public assessment report decentralised procedure altyonz ... · public assessment report...

Public Assessment Report

Decentralised Procedure

Altyonz CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution

(Ipratropium bromide monohydrate)

Procedure No: UK/H/6282/001/DC

UK Licence No: PL 36390/0190

Cipla (EU) Limited


UK/H/6282/001/DC

2

LAY SUMMARY


(ipratropium bromide monohydrate) This is a summary of the Public Assessment Report (PAR) for Altyonz CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution (PL 36390/0190; UK/H/6282/001/DC). It explains how Altyonz CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Altyonz CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution. For practical information about using Altyonz CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution, patients should read the package leaflet or contact their doctor or pharmacist. The product may be referred to as Altyonz CFC-Free Inhaler in this Lay summary. What is Altyonz CFC-Free Inhaler and what is it used for? Altyonz CFC-Free Inhaler is used to make breathing easier for people with asthma or ‘chronic obstructive pulmonary disease’ (COPD), often referred to as chronic bronchitis. In asthma or COPD, patients may have difficulty in breathing, shortness of breath, wheezing or tightness in the chest. Altyonz CFC-Free Inhaler should not be used in children, 12 years of age and younger or adolescents 13 to 17 years of age. Altyonz CFC-Free Inhaler is a ‘hybrid’ medicine. This means that Altyonz CFC-Free Inhaler contains the same active substance as, and is similar to, a reference medicine already authorised in the European Union (EU) called Atrovent dosis-aërosol 20 μg/dosis, aërosol, oplossing (NL – RVG 2683; Boehringer Ingelheim B.V) first approved in the Netherlands in a chlorofluorocarbon (CFC)-free hydrofluoroalkane (HFA)-containing formulation in November 2001. The corresponding reference product in the UK is ATROVENT Inhaler CFC-Free 20 micrograms/actuation pressurised inhalation solution (Boehringer Ingelheim Limited, UK; PL 00015/0266), approved in the UK on 01 March 2004. How does Altyonz CFC-Free Inhaler work? Altyonz CFC-Free Inhaler contains the active substance, ipratropium bromide monohydrate, which belongs to a group of medicines called bronchodilators. In asthma or COPD, ipratropium bromide works by opening up airways. How is Altyonz CFC-Free Inhaler used? The patient should always use Altyonz CFC-Free Inhaler exactly as instructed by his/her doctor. The patient should check with his/her doctor if unsure. Altyonz CFC-Free Inhaler is inhaled through the mouth. The inhaler can be used with a device called Aerochamber Plus spacer. This may be useful for people who find it difficult to synchronise breathing in and inhaler actuation. Please talk to your doctor if you have difficulties to use the Altyonz Inhaler The usual recommended dose in adults (including the elderly) with either asthma or COPD is 1 or 2 puffs to be inhaled three or four times daily. However, in early treatment some patients may need up to 4 puffs at a time to obtain maximum effect. The recommended dose should not be exceeded. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment.


UK/H/6282/001/DC

3

Altyonz CFC-Free Inhaler can only be obtained on prescription. What benefits of Altyonz CFC-Free Inhaler has been shown in studies?

As Altyonz CFC-Free Inhaler is a hybrid medicine, studies in patients have been limited to tests to

determine it is therapeutically equivalent to the reference medicine, ATROVENT Inhaler CFC-Free

20 micrograms/actuation pressurised inhalation solution (Boehringer Ingelheim Limited, UK). Two

medicines are therapeutically equivalent when they produce the same measure of therapeutic effect in

the body. What are the benefits and risks of Altyonz CFC-Free Inhaler? Because Altyonz CFC-Free Inhaler is a hybrid medicine and is therapeutically equivalent to the reference medicine, its benefits and risks are taken as being the same as those of the reference medicine.

What are the possible side effects from Altyonz CFC-Free Inhaler? Like all medicines, Altyonz CFC-Free Inhaler can cause side effects, although not everybody gets them. Since Altyonz CFC-Free Inhaler is a generic hybrid medicine, the benefits and possible side effects are taken as being the same as the reference medicine. For the full list of all side effects reported with Altyonz CFC-Free Inhaler, see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet for Altyonz CFC-Free Inhaler.

