Public Assessment Report TAPCLOB 5MG/5ML ORAL SUSPENSION ... · TAPCLOB 5MG/5ML AND 10MG/5ML ORAL...

TAPCLOB 5MG/5ML AND 10MG/5ML ORAL SUSPENSION UK/H/4647/001-002/DC

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Public Assessment Report

Decentralised Procedure

TAPCLOB 5MG/5ML ORAL SUSPENSION

TAPCLOB 10MG/5ML ORAL SUSPENSION

(Clobazam)

European Procedure Numbers: UK/H/4647/001-002/DC

UK Marketing Authorisation Numbers: PL 00156/0322-0323

Martindale Pharmaceuticals Ltd


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Lay summary

On 11 February 2013 The Medicines and Healthcare products Regulatory Agency (MHRA) granted Marketing Authorisations to Martindale Pharmaceuticals Ltd for the medicinal products Tapclob 5mg/5ml Oral Suspension and Tapclob 10mg/5ml Oral Suspension (PL 00156/0322-0323; UK/H/4647/001-002/DC). These medicines are available on prescription only. Tapclob 5mg/5ml and 10mg/5ml Oral Suspension contain clobazam, which belongs to a group of medicines called benzodiazepines. Clobazam works by having a calming effect on the brain. Tapclob Oral Suspension is used to treat: - Severe anxiety over a short time - Epilepsy (fits) over a longer time (in combination with other treatments) - Mental illness such as schizophrenia (in combination with other treatments)

No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Tapclob 5mg/5ml and 10mg/5ml Oral Suspension outweigh the risks; hence Marketing Authorisations were granted.


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TABLE OF CONTENTS

Module 1: Information about Decentralised Procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 6 Module 4: Labelling Page 7 Module 5: Scientific Discussion Page 13

I Introduction II About the product III Scientific overview and discussion III. 1 Quality aspects III. 2 Non-clinical aspects III. 3 Clinical aspects IV Overall conclusion and benefit/risk assessment Module 6: Steps taken after initial procedure Page 24


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Module 1

Information about Decentralised Procedure

Name of the products in the Reference Member State

Tapclob 5mg/5ml Oral Suspension Tapclob 10mg/5ml Oral Suspension

Type of application Article 10.3 (hybrid)

Name of the drug substance Clobazam

Pharmacotherapeutic classification (ATC code) of the medicinal products

Benzodiazepine derivatives (N05BA09)

Pharmaceutical form and strengths of the medicinal products

Oral Suspension; 5mg/5ml and 10mg/5ml

Reference numbers for the Decentralised Procedure

UK/H/4647/001/DC UK/H/4647/002/DC

Reference Member State

United Kingdom

Member State concerned

Malta

Start date of the Decentralised Procedure 15 June 2011

End date of the Decentralised Procedure 11 January 2013

Marketing Authorisation numbers PL 00156/0322 PL 00156/0323

Name and address of the authorisation holder

Martindale Pharmaceuticals Ltd Trading As Martindale Pharma Bampton Road Harold Hill Essex RM3 8UG UK


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Module 2

Summary of Product Characteristics In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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Module 3

Product Information Leaflet

In accordance with Directive 2010/84/EU the Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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Module 4

Labelling

Tapclob 5mg/5ml Oral Suspension Label:


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Cartons:


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Tapclob 10mg/5ml Oral Suspension Labels:


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Cartons:


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Module 5

Scientific Discussion

I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the applications for Tapclob 5mg/5ml and 10mg/5ml Oral Suspension for the treatment of anxiety and as adjunctive therapy for schizophrenia or other psychotic illnesses or epilepsy could be approved. The products are prescription-only medicines (POM). These applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Malta as Concerned Member State (CMS). The applications were submitted under Article 10.3 of Directive 2001/83/EC, as amended, as hybrid applications. The reference product is Frisium® Tablets 10mg (PL 04425/0214), which was first licensed to Hoechst UK Ltd in the UK on 25

August 1980. Following a Change of Ownership on 15 January 2002 the Marketing Authorisation for the reference product is now owned by Aventis Pharma Limited. The reference product has been authorised in the EEA for at least 10 years, therefore, the legal basis of these applications is acceptable. The active ingredient clobazam is a 1,5-benzodiazepine. It is well absorbed from the gastrointestinal tract and peak plasma concentrations have been reached 0.5 to 4 hours after oral administration. Approximately 85% of the drug is bound to plasma proteins. Clobazam is highly lipophilic and rapidly crosses the blood-brain barrier. Clobazam is metabolized in the liver by demethylation and hydroxylation. It is excreted both unchanged and as metabolites, mainly in the urine. Mean half-lives of 10 hours and 30 hours have been reported for clobazam and its main active metabolite N desmethylclobazam, respectively. General Comments on the Submitted Dossier The submitted documentation in relation to the proposed products is of sufficient quality and is consistent with the current EU regulatory requirements. Satisfactory overall quality, non-clinical and clinical overviews have been submitted. They represent an adequate summary of the dossier. General Comments on Compliance with GMP, GLP, GCP and Agreed Ethical Principles GMP The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.


