinical trial with trospium chloride 20 mg bid found an increase of QT> 60 ms in 1.5% (3/197) of included patients. The clinical relevance of these findings has not been established. Routine safety monitoring in two other placebo-controlled clinical trials of three months duration does not support such an influence of trospium chloride: In the first study an increase of QTcF >= 60 msec was seen in 4/258 (1.6%) in trospium-treated patients vs. 9/256 (3.5%) in placebo-treated patients. Corresponding figures in the second trial were 8/326 (2.5%) in trospium-treated patients vs. 8/325 (2.5%) in placebo-treated patients.

5.2 PHARMACOKINETIC PROPERTIES

After oral administration of trospium chloride maximum plasma levels are reached at 4-6 hours. Following a single dose of 20 mg the maximum plasma level is about 4 ng/mL. Within the tested interval, 20 to 60 mg as a single dose, the plasma levels are proportional to the administered dose. The absolute bioavailability of a single oral dose of 20 mg of trospium chloride is 9.6 ± 4.5% (mean value ± standard deviation). At steady state the intraindividual variability is 16%, the interindividual variability is 36%. Simultaneous intake of food, especially high fat diets, reduces the bioavailability of trospium chloride. After a high-fat meal mean Cmax and AUC are reduced to 15-20% of the values in the fasted state. Trospium chloride exhibits diurnal variability in exposure with a decrease of both Cmax and AUC for evening relative to morning doses. Most of the systemically available trospium chloride is excreted unchanged by the kidneys, though a small portion (10% of the renal excretion) appears in the urine as the spiroalcohol, a metabolite formed by ester hydrolysis. The terminal elimination half-life is in the range of 10-20 hours. No accumulation occurs. The plasma protein binding is 50-80%. Pharmacokinetic data in elderly patients suggests no major differences. There are also no gender differences. In a study in patients with severe renal impairment (creatinine clearance 8-32 mL/min) mean AUC was 4-fold higher, Cmax was 2-fold higher and the mean half-life was prolonged 2-fold compared with healthy subjects. Pharmacokinetic results of a study with mild and moderate hepatically impaired patients do not suggest a need for dose adjustment in patients with hepatic impairment, and are consistent with the limited role of hepatic metabolism in the elimination of trospium chloride.

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5.3 PRECLINICAL SAFETY DATA Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and toxicity to reproduction. Placental transfer and passage of trospium chloride into the maternal milk occurs in rats.

6 PHARMACEUTICAL PARTICULARS 6.1 LIST OF EXCIPIENTS

Tablet core: Wheat starch Microcrystalline cellulose Lactose monohydrate Povidone Croscarmellose sodium Stearic acid Silica colloidal anhydrous

Talc Tablet coat: Sucrose Carmellose sodium Talc Silica colloidal anhydrous Calcium carbonate E 170 Macrogol 8000 Titanium dioxide E 171 Iron oxide hydrate yellow E 172 Beeswax white Carnauba wax Note for diabetics: one coated tablet corresponds to 0.06 g carbohydrate (equivalent to 0.005 bread units

6.2 INCOMPATIBILITIES

Not applicable 6.3 SHELF LIFE

5 Years 6.4 SPECIAL PRECAUTIONS FOR STORAGE

This medicinal product does not require any special storage conditions. 6.5 NATURE AND CONTENTS OF CONTAINER

PVC foiled aluminium blister Pack sizes approved: 2, 20, 28, 30, 40, 50, 56, 60, 90, 100, 120, 150, 200, 500, 600, 1000, 1200, 2000 Not all pack sizes may be marketed.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL

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

7 MARKETING AUTHORISATION HOLDER

Madaus GmbH Colonia-Allee, 15 Cologne, D-51067 Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 25843/0011

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9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 14/03/2011

10 DATE OF REVISION OF THE TEXT

20/07/2011

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UKPAR Uraplex 20mg Coated Tablets PL 25843/0011-006

The below text was approved for this product at the end of the Change of Ownership (CoA) procedure. The Marketing Authorisation Holder is required to submit the mock-up of the leaflet to the regulatory authorities before marketing any pack size.

PATIENT INFORMATION LEAFLET

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19


20


21


22


LABELLING The below text was approved for this product at the end of the Change of Ownership (CoA) procedure. The Marketing Authorisation Holder is required to submit the mock-up labelling to the regulatory authorities before marketing any pack size.