Why is Altyonz CFC-Free Inhaler approved? It was concluded that, in accordance with EU requirements, Altyonz CFC-Free Inhaler has been shown to have comparable quality and to be therapeutically equivalent to ATROVENT Inhaler CFC-Free 20 micrograms/actuation pressurised inhalation solution (Boehringer Ingelheim Limited, UK). Therefore, the view was that, as for ATROVENT Inhaler CFC-Free 20 micrograms/actuation pressurised inhalation solution (Boehringer Ingelheim Limited, UK), the benefit outweighs the identified risk. What measures are being taken to ensure the safe and effective use of Altyonz CFC-Free Inhaler?

A Risk Management Plan has been developed to ensure that Altyonz CFC-Free Inhaler is used as

safely as possible. Based on this plan, safety information has been included in the Summary of Product

Characteristics and the package leaflet for Altyonz CFC-Free Inhaler, including the appropriate

precautions to be followed by healthcare professionals and patients. Other information about Altyonz CFC-Free Inhaler Austria, Italy and the UK agreed to grant a Marketing Authorisation to Cipla (EU) Limited for Altyonz CFC-Free Inhaler on 20 February 2017. A Marketing Authorisation was granted in the UK on 15 March 2017. The full PAR for Altyonz CFC-Free Inhaler follows this summary. For more information about treatment with Altyonz CFC-Free Inhaler, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in January 2019.


UK/H/6282/001/DC

4

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 6 III Non-clinical aspects Page 8 IV Clinical aspects Page 8 V User consultation Page 10 VI Overall conclusion, benefit/risk assessment and recommendation Page 10 Annex 1 - Table of content of the PAR update for MRP and DCP Page 13


UK/H/6282/001/DC

5

I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the application for Altyonz CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution (PL 36390/0190; UK/H/6282/001/DC) could be approved. Altyonz CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution may be referred to as Altyonz CFC free Inhaler in this Scientific Discussion. The product is a prescription-only medicine (POM). Altyonz CFC free Inhaler is indicated for the regular treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD) and chronic asthma. Altyonz CFC free Inhaler is not indicated for use in children 12 years of age and younger or adolescents 13 to 17 years of age. The product is not to be used with any spacing device. If a spacing device is required the patient will have to have their anticholinergic treatment changed to an alternative product that can be used with a spacing device. The applicant has provided a post-authorisation commitment to develop a spacing device for use with Altyonz CFC free Inhaler. This is a duplicate application of Ipravent CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution (UK/H/5289/001/DC), which was granted a Marketing Authorisation in the UK (PL 36390/0083) to the same Marketing Authorisation Holder (Cipla (EU) Limited) on 05 November 2013. The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Austria and Italy as Concerned Member States (CMS). The application was submitted under Article 10(3) of Directive 2001/83/EC, as amended, as a hybrid application. The reference medicinal product for this application is Atrovent dosis-aërosol 20 μg/dosis, aërosol, oplossing (Boehringer Ingelheim B.V., Netherlands), which was first approved in the Netherlands on 14 November 2001. The corresponding reference product in the UK is ATROVENT Inhaler CFC-Free 20 micrograms/actuation pressurised inhalation, solution (PL 00015/0266; Boehringer Ingelheim Limited, UK), which was approved in the UK on 01 March 2004. Prior to March 2004, Atrovent (ipratropium bromide) had been available in the UK as a CFC-containing pressurised metered dose inhaler (pMDI; Marketing Authorisation Holder: Boehringer Ingelheim Limited, UK), which has been replaced with the CFC-free, HFA-containing, orally inhaled reference product. Altyonz CFC-Free Inhaler 20 micrograms per actuation pressurised inhalation, solution contains the active ingredient, ipratropium bromide (as ipratropium bromide monohydrate), a quaternary ammonium compound. Ipratropium bromide is a synthetic anticholinergic agent which acts as a non-selective antagonist at the muscarinic receptor. When inhaled orally, ipratropium bromide blocks M1, M2 and M3 muscarinic receptors located on airway smooth muscle, producing relaxation of smooth muscle and bronchodilation. Bronchodilation is primarily a local effect and is not due to systemic absorption. Ipratropium bromide is a short-acting bronchodilator. A single-dose pharmacokinetic (bioequivalence) study was submitted to support this application, comparing the applicant’s test product Ipratropium bromide HFA pMDI (containing ipratropium bromide 20 micrograms/actuation) with the reference product Atrovent CFC-free (containing ipratropiun bromide 20 micrograms/actuation; Boehringer Ingelheim Limited, UK) in healthy adult male human subjects under fasting conditions. The study was conducted according to the current version of the Principles of Declaration of Helsinki (Revised Seoul, October 2008) and in compliance with the current ICH GCP, OECD GLP, National Regulations (ICMR Guidelines), Indian GCP and “Schedule Y” of Indian Drugs and Cosmetic Act, the European Guideline on bioequivalence (CPMP/QWP/EWP/1401/98 Rev. 1, dated January 2010) and the CHMP Guideline on orally inhaled products (CPMP/EWP/4151/00 Rev. 1, dated January 2009). With the exception of the clinical pharmacokinetic study, no new non-clinical or clinical efficacy studies were performed for this application, which is acceptable given that this is a hybrid application based on an originator product that has been in clinical use for over 10 years. The non-clinical dossier consists of published literature and this is acceptable.