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GLP and GCP With the exception of the bioequivalence study, no new non-clinical or clinical studies were conducted, which is acceptable given that this is a hybrid application cross-referring to a product that has been licensed for over 10 years. The bioequivalence study was conducted in line with GCP. II. ABOUT THE PRODUCT Name of the products in the Reference Member State

UK/H/4647/001/DC: Tapclob 5mg/5ml Oral Suspension UK/H/4647/002/DC: Tapclob 10mg/5ml Oral Suspension

Name of the active substance (INN) Clobazam

Pharmacotherapeutic classification (ATC code)

Benzodiazepine derivatives (N05BA09)

Pharmaceutical form and strengths Oral Suspension; 5mg/5ml and 10mg/5ml Reference numbers for the Decentralised Procedure

UK/H/4647/001/DC UK/H/4647/002/DC

Reference Member State (RMS) United Kingdom Concerned Member State(s) (CMS) Malta Marketing Authorisation Numbers PL 00156/0322

PL 00156/0323 Name and address of the authorisation holder

Martindale Pharmaceuticals Ltd (trading as Martindale Pharma) Bampton Road Harold Hill Essex RM3 8UG UK

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS Drug Substance International non-priority name (INN): Clobazam Chemical name: 7-Chloro-1-methyl-5-phenyl-1,5-

dihydro-3H-1,5-benzodiazepine-2,4-dione

CAS registry number: 22316-47-8 Structural formula:

Molecular formula: C16H13ClN2O2 Relative molecular mass: 300.7


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Description: A white or almost white, crystalline powder.

Solubility: Slightly soluble in water, freely soluble in methylene chloride, sparingly soluble in alcohol.

Clobazam is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance clobazam are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. DRUG PRODUCT Other Ingredients Other ingredients in the oral suspension are the pharmaceutical excipients sorbitol (E420), xanthan gum (E415), acesulfame potassium (E950), raspberry flavour, sodium propyl hydroxybenzoate (E217), sodium methyl hydroxybenzoate (E219), disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate and purified water. All excipients comply with their respective Ph Eur monograph, with the exception of raspberry flavour which is controlled by a suitable in-house specification. In the absence of a Ph Eur monograph for this excipient this is satisfactory. Certificates of Analysis are provided for each excipient, showing compliance with their respective monographs. None of the excipients contain materials of animal or human origin. No genetically modified organisms have been used in the preparation of these excipients. Pharmaceutical Development Details of the pharmaceutical development of the drug products have been supplied and are satisfactory. The objective was to develop stable, aqueous, sugar- and alcohol-free products containing clobazam as a non-sedimenting suspension. Manufacture Satisfactory batch formulae have been provided for the manufacture of both strengths of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated with production-scale batches and has shown satisfactory results. Control The finished product specifications are satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for any working standards used. Container Closure System The oral suspensions are stored in amber glass bottles sealed with tamper evident, child-proof plastic screw caps. Pack sizes of 100ml and 150ml have been authorised.


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Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability of the Drug Products Finished product stability studies were performed in accordance with current guidelines on batches of the finished products packed in the packaging proposed for marketing. Based on the results, a shelf-life of 2 years has been approved for suspension stored in unopened bottles. Once the bottle is first opened a shelf life of 28 days applies. These shelf lives are appropriate when the storage precaution ‘Do not store above 25°C’ is applied. Quality Overall Summary A satisfactory Quality Overall Summary prepared by an appropriately qualified expert has been provided. The CV of the expert has also been supplied. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPCs, PIL and product labelling are pharmaceutically acceptable. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Marketing Authorisation Application (MAA) Forms The MAA forms are satisfactory. Quality Conclusion There are no objections to approval of Tapclob 5mg/5ml Oral Suspension and Tapclob 10mg/5ml Oral Suspension from a pharmaceutical point of view. III.2 NON-CLINICAL ASPECTS As the pharmacological, pharmacokinetic and toxicological properties of clobazam are well known, no further non-clinical studies are required and none have been provided. Non-clinical Overview The non-clinical overview has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. Environmental Risk Assessment A suitable justification for the absence of a formal environmental risk assessment has been provided, based on the expectation that introduction of this generic product onto the market is unlikely to result in an increase in the combined sales of all clobazam-


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containing products, which, in turn, is unlikely to increase exposure of the environment to clobazam. Product Literature The product literature is acceptable from a non-clinical point of view. Non-clinical Conclusion There are no objections to the approval of Tapclob 5mg/5ml Oral Suspension and Tapclob 10mg/5ml Oral Suspension from a non-clinical point of view. III.3 CLINICAL ASPECTS