Labelling for PL 25843/0011

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Annex 1

Reference: PL 25843/0011-0006 Product: Uraplex 20mg Coated Tablets Marketing Authorisation Holder: Madaus GmbH Active Ingredient(s): Trospium chloride Reason: To update, section 2 (Qualitative and quantitative composition), 4.2 (Posology and method of administration), 4.4 (Special warnings and precautions for use), 4.5 (Interaction with other medicinal products and other forms of interaction), 4.7 (Effects on ability to drive and use machines), 4.8 (Undesirable effects), 5.1 (Pharmacodynamic properties), 5.2 (Pharmacokinetic properties), 6.1 (List of excipients), 6.3 (Shelf life) and 6.6 (Special precautions for disposal and other handling) of the Summary of Product Characteristics (SmPC) to bring it in line with the reference product (Regurin 20 mg tablets). As a consequence, the Patient Information Leaflet (PIL) and the labelling have been updated. Supporting Evidence Revised SmPC, PIL and labelling have been provided. Evaluation The final SmPC fragments, PIL and the labelling are acceptable. The final granted SmPC fragments, PIL and the labelling are presented below: 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient is trospium chloride. Each coated tablet contains 20 mg trospium chloride.

Excipients: includes 7 mg lactose monohydrate, 39 mg sucrose and 19 mg wheat starch per coated tablet.

For a full list of excipients, see section 6.1. Brownish-yellow, glossy coated biconvex tablets.

4 CLINICAL PARTICULARS 4.2 POSOLOGY AND METHOD OF ADMINISTRATION

For oral administration. One coated tablet twice daily (equivalent to 40 mg of trospium chloride per day). In patients with severe renal impairment (creatinine clearance between 10 and 30 mL/min/1.73 m2) the recommended dosage is: One coated tablet per day or every second day (equivalent to 20 mg of trospium chloride per day or every second day). The coated tablet should be swallowed whole with a glass of water before meals on an empty stomach. The need for continued treatment should be reassessed at regular intervals of 3-6 months. Since no data are available, the use in children under 12 years of age is contraindicated.

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4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Trospium chloride should be used with caution by patients: with obstructive conditions of the gastrointestinal tract such as pyloric stenosis with obstruction of the urinary flow with the risk of formation of urinary retention with autonomic neuropathy with hiatus hernia associated with reflux oesophagitis in whom fast heart rates are undesirable e.g. those with hyperthyroidism, coronary artery disease and congestive heart failure. As there are no data in patients with severe hepatic impairment, treatment of these patients with trospium chloride is not recommended. In patients with mild to moderate liver impairment caution should be exercised. Trospium chloride is mainly eliminated by renal excretion. Marked elevations in the plasma levels have been observed in patients with severe renal impairment. Therefore in this population and also in patients with mild to moderate renal impairment caution should be exercised (see section 4.2). Before commencing therapy organic causes of urinary frequency, urgency, and urge incontinence, such as heart diseases, diseases of the kidneys, polydipsia, or infections, or tumours of urinary organs should be excluded. Uraplex 20mg contain lactose-monohydrate, sucrose and wheat starch. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Patients with rare hereditary problems of fructose intolerance or sucrase-isomaltase insufficiency should not take this medicine. Patients with wheat allergy (different from coeliac disease) should not take this medicine. Apart from that, trospium chloride is suitable for people with coeliac disease.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION Pharmacodynamic interactions: The following potential pharmacodynamic interactions may occur: Potentiation of the effect of drugs with anticholinergic action (such as amantadine, tricyclic antidepressants), enhancement of the tachycardic action of ß-sympathomimetics, decrease in efficacy of pro-kinetic agents (e.g. metoclopramide). Since trospium chloride may influence gastro-intestinal motility and secretion, the possibility cannot be excluded that the absorption of other concurrently administered drugs may be altered. Pharmacokinetic interactions: An inhibition of the absorption of trospium chloride with drugs like guar, colestyramine and colestipol cannot be excluded. Therefore the simultaneous administration of these drugs with trospium chloride is not recommended. Metabolic interactions of trospium chloride have been investigated in vitro on cytochrome P450 enzymes involved in drug metabolism (P450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). No influence on their metabolic activities was observed. Since trospium chloride is metabolised only to a low extent and since ester hydrolysis is the only relevant metabolic pathway, no metabolic interactions are expected. Though trospium chloride was shown not to affect pharmacokinetics of digoxin, an interaction with other active substances eliminated by active tubular secretion cannot be excluded.