UK/H/6282/001/DC

6

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacture, assembly and batch release 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. The RMS and CMS considered that the application could be approved at the end of procedure (Day 209) on 20 February 2017. After a subsequent national phase, a licence was granted in the UK on 15 March 2017. II. QUALITY ASPECTS II.1 Introduction The submitted documentation concerning the proposed product is of sufficient quality and meets the current EU regulatory requirements. The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Altyonz CFC-Free Inhaler is a pressurised inhalation solution. Each metered dose (ex-valve) contains 20 micrograms of ipratropium bromide (as the monohydrate). This is equivalent to a delivered dose (ex-actuator) of 18 micrograms ipratropium bromide (as the monohydrate). The product also contains pharmaceutical excipients namely 1, 1, 1, 2- tetrafluoroethane (HFA 134a; propellant), ethanol anhydrous, purified water and citric acid anhydrous. Appropriate justification for the inclusion of each excipient has been provided. Altyonz CFC-Free Inhaler does not contain any chlorofluorocarbons (CFCs). The finished product is supplied in an inhaler comprising of a 19 ml pressurised pure aluminium anodized canister (containing 12.8 ml of solution) sealed with a 50 µl metering valve made up of a thermoplastic and a plastic (polypropylene) actuator having a white mouthpiece fitted with a green mouthpiece cover. Each canister contains 200 metered actuations of 20 micrograms of ipratropium bromide. Satisfactory specifications and Certificates of Analysis for the primary packaging material have been provided. All primary packaging is controlled to European Pharmacopoeia standards that comply with guidance concerning materials in contact with foodstuff. II.2 Drug substance INN: Ipratropium bromide Chemical Name: (1R,3r,5S,8r)-3-[[(2RS)-3-Hydroxy-2-phenylpropanoyl]oxy]-8-methyl-8-(1-

methylethyl)-8-azoniabicyclo[3.2.1]octane bromide monohydrate Molecular formula: C20H30BrNO3•H2O

Structure:

Molecular mass: 430.4


UK/H/6282/001/DC

7

Appearance: A white or almost white crystalline powder Solubility: Soluble in water, freely soluble in methanol and slightly soluble in ethanol

(96%).

Ipratropium bromide is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, ipratropium bromide, are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability. II.3 Medicinal Product Pharmaceutical Development The objective of the pharmaceutical development programme was to produce a safe, efficacious pressurised inhalation, solution that was comparable in performance to the originator product, Atrovent Inhaler CFC-Free 20 micrograms/actuation pressurised inhalation, solution (Boehringer Ingelheim Limited). Suitable pharmaceutical development data have been provided for this application. Comparative in-vitro data have been provided for this product and the reference product. All excipients comply with their respective European Pharmacopoeia monographs, with the exception of 1, 1, 1, 2-tetrafluoroethane (HFA 134a) which is controlled to a suitable in-house specification. Certificates of Analysis have been provided for all excipients, showing compliance with their respective specifications. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients. Manufacturing Process A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated with full production-scale batches that have shown satisfactory results. Control of Finished Product The finished product specification is acceptable. Test methods have been described and have been validated adequately. Batch data have been provided, which comply with the release specification. Certificates of Analysis have been provided for all working standards used. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of finished product in the packaging proposed for marketing. The data from these studies support a shelf-life of 24 months, with the special storage instructions ‘Do not store above 25°C. Protect from direct sunlight, heat and frost. The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not pierce the canister.’ Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. Bioequivalence/Bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence study. The bioequivalence study is discussed in Section IV, Clinical Aspects. II.4 Discussion on chemical, pharmaceutical and biological aspects It is recommended that a Marketing Authorisation is granted for this application, from a quality point of view.


