Applicant: Zentiva A.S., Prague, Czech Republic

Public Assessment Report Scientific discussion

NEUROL SR 0,5 NEUROL SR 1,0 NEUROL SR 2,0 Alprazolamum

CZ/H/0118/01-03/MR

Applicant: Zentiva a.s., Prague, Czech Republic

This module reflects the scientific discussion for the approval of Neurol SR. The procedures were finalised at 30-05-2006. INTRODUCTION

This generic application for marketing authorisation concerns NEUROL SR, Zentiva a.s., tablets in the strength 0,5; 1,0 and 2,0 mg. These three strengths of Neurol SR are approved in a Mutual Recognition Procedure on 30th May 2006. The Concerned Member State were EE, LV (Neurol SR 0,5), PL and SK (Neurol SR 0,5; 1 and 2 mg).

The national marketing authorisation was granted on 30th April 2004.

The tablets are claimed to be essentially similar to XANAX SR, tablets, Pharmacia NV/SA, Puurs, Belgium, authorised in the Czech Republic since 1995. The reference medicinal product has therefore been authorised in the EU for more than 10 years.

The products are indicated for the treatment of panic disorder with or without agoraphobia, generalized anxiety disorder, anxiety associated with depression.

The reference products used in the bioequivalence study was Xanax SR. No new pre-clinical and clinical studies, besides the bioequivalence studies, were conducted. This is acceptable for this abridged application.

QUALITY ASPECTS

Introduction

Neurol SR 0,5 and 1,0 and 2,0 mg is presented in the form of prolonged release tablets containing 0,5 mg or 1,0 mg or 2,0 mg of alprazolam as the active substance. The excipients are lactose monohydrate, hypromellose 2208/4000, hypromellose 2208/100, silica colloidal anhydrous, indigo carmine aluminium lake and magnesium stearate.

The tablets are packed in Al/Al blisters or in glass bottles with PE screw cap with desiccant. The materials comply with the Ph.Eur. Blisters or bottles are placed, together with a package leaflet, into a paper folding box.

Active Substance

The active substance is described in the European Pharmacopoeia. It is a white to almost white crystalline powder. It is practically insoluble in water, sparingly soluble in acetone and alcohol, freely soluble in methylene chloride. The manufacturer of drug substance is a holder of CEP, the Ph.Eur. specification has been completed by test on residual solvents which is attached to CEP. Average particle size and microbilogical quality are further tests done on request by manufacturer of drug product.

Certificates of analysis have been provided. Results comply with the proposed specification and confirm the consistency of the manufacturing process.

The re-test period stated on the CEP is 5 years if stored in double polyethylene bags placed in HDPE drum. No stability data were requested.

Medicinal Product Excipients are controlled according to current Ph.Eur. The colouring agent Indigo carmine aluminium lake (E 132) is controlled according to the in-house specification. Statement for Lactose as an excipient of animal origin, that in terms of TSE safety, it is in compliance with CPMP guidelines. Magnesium stearate is of vegetable origin.

Pharmaceutical Development The formulation was intended to be tablets with a prolonged drug release similar to that of the innovator product. The different ratios of excipients were tested to find a optimal composition with required hardness and dissolution profile. Satisfactory Certificates of analysis of all excipients have been provided.

Manufacturing of the product The manufacturing process is stated as standard. Those pre-validation results give a good picture of the manufacturing process. The manufacturer provides the statement that the validation on first three manufacturing batches will be provided.

Product specification Satisfactory control tests are applied at time of release and during the shelf-life. The release and shelf life limits for the assay of alprazolam are in line with batch and stability data. Acceptable multistage limits for dissolution are provided. Limits for related substances are in line with ICH guidelines and stability data. Analytical methods have been satisfactorily described and validated in accordance to regulatory requirements. Satisfactory batch data are provided for three pilot batches and one laboratory batch for each of strenght.

Stability of the product Stability trials were performed on the drug product according to the stability protocols and ICH guidelines. The shelf-life of 3 years without any special conditions has been documented for both of two packagings.

Discussion on chemical and pharmaceutical aspects Information on development, manufacture and control of the drug substance and drug product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics, and these in turn lead to the conclusion that the product should have a satisfactory and uniform performance in the clinic.