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4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Principally, disorders of accommodation can lower the ability to actively participate in road traffic and to use machines. However, examinations of parameters characterising the ability to participate in road traffic (visual orientation, general ability to react, reaction under stress, concentration and motor coordination) have not revealed any effects of trospium chloride.

4.8 UNDESIRABLE EFFECTS

Undesirable effects observed with trospium chloride such as dry mouth, dyspepsia and constipation mainly reflect the typical anticholinergic properties of the active ingredient. In Phase-III clinical studies, dry mouth was very common and occurred in approximately 18% of patients treated with trospium chloride and in approximately 6% treated with placebo (total of 1931 patients of which 911 received placebo). The following table lists possibly related drug reactions reported for patients treated with Uraplex 20 mg:

Very

common (>1/10)

Common (≥1/100,<1/10)

Uncommon (≥1/1000, <1/100)

Rare (≥1/10.000, <1/1000)

Very Rare (<1/10.000)


Cardiac disorders

Tachycardia Tachyarrhythmia

Nervous system disorders

Headache

Dizziness Hallucination* confusion* agitation*

Eye disorders Vision disorders

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Dry mouth Dyspepsia Constipation Abdominal pain Nausea

Flatulence Diarrhoea

Renal and urinary disorders

Micturition disorders Urinary retention

Skin and subcutaneous disorders

Rash Angio-oedema

Pruritus Urticaria Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN)

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Very common (>1/10)

Common (≥1/100,<1/10)

Uncommon (≥1/1000, <1/100)

Rare (≥1/10.000, <1/1000)

Very Rare (<1/10.000)


Muscoskeletal and connective tissue disorders

Myalgia Arthralgia

General disorders and administration site conditions

Chest pain Asthenia

Immune system disorders

Anaphylaxis

Investigations Mild to moderate increase in serum transaminase levels

*These adverse effects occurred mostly in elderly patients and can be facilitated by neurological diseases and/or concomitant intake of other anticholinergic drugs (see section 4.5).

5 PHARMACOLOGICAL PROPERTIES 5.1 PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Urinary Antispasmodic, ATC code G04BD09 Trospium chloride is a quaternary derivative of nortropane and therefore belongs to the class of parasympatholytic or anticholinergic drugs, as it competes concentration-dependently with acetylcholine, the body's endogenous transmitter at postsynaptic, parasympathic binding sites. Trospium chloride binds with high affinity to muscarinic receptors of the so called M1-, M2- and M3- subtypes and demonstrates negligible affinity to nicotinic receptors. Consequently, the anticholinergic effect of trospium chloride exerts a relaxing action on smooth muscle tissue and organ functions mediated by muscarinic receptors. Both in preclinical as well as in clinical experiments, trospium chloride diminishes the contractile tone of smooth muscle in the gastrointestinal and genito-urinary tract. Furthermore, it can inhibit the secretion of bronchial mucus, saliva, sweat and the occular accommodation. No effects on the central nervous system have so far been observed. In two specific safety studies in healthy volunteers trospium chloride has been proven not to affect cardiac repolarisation, but has been shown to have a consistent and dose dependant heart rate accelerating effect. A long term clinical trial with trospium chloride 20 mg bid found an increase of QT> 60 ms in 1.5% (3/197) of included patients. The clinical relevance of these findings has not been established. Routine safety monitoring in two other placebo-controlled clinical trials of three months duration does not support such an influence of trospium chloride: In the first

28


study an increase of QTcF >= 60 msec was seen in 4/258 (1.6%) in trospium-treated patients vs. 9/256 (3.5%) in placebo-treated patients. Corresponding figures in the second trial were 8/326 (2.5%) in trospium-treated patients vs. 8/325 (2.5%) in placebo-treated patients.