UK/H/6282/001/DC

8

III. NON-CLINICAL ASPECTS III.1 Introduction The pharmacodynamic, pharmacokinetic and toxicological properties of ipratropium bromide are well known. No new non-clinical data have been submitted for this application and none are required. The applicant has provided an overview based on published literature. 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. III.2 Pharmacology No new data have been submitted and none are required for an application of this type. Refer to Section III.1, Introduction, above. III.3 Pharmacokinetics No new data have been submitted and none are required for an application of this type. Refer to Section III.1, Introduction, above. III.4 Toxicology No new data have been submitted and none are required for an application of this type. Refer to Section III.1, Introduction, above. III.5 Ecotoxicity/Environmental Risk Assessment (ERA) Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As the application is for a generic version of already authorised product, it is not expected that environmental exposure of ipratropium bromide will increase following approval of the Marketing Authorisation for the proposed product. III.6 Discussion of the non-clinical aspects It is recommended that a Marketing Authorisation is granted, from a non-clinical point of view. IV. CLINICAL ASPECTS IV.1 Introduction. The clinical pharmacology of ipratropium bromide is well-known. With the exception of data from the bioequivalence study detailed in Section IV.2, Pharmacokinetics below, no new pharmacokinetic or pharmacodynamic data are provided or required for this application. IV.2 Pharmacokinetics In support of the application, the Marketing Authorisation Holder submitted the following pharmacokinetic (bioequivalence) study to demonstrate therapeutic equivalence between the test product and the reference product. The CHMP Guideline for orally inhaled products (CPMP/EWP/4151/00 Rev. 1) states that pharmacokinetic studies should be carried out in the intended patient population; the applicant has provided suitable justification for carrying out the study in healthy adult volunteers. A randomised, single dose, open label, two-treatment, two-period, two-sequence, crossover bioequivalence study comparing the test product Ipratropium bromide HFA pMDI (containing ipratropium bromide 20 micrograms/actuation; Cipla Limited) with the reference product Atrovent CFC-free (containing ipratropiun bromide 20 micrograms/actuation; Boehringer Ingelheim Limited, UK), both administered as 4 puffs in healthy adult male human subjects under fasting conditions. The subjects self-administered (orally inhaled) a single dose (4 x 20 micrograms per actuation/puff; 80 micrograms) of either the test or the reference product on the two treatment days in a cross-over fashion as per the randomisation sequence, after at least a 10-hour overnight fast. A dose of 80 micrograms was chosen as 80 micrograms is the highest recommended single dose of the reference product. Spacing devices were not used.


UK/H/6282/001/DC

9

Blood samples were collected pre-dose and up to 24 hours after each administration. The washout period between the treatment arms was six days. The pharmacokinetic results are presented below.

Pharmacokinetic parameters (geometric means, ratios and 90% confidence

intervals (CI)) for ipratropium bromide

Pharmacokinetic Parameters

Geometric Mean *(%)T/R 90% Confidence

Interval Test (T) Reference (R)

Cmax(pg/ml) 71.10 69.07 102.93 87.33 – 121.30

AUC0-t (hr.pg/ml) 329.99 318.97 103.46 88.94 – 120.34 Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours *(%) T/R is ratio Test Geometric Least Square Mean/Reference Geometric Least Square Mean