Pharmacokinetics The applicant conducted a randomised, open-label, two-way cross-over bioequivalence study comparing a single dose of Tapclob 10mg/5ml Oral Suspension with Frisium® Tablets 10mg under fasting conditions in healthy volunteers. Study design 32 volunteers (12 female and 20 male), aged 22-55 years, were randomised to receive a single 10mg oral dose of either Tapclob 10mg/5ml Oral Suspension (test product) or Frisium® Tablets 10mg (reference product). Serum drug levels were followed for 72 hours following dosing and the washout period between phases was 14 days. Plasma samples were analysed to quantify the concentration of clobazam via a validated LC/MS/MS bioanalytical method. Results The pharmacokinetic parameters for clobazam (ln transformed as appropriate) are as follows:

The ratio of geometric least squares mean of test and reference for Cmax was 121.1%. The 90% confidence interval for the ratio of geometric least squares mean was 111.95%-130.98%. This interval exceeds the upper limit of the acceptance limits (80.00%-125.00%) required to conclude bioequivalence, according to the protocol. However, it is not an absolute requirement to demonstrate bioequivalence under Article 10(3) of Directive 2001/83/EC and the applicant has demonstrated acceptable product safety (see below). Pharmacodynamics No new pharmacodynamic data were submitted and none are required for this application.


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Clinical Efficacy In the bioequivalence study comparing a single dose of Tapclob 10mg/5ml Oral Suspension with Frisium® Tablets 10mg AUC was within conventional bioequivalence criteria. Therefore, there are no concerns relating to the efficacy of the oral suspension. Clinical Safety In the bioequivalence study 32 healthy subjects received single oral doses of Tapclob 10mg/5ml Oral Suspension and Frisium® Tablets 10mg in a standard randomised, cross-over design study. No serious adverse events were reported. Ten subjects reported a total of 13 adverse events (AEs) during the study. There were 12 mild and one moderate adverse event reported, of which 12 were considered possibly treatment related. Seven subjects experienced a total of seven AEs after administration of the Tapclob 10mg/5ml Oral Suspension reported as six instances of somnolence and one of dizziness. All were mild in severity and resolved without intervention. Three subjects experienced a total of three AEs after administration of Frisium® Tablets, reported as one instance each of somnolence, dizziness and catheter site swelling. All were mild in severity and resolved without intervention (other than catheter adjustment). Increased eosinophil counts were observed at the end of the study in three subjects; these were resolved spontaneously in two cases and one subject was lost to follow-up. The table below shows details of the eight subjects who reported neurologically-related adverse events. Details are given of the AEs reported (somnolence or dizziness) and peak plasma levels recorded in the relevant treatment period. Dizziness was reported by one subject each after administration of the Tapclob 10mg/5ml Oral Suspension and the Frisium® Tablets 10mg. Six reports of somnolence occurred after the oral suspension and one after the tablet (this subject experienced somnolence with both treatments). Although these AEs occurred more frequently after the oral suspension than after the tablet, there was no consistent direct correlation with the peak plasma levels of clobazam. There were no reports of respiratory depression in this study and a review of the patient data from the study report indicates that there was no effect on respiratory rate: Clobazam peak plasma levels in eight subjects reporting neurologically-related adverse events Subject Tapclob 10mg/5ml Oral Suspension Frisium Tablets 10mg Comment Cmax ng/mL Adverse event Cmax ng/mL Adverse event 1 232.69 - 208.41 Dizziness Dizziness only on

tablet at Cmax lower than with suspension

2 233.3 Somnolence 180.37 - 3 236.7 Somnolence 318.96 Somnolence Somnolence on

both test and reference. Higher Cmax with tablet

4 247.8 Dizziness 267.45 - No dizziness on tablet despite Cmax lower than with suspension

5 223.32 Somnolence 326.32 - No somnolence on tablet despite Cmax


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lower than with suspension

6 433.96 Somnolence 213.36 - 7 351.58 Somnolence 220.49 - 8 422.02 Somnolence 225.85 - In order to relate the plasma levels obtained after a single dose of Tapclob 10mg/5ml Oral Suspension with the exposure likely to occur following clinical use with repeated administration at a range of therapeutic doses, multiple dose simulations were performed. Non-parametric superposition was used to predict the plasma concentration-time curves at steady state for both the test and reference formulations in all 32 subjects individually. Simulations based on both once-daily and twice-daily dosing of 10mg test or reference formulations were generated. The method for computations was set to ‘log’ since the plasma data were not log-transformed. The terminal phase was defined as 16-72 hr for all subjects/treatments. Visual inspection of all individual profiles indicated that this provided an appropriate definition of terminal phase. The simulated steady-state profiles were then subjected to bioequivalence analysis by calculating the 90% confidence interval of the ratio of the geometric mean for the test and reference products. The simulated average profiles are shown in Figure 1 below.