5.2 PHARMACOKINETIC PROPERTIES

After oral administration of trospium chloride maximum plasma levels are reached at 4-6 hours. Following a single dose of 20 mg the maximum plasma level is about 4 ng/mL. Within the tested interval, 20 to 60 mg as a single dose, the plasma levels are proportional to the administered dose. The absolute bioavailability of a single oral dose of 20 mg of trospium chloride (1 coated tablet Uraplex 20 mg) is 9.6 ± 4.5% (mean value ± standard deviation). At steady state the intraindividual variability is 16%, the interindividual variability is 36%. Simultaneous intake of food, especially high fat diets, reduces the bioavailability of trospium chloride. After a high-fat meal mean Cmax and AUC are reduced to 15-20% of the values in the fasted state. Trospium chloride exhibits diurnal variability in exposure with a decrease of both Cmax and AUC for evening relative to morning doses. Most of the systemically available trospium chloride is excreted unchanged by the kidneys, though a small portion (10% of the renal excretion) appears in the urine as the spiroalcohol, a metabolite formed by ester hydrolysis. The terminal elimination half-life is in the range of 10-20 hours. No accumulation occurs. The plasma protein binding is 50-80%. Pharmacokinetic data in elderly patients suggests no major differences. There are also no gender differences. In a study in patients with severe renal impairment (creatinine clearance 8-32 mL/min) mean AUC was 4-fold higher, Cmax was 2-fold higher and the mean half-life was prolonged 2-fold compared with healthy subjects. Pharmacokinetic results of a study with mildly and moderately hepatically impaired patients do not suggest a need for dose adjustment in patients with hepatic impairment, and are consistent with the limited role of hepatic metabolism in the elimination of trospium chloride. The Blood Brain Barrier permeability of trospium chloride is virtually absent due to its chemical properties (low lipophilicity as a quaternary amine).

6 PHARMACEUTICAL PARTICULARS 6.1 LIST OF EXCIPIENTS

Tablet core: Wheat starch Microcrystalline cellulose Lactose monohydrate Povidone (K 29-32) Croscarmellose sodium Stearic acid Silica colloidal anhydrous

Talc Tablet coat: Sucrose Carmellose sodium Talc Silica colloidal anhydrous Calcium carbonate E 170 Macrogol 8000

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Titanium dioxide E 171 Iron oxide hydrate yellow E 172 Beeswax white Carnauba wax Note for diabetics: 1 coated tablet corresponds to 0.06 g carbohydrate (equivalent to 0.005 bread units

6.3 SHELF LIFE

5 years 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.

7 MARKETING AUTHORISATION HOLDER

Madaus GmbH 51101 Cologne, Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 25843/0011 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 14/03/2011

10 DATE OF REVISION OF THE TEXT

18/01/2012

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The Marketing Authorisation Holder has submitted the below text version of the PIL and has committed to submitting the mock-ups to the MHRA before marketing any pack size.

PACKAGE LEAFLET: INFORMATION FOR THE USER

Uraplex 20mg Coated Tablets

Trospium chloride

Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may

harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed

in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Uraplex is and what it is used for 2. Before you take Uraplex 3. How to take Uraplex 4. Possible side effects 5. How to store Uraplex 6. Further information 1. WHAT URAPLEX IS AND WHAT IT IS USED FOR Uraplex is a medicine used for the relaxation of the bladder. It is used for the treatment of symptoms associated with involuntary loss of urine (wetting) and/or increased frequency of urination and imperative urge of urination in patients with hyperactive bladder (involuntary urge of urination and voiding problems of unknown origin or due to nervous system disorders). 2. BEFORE YOU TAKE URAPLEX Do not take Uraplex − If you have ever had an allergic reaction to trospium chloride or any of the other

ingredients of Uraplex (An allergic reaction can be a rash, itchiness or shortness of breath). For the list of ingredients in Uraplex, please see section 6.

− If you suffer from any of the following: o urinary retention, i.e. blockage of the urinary tract, o the eye condition narrow-angle glaucoma, o abnormal/faster than normal heart beats, o myasthenia gravis (a disorder that causes muscle fatigue), o a severe gastro-intestinal condition, such as toxic megacolon.