Steps taken after authorisation

The quality of the product, above all in respect for the manufacture and control, has been regularly updated to take account of technical and scientific progress and necessary changes were made by variation procedures.

STEPS TAKEN AFTER AUTHORISATION – SUMMARY Application type and scope Variation IA/7b1 and consequent IA/7a - addition of manufacturing site responsible for packaging of the finisched product. - addition of manufacturing site responsible for secondary packaging of the finished product. Variation IA/19a - change in specification of an excipient.

CLINICAL ASPECTS

It’s acceptable that specific studies have not been performed, as the application is submitted in accordance with Article 10.1 of Directive 2001/83/EC. Alprazolam is authorised for more than 10 years in Europe and therefore it is a well-known active substance.

Alprazolam is well absorbed after ingestion by mouth. Peak plasma level occurs 1-2 hours after a single dose. When a slow-release formulation is given after high-fat meal the Cmax increases by approximately 25%.

Up to 80% of the drug bind to proteins in plasma. The distribution half-life is 12 hours. Apparent volume of distribution is reported between 0.9-1.2 l/kg. Alprazolam is metabolized in liver by cytochrome p450 3A4. A few hydroxy- metabolites are minimally pharmacologically active.

Alprazolam is excreted mainly in urine (80% of the dose). Elimination half-life is about 10-15 hours, prolonged in obese patients up to 22 hours and in patients with liver disease up to 20 hours.

To support the application, the applicant has submitted as report 5 bioequivalence studies. Neurol SR is a modified release formulation with multiple strengths. Single-dose bioequivalence study at fasted state has been conducted for each individual strength, BE study at fed state and under steady state conditions have been done with the highest strength.

A TWO-WAY, RANDOMIZED, SINGLE-DOSE, CROSS-OVER, BALANCED, FASTED BIOEQUIVALENCE STUDY OF NEUROL RETARD 0.5 MG TABLETS IN NORMAL MALE VOLUNTEERS

A two-way, randomized, single-dose, cross-over, fasted study of Neurol retard 0.5 mg tablets in healthy male subjects has been conducted. The study evaluated the comparative bioavailability of Neurol retard 0.5 mg with Xanax SR 0.5mg. Twenty-six healthy male Caucasians were enrolled into the study when fulfilling inclusion criteria, mainly physical examination, medical history, basic biochemistry, and haematology screens as specified in protocol. All enrolled subjects completed the study and were included in the PK evaluation. Plasma concentration of alprazolam was determined by HPLC method and statistically evaluated. There were no reported deviations from protocol, no adverse events, and no subject was excluded throughout the study. Pharmacokinetic parameters Cmax and tmax were determined directly from concentration-time profiles of individual sujects, t1/2 was estimated by least squares regression analysis, half value duration (HVD) was calculated from value of 50% Cmax and corresponding points, when using linear interpolation between two adjacent sampling points, and AUCt by linear trapezoidal rule with extrapolation to infinity for AUCinf. Geometric means of HVD, and AUC were considered as primary parameters to test the bioequivalence as pre-specified in the protocol, 90% confidence intervals were estimated. Acceptance range of bioequivalence was 0.80-1.25 for AUC and 0.70- 1.43 for HVD. Descriptive statistics was used to summarize the results. Two-way ANOVA was carried out on all AUCs, HVD, Cmax, tmax and t1/2 values in which subject, treatment, sequence, and period were evaluated.

The results show generally low intra-individual variation after administration of both products. The individual AUCt/AUCinf. ratios ranged from 78.7% to 97.0%, and 79.8%-95.7% for Xanax, and Neurol, respectively. ANOVA performed on the PK parameters did not detect any significant difference between the test and reference products for any of the parameters AUCt, AUCinf., HVD, Cmax.

Bioequivalence has been satisfactorily demonstrated.