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The results of the bioequivalence analysis are shown in the tables below.


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The analysis of the ratio of the geometric mean maximum and minimum steady state plasma concentrations generated for simulated once daily and twice daily administration indicated that the 90% confidence intervals for test and reference products were contained within the bounds of the acceptance interval of 80% to 125% in all cases. Once-daily dosing simulation (every 24 hours) resulted in clobazam Cmax values that were 25% higher for the Tapclob 10mg/5ml Oral Suspension compared with the reference tablet. However, the pre-dose Cmin levels were within 0.5% of each other. This finding was identical for 10 mg, 20 mg and 30 mg every 24 hours. Simulated twice-daily administration steady state profiles following 10 mg or 30 mg every 12 hours showed Cmax values that were 17% higher for Tapclob 10mg/5ml Oral Suspension compared to the reference tablet and the Cmin values that were within 1% of each other. The doses selected for simulation represent the schedules employed for the management of patients with epilepsy. Cmin values are used clinically to guide treatment and these were almost identical between the oral suspension and the reference tablet, with the variability being <0.5 to 1.0%, and were within the recognised therapeutic range. The higher Cmax values observed for the Tapclob 10mg/5ml Oral Suspension would not be detrimental because management of epilepsy is based on seizure control and the presence or absence of adverse effects and is guided by steady state trough levels. Some patients experience optimal therapeutic seizure control below the therapeutic range of clobazam plasma concentrations while others require levels that are much higher than the upper limit of the therapeutic range. In this context, the higher Cmax values associated with the Tapclob 10mg/5ml Oral Suspension may actually be therapeutically useful and advantageous. However, it is appropriate to draw the attention of prescribers to the slightly higher peak plasma levels of clobazam observed in the bioequivalence study and a statement to this effect is included in section 5.2 of the SmPC. The bioequivalence study raises no safety concerns and appropriate information about the higher peak plasma levels of clobazam observed in the bioequivalence study is included in the SmPC. This issue is also addressed adequately in the Risk Management Plan (RMP). Pharmacovigilance System The RMS considers that the pharmacovigilance system fulfils the requirements. The applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the collection and notification of any adverse reaction suspected of occurring in the Community or in a third country. Risk Management Plan The RMP for this product may be summarised as follows:


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Safety concern

Proposed pharmacovigilanceactivities

Proposed risk minimisation activities (routine and additional)

Important Identified Risks Development of dependence. Withdrawal effects. Development of tolerance.

Routine pharmacovigilance

Warnings in product information. Routine pharmacovigilance, signal detection and review in each PSUR.

Important Potential Risks Sedation Respiratory depression

Routine pharmacovigilance

Inform prescribers on the need for care when initiating or switching between clobazam products. This will consist of a launch letter, statement in promotional material and information on website. Warnings in product information. Routine pharmacovigilance, signal detection and review in each PSUR.

The RMP is appropriate and adequate. Clinical Overview A Clinical Overview written by an appropriately qualified physician has been provided and is a satisfactory summary of the clinical part of the dossier. Product Literature All product literature (SmPC, PIL and labelling) is medically satisfactory. Clinical Conclusion There are no objections to the approval of Tapclob 5mg/5ml Oral Suspension and Tapclob 10mg/5ml Oral Suspension from a clinical point of view. IV OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The quality characteristics of Tapclob 5mg/5ml Oral Suspension and Tapclob 10mg/5ml Oral Suspension are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit-risk balance. NON-CLINICAL No new non-clinical data were submitted. As the pharmacokinetics, pharmacodynamics and toxicology of clobazam are well-known, no additional data were required.


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EFFICACY With the exception of the bioequivalence study, no new data were submitted and none are required for applications of this type. In the bioequivalence study comparing a single dose of Tapclob 10mg/5ml Oral Suspension with Frisium® Tablets 10mg AUC values were within conventional bioequivalence criteria. Therefore, there are no concerns relating to the efficacy of the oral suspension. SAFETY With the exception of the safety data from the bioequivalence studies, no new data were submitted. Concerns regarding the higher Cmax exhibited by Tapclob 10mg/5ml Oral Suspension in comparison with the reference product were addressed in the SmPC and through appropriate risk management. PRODUCT LITERATURE The SmPCs, PIL and labelling are consistent with those for the reference products and comply with current guidelines. BENEFIT: RISK ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with clobazam is considered to have demonstrated the therapeutic value of the compound. The benefit: risk balance is, therefore, considered to be acceptable. Marketing Authorisations should be granted.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE

Date submitted

Application type

Scope Outcome

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