Take special care with Uraplex If you suffer from any of the following: - any type of stomach or bowel obstruction, - difficulties in passing urine and/or a poor stream of urine (male prostate disorders),

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- neuropathy ie. nerve damage, - a hernia of the diaphragm with inflammation of the oesophagus due to reflux

of gastric acid (hiatus hernia associated with reflux oesophagitis). This is usually associated with heartburn which worsens on bending or lying down,

- an overactive thyroid, - any heart conditions, such as coronary artery disease or congestive heart failure, - any liver problems, - any kidney problems. If any of the above apply to you, it is important that you speak to your doctor or pharmacist before taking Uraplex and they will decide what to do. PATIENTS WITH LIVER DISORDERS You should not take Uraplex if you have a serious liver disorder. If you have a slight to moderate liver impairment you should talk to your doctor before taking this medicine. PATIENTS WITH KIDNEY DISORDERS If you have a kidney disorder you should talk to your doctor before taking this medicine. Your doctor will, if necessary, give you a lower dose (see dosage instructions in Section 3 – How to take For patients with kidney disorders). Children under the age of 12 years Do not give Uraplex to children under the age of 12 years. TAKING OTHER MEDICINES Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Inform your doctor in particular if you are taking any of the following medicines: - certain medicines for the treatment of abnormal sadness (depression), e.g.

amitriptyline or imipramine - medicines for the treatment of asthma that may accelerate the heart rate (e.g.

salbutamol) - other medicines with anticholinergic action (such as those used to treat

Parkinson’s disease, asthma and stomach cramps) - medicines for the stimulation of motility of the gastro-intestinal tract which are

used to treat impaired gastric emptying or complaints due to reflux of gastric acid (reflux disease), e.g. metoclopramide

- medicines containing the substances guar, colestipol or cholestyramine which should not be taken simultaneously with Uraplex.

Please note that this information may also apply to medicines that you have used recently. TAKING URAPLEX WITH FOOD AND DRINK As high fat diets can affect the action of Uraplex, the medicine should be taken before meals on an empty stomach.

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Pregnancy and breast-feeding Please tell your doctor if you are pregnant, think you might be pregnant, or are breast-feeding. Your doctor will decide if this medicine is suitable for you. Driving and using machines Uraplex can cause blurred vision. If you experience this, do not drive or use any tools or machines. Important information about some of the ingredients of Uraplex This product contains lactose (milk sugar) and sucrose (sugar). If you have been told by your doctor that you have an intolerance to some sugars, please contact your doctor before taking this medicinal product. This product also contains wheat starch. If you suffer from wheat allergy (different from coeliac disease) you should not take this product. Uraplex is suitable for patients with coeliac disease. 3. HOW TO TAKE URAPLEX Always take Uraplex exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Usual dose unless otherwise prescribed by your doctor Unless otherwise prescribed by your doctor, the usual daily dose for adults and children over the age of 12 years is one Uraplex tablet taken twice daily (equivalent to 40 mg of trospium chloride daily). Method of administration Swallow one tablet whole with a glass of water. Take the tablet before a meal on an empty stomach. Duration of treatment Your doctor will determine the duration of treatment. The need for continued treatment should be checked by your doctor at regular intervals of 3–6 months. For patients with kidney disorders If your kidney function is slightly to moderately impaired, no dose adjustment of Uraplex is required. In severely impaired kidney function, the dose should be reduced to one tablet once daily or every second day (equivalent to 20 mg of trospium chloride daily or every second day). You should consult with your doctor about the correct dose for you. IF YOU TAKE MORE URAPLEX THAN YOU SHOULD If you have taken too much Uraplex you should contact your doctor or go to the nearest hospital casualty department immediately. If you forget to take Uraplex If you forget to take a tablet, take your tablet as soon as you remember, but do not take more than two tablets in one day (unless prescribed otherwise).

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If you stop taking Uraplex Your symptoms may return if you stop the intake of Uraplex before recommended by your doctor. Therefore, you should take Uraplex for as long as prescribed by your doctor. Please consult your doctor if you wish to stop treatment. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Uraplex can cause side effects, although not everybody gets them. The side effects occurring most frequently are typical for this kind of medicine and comprise dry mouth, dyspepsia and constipation. The following side effects below are serious and will require immediate action if you experience them. You should stop taking Uraplex and see your doctor immediately if the following symptoms occur:

• swelling of the face, tongue and windpipe which can cause great difficulty in breathing (affects less than 1 user in 10,000)

• a sudden allergic reaction with shortness of breath, rash, wheezing and drop of blood pressure (frequency unknown)

• serious reactions with severe blistering and peeling of the skin and/or mucous membranes like for example in the lips, eyes, mouth, nose, and genitals. This may be accompanied by a fever and chills, aching muscles and generally feeling unwell (frequency unknown).