A TWO-WAY, RANDOMIZED, SINGLE-DOSE, CROSS-OVER, BALANCED, FASTED BIOEQUIVALENCE STUDY OF NEUROL RETARD 1MG TABLETS IN NORMAL MALE VOLUNTEERS

A two-way, randomized, single-dose, cross-over, fasted study of Neurol retard 1mg tablets in healthy male subjects has been conducted. The study evaluated the comparative bioavailability of Neurol retard 1 mg with Xanax SR 1mg. Twenty- four healthy male Caucasians were enrolled into the study when fulfilling inclusion criteria, mainly physical examination, medical history, basic biochemistry, and haematology screens as specified in protocol.All enrolled subjects completed the study and were included in the PK evaluation. Plasma concentration of alprazolam was determined by HPLC method and statistically evaluated. There were no reported deviations from protocol, no adverse events, and no subject was excluded throughout the study. Pharmacokinetic parameters Cmax and tmax were determined directly from concentration-time profiles of individual sujects, t1/2 was estimated by least squares regression analysis, half value duration (HVD) was calculated from value of 50% Cmax and corresponding points, when using linear interpolation between two adjacent sampling points, and AUCt by linear trapezoidal rule with extrapolation to infinity for AUCinf. Geometric means of HVD, and AUCinf.. were considered as primary parameters to test the bioequivalence as pre-specified in the protocol, 90% confidence intervals were estimated. Acceptance range of bioequivalence was 0.80-1.25 for AUC and 0.70- 1.43 for HVD. Descriptive statistics was used to summarize the results. Two-way ANOVA was carried out on all AUCs, HVD, Cmax, tmax and t1/2 values in which subject, treatment, sequence, and period were evaluated.

The results show generally low intra-individual variation after administration of both products. The individual AUCt/AUCinf. ratios ranged from 74.2%-98.2%, and 73.4% to 97.7% for Xanax, and Neurol, respectively. ANOVA performed on the PK parameters did not detect any significant difference between the test and reference products for any of the parameters AUCt, AUCinf., HVD, Cmax.

A TWO-WAY, RANDOMIZED, SINGLE-DOSE, CROSS-OVER, BALANCED, FASTED BIOEQUIVALENCE STUDY OF NEUROL RETARD 2MG TABLETS IN NORMAL MALE VOLUNTEERS A two-way, randomized, single-dose, cross-over, fasted study of neurol retard 2mg tablets in healthy male subjects has been conducted. The study evaluated the comparative bioavailability of Neurol retard 2mg with Xanax SR 2mg. Twenty-six healthy male Caucasians were enrolled into the study when fulfilling inclusion criteria, mainly physical examination, medical history, basic biochemistry, and haematology screens as specified in protocol. All enrolled subjects completed the study and were included in the PK evaluation. Plasma concentration of alprazolam was determined by HPLC method and statistically evaluated. There were no reported deviations from protocol, no adverse events, and no subject was excluded throughout the study. Pharmacokinetic parameters Cmax and tmax were determined directly from concentration-time profiles of individual sujects, t1/2 was estimated by least squares regression analysis, half value duration (HVD) was calculated from value of 50% Cmax and corresponding points, when using linear interpolation between two adjacent sampling points, and AUCt by linear trapezoidal rule with extrapolation to infinity for AUCinf. Geometric means of HVD, and AUC. were considered as primary parameters to test the bioequivalence as pre-specified in the protocol, 90% confidence intervals were estimated. Acceptance range of bioequivalence was 0.80-1.25 for AUC and 0.70- 1.43 for HVD. Descriptive statistics was used to summarize the results. Two-way ANOVA was carried out on all AUCs, HVD, Cmax, tmax and t1/2 values in which subject, treatment, sequence, and period were evaluated.

The results show generally low intra-individual variation after administration of both products. The individual AUCt/AUCinf. ratios ranged from 81.4% to 95.4%, and 81.7%-97.0% for Xanax, and Neurol, respectively. ANOVA performed on the PK parameters did not detect any significant difference between the test and reference products for any of the parameters AUCt, AUCinf., HVD, Cmax.