The following side effects have been reported for Uraplex: Very common side effects, affects more than 1 user in 10 • dryness of the mouth. Common side effects, affects 1 to 10 users in 100 • constipation, nausea, abdominal pain, indigestion (dyspepsia). Uncommon side effects, affects 1 to 10 users in 1,000 • fast heart rate (tachycardia), • headache, • flatulence, diarrhoea, • chest pain. RARE SIDE EFFECTS, AFFECTS 1 TO 10 USERS IN 10,000 • dizziness, • difficulty emptying of the bladder, urinary retention, • difficulty seeing objects close-up, • rash, • joint and muscle pains. Other possible side effects, for which the frequency is not known

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• accelerated and irregular heart rate (tachyarrhythmia), • difficulty in breathing, • itchiness, nettle-rash (hives), • general feeling of weakness (asthenia), • slight to moderate increase of certain liver values (serum transaminases), • sporadic cases of hallucination, confusion and agitation have occurred mostly in

elderly patients and can be facilitated by neurological diseases and/or other drugs with a similar mechanism of action taken at the same time.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE URAPLEX Keep out of the reach and sight of children. Do not use Uraplex after the expiry date which is stated on the carton and the blister foil after EXP. The expiry date refers to the last day of that month. Storage conditions This medicinal product does not require any special storage conditions. Do not use Uraplex if you notice that the pack or any of the tablets are damaged. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Uraplex contains The active substance is trospium chloride Each coated tablet contains 20 mg trospium chloride. The other ingredients are: Tablet core: Wheat starch, microcrystalline cellulose, lactose monohydrate, povidone (K29-32), croscarmellose sodium, stearic acid, talc. Tablet coating: Sucrose, carmellose sodium, talc, silica colloidal anhydrous, calcium carbonate (E 170), macrogol 8000, titanium dioxide (E 171), iron oxide hydrate yellow (E 172), white beeswax, carnauba wax. Note for diabetics: one coated tablet corresponds to 0.06 g carbohydrate (equivalent to 0.005 bread units). What Uraplex looks like and contents of the pack Uraplex tablets are brownish-yellow, glossy coated tablets with a diameter of approximately 7 mm.

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Uraplex is available in packs containing 2, 20, 28, 30, 50, 56, 60, 90, 100, 120, 150, 200, 500, 600, 1000, 1200 and 2000 tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Madaus GmbH, 51101 Cologne, Germany This leaflet was last approved in August 2011

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Labelling The Marketing Authorisation Holder has submitted the below text version of the labelling and has committed to submitting the mock-ups to the MHRA before marketing any pack size. PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Uraplex 20mg coated tablets Trospium chloride 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each coated tablet contains 20 mg trospium chloride. 3. LIST OF EXCIPIENTS Contains lactose, sucrose and wheat starch. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 2 coated tablets 20 coated tablets 28 coated tablets 30 coated tablets 40 coated tablets 50 coated tablets 56 coated tablets 60 coated tablets 90 coated tablets 100 coated tablets 120 coated tablets 150 coated tablets 200 coated tablets 500 coated tablets 600 coated tablets 1000 coated tablets 1200 coated tablets 2000 coated tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use Read the package leaflet before use.

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6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Madaus GmbH 51101 Cologne, Germany 12. MARKETING AUTHORISATION NUMBER(S) PL 25843/0011 13. BATCH NUMBER BN: 14. GENERAL CLASSIFICATION FOR SUPPLY POM 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Uraplex 20mg coated tablets

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTER 1. NAME OF THE MEDICINAL PRODUCT Uraplex 20mg coated tablets Trospium chloride 2. NAME OF THE MARKETING AUTHORISATION HOLDER MA-holder: Madaus GmbH 3. EXPIRY DATE EXP: 4. BATCH NUMBER BN: 5. OTHER

Conclusion The proposed SmPC, PIL and labelling amendments are in-line with the reference product and there are no objections to approval.

Decision Approved (18/01/2012).

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URAPLEX 20 MG COATED TABLETS PL 25843/0011 … · the proposed product is manufactured to the same...

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