A TWO-WAY, RANDOMIZED, MULTIPLE-DOSE, CROSS-OVER, BALANCED, FASTED BIOEQUIVALENCE STUDY OF NEUROL RETARD 2MG TABLETS IN NORMAL MALE VOLUNTEERS

A two-way, randomized, multiple-dose, cross-over, fasted study of neurol retard 2mg tablets in healthy male subjects has been conducted. The study evaluated the comparative bioavailability of Neurol retard 2mg with Xanax SR 2mg. Twenty-six healthy male Caucasians were enrolled into the study when fulfilling inclusion criteria, mainly physical examination, medical history, basic biochemistry, and haematology screens as specified in protocol. All enrolled subjects completed the study and were included in the PK evaluation. Plasma concentration of alprazolam was determined by HPLC method and statistically evaluated. There were no reported deviations from protocol, no adverse events, and no subject was excluded throughout the study. th Pharmacokinetic parameters Cmax and tmax over the 4 dosing interaval were determined directly from concentration-time profiles of individual sujects, peak-trough fluctuation (PFT) was calculated from the ratio of the peak trough difference to the average concentration, plateau time was defined as time span of one dosing cycle during which the plasma concentration deviates from the the maximum concentration by less than 25%, and AUC over the 4th dose interval was derived by linear trapezoidal rule. Geometric means of PTF, and AUC. were considered as primary parameters to test the bioequivalence as pre-specified in the protocol, 90% confidence intervals were estimated. Acceptance range of bioequivalence was 0.80-1.25 for AUC and 0.70-1.43 for PTF. Descriptive statistics was used to summarize the results. Two-way ANOVA was carried out on AUC, PTF, Cmax, Cmin, tmax and tplat values in which subject, treatment, sequence, and period were evaluated. Individual data are presented, logarithmic transformation used. The results show generally low intra-individual variation after administration of both products. ANOVA performed on the PK parameters did not detect any significant difference between the test and reference products for any of the tested parameters.

A TWO-WAY, RANDOMIZED, SINGLE-DOSE, CROSS-OVER, BALANCED, FOOD- EFFECTS BIOEQUIVALENCE STUDY OF NEUROL RETARD 2MG TABLETS IN NORMAL MALE VOLUNTEERS

A two-way, randomized, single-dose, cross-over, food-effects study of neurol retard 2mg tablets in healthy male subjects has been conducted. The study evaluated the comparative bioavailability of Neurol retard 2mg with Xanax SR 2mg. Twenty-six healthy male Caucasians were enrolled into the study when fulfilling inclusion criteria, mainly physical examination, medical history, basic biochemistry, and haematology screens as specified in protocol. All enrolled subjects completed the study and were included in the PK evaluation. Plasma concentration of alprazolam was determined by HPLC method and statistically evaluated. There were no reported deviations from protocol, no adverse events, and no subject was excluded throughout the study. Pharmacokinetic parameters Cmax and tmax were determined directly from concentration-time profiles of individual sujects, t1/2 was estimated by least squares regression analysis, half value duration (HVD) was calculated from value of 50% Cmax and corresponding points, when using linear interpolation between two adjacent sampling points, and AUCt by linear trapezoidal rule with extrapolation to infinity for AUCinf. Geometric means of HVD, and AUCinf.. were considered as primary parameters to test the bioequivalence as pre-specified in the protocol, 90% confidence intervals were estimated. Acceptance range of bioequivalence was 0.80-1.25 for AUC and 0.70- 1.43 for HVD. Descriptive statistics was used to summarize the results. Two-way ANOVA was carried out on all AUCs, HVD, Cmax, tmax and t1/2 values in which subject, treatment, sequence, and period were evaluated. Individual data are presented, logarithmic transformation used.

The results of the bioequivalence study are summarized in Table 1. Individual data are reported in the application, plasma-time concentration profiles are shown. The results show generally low intra- individual variation after administration of both products. The individual AUCt/AUCinf. ratios ranged from 77.0%-97.8%, and 75.5% to 97.6% for Xanax, and Neurol, respectively. ANOVA performed on the PK parameters did not detect any significant difference between the test and reference products for any of the parameters AUCt, AUCinf., HVD, Cmax.

Bioequivalence of Neurol SR 0.5 with the reference product has been satisfactorily demonstrated.

Bioequivalences of Neurol SR 1.0 and 2.0 with the reference products have been satisfactorily demonstrated.

Since this product has been shown to be essentially similar and refer to a product approved based on a full application with regard to clinical efficacy/safety data, no further such data have been submitted or are considered necessary.

User testing of the package leaflet for Neurol has been shown to provide the tested consumers with all required information in a clear and comprehensive form. The Readability testing was performed according to the guidelines. The risk/benefit ratio is considered positive and Neurol SR 0,5; 1,0; and 2,0, tablets is recommended for approval.