Ratios and 90% CI calculated from ln-transformed data Conclusion of study The pharmacokinetic parameters measured in this study are appropriate parameters to measure in the assessment of therapeutic equivalence between two orally inhaled products. The pulmonary available dose is reflected through measurement of AUO0-t and the regional pulmonary deposition through the measurement of Cmax. The results demonstrate that the pulmonary available dose (via AUO0-t) and regional lung deposition (via Cmax) are similar between the test and reference product. The 90% CI for the least square mean ratio of the test product to the reference product for both AUO0-t and Cmax lie within the acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the applicant’s test product is bioequivalent to, and thus therapeutically equivalent to, the reference product under fasting conditions. IV.3 Pharmacodynamics The clinical pharmacodynamic properties of ipratropium bromide are well-known. No new pharmacodynamic data were submitted and none are required for this type of application. IV.4 Efficacy The efficacy of ipratropium bromide is well-known. No new efficacy data have been submitted and none are required for this type of application. IV.5 Safety With the exception of the safety data generated during the bioequivalence study, no new safety data were submitted and none are required for this type of application. No new or unexpected safety issues arose during the bioequivalence study. IV.6 Risk Management Plan The MAH has submitted a Risk Management Plan (RMP), in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Altyonz CFC-Free Inhaler. A summary of safety concerns is listed in the table below:


UK/H/6282/001/DC

10

Routine pharmacovigilance and risk minimisation activities are planned for all safety concerns which are considered acceptable. IV.7 Discussion of the clinical aspects It is recommended that a Marketing Authorisation is granted, from a clinical point of view. V. USER CONSULTATION A package leaflet (Patient Information Leaflet) has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the pack leaflet was English. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Therapeutic equivalence has been demonstrated between the applicant’s test product and the reference product ATROVENT CFC-free (containing ipratropium bromide 20 micrograms/actuation; Boehringer Ingelheim Limited, UK). The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with ipratropium bromide is considered to have demonstrated the therapeutic value of the compound. Therapeutic equivalence has been demonstrated between the applicant’s test product and the reference product ATROVENT CFC-free (containing ipratropium


UK/H/6282/001/DC

11

bromide 20 micrograms/actuation; Boehringer Ingelheim Limited, UK). The benefit/risk balance is, therefore, considered to be positive.

The grant of a Marketing Authorisation is recommended.


UK/H/6282/001/DC

12

In accordance with Directive 2010/84/EU, the current version of the SmPC and PIL are available on the MHRA website. The current labelling is presented in Annex 1.1 below:


UK/H/6282/001/DC

13

Annex 1 - Table of content of the PAR update for MRP and DCP

Steps Taken After The Initial Procedure With An Influence On The Public Assessment Report

Scope Procedure number Product information affected

Date of start of the procedure

Date of end of procedure

Approval/ non approval

Assessment report attached Y/N (version)

To submit a pharmacokinetic study, in fulfilment of the Day 210 (Decentralised Procedure UK/H/6282//001/DC) commitment to further development to allow administration of Altyonz CFC-Free Inhaler 20 micrograms/actuation pressurised inhalation, solution via the Aerochamber Plus spacer device. Consequently, section 4.2 of the SmPC, section 3 of the PIL and the labelling have been updated. In addition, the PIL has been updated with minor editorial changes.

UK/H/6282/001/II/003 SmPC PIL

02/05/2018 28/11/2018 Approval Yes (Annex 1.1)


14

Annex 1.1 Our Reference: PL 36390/0190, Application 0004 Product: Altyonz CFC-Free Inhaler pressurised inhalation, solution

20 micrograms Marketing Authorisation Holder: Cipla (EU) Limited Active Ingredient(s): Ipratropium bromide monohydrate Type of Procedure: Mutual Recognition Submission Type: Variation Submission Category: Type II Submission Complexity: Standard EU Procedure Number (if applicable): UK/H/6282/001/II/003 REASON To submit a pharmacokinetic study, in fulfilment of a Day 210 commitment to further develop Altyonz CFC-Free Inhaler 20 micrograms/actuation pressurised inhalation, solution for use with the Aerochamber Plus spacer device. Consequently, section 4.2 of the SmPC, section 3 of the PIL and the labelling have been updated. In addition, the PIL has been updated with minor editorial changes. SUPPORTING EVIDENCE Results of a bioequivalence study. The MAH has confirmed that the study was undertaken in accordance with Good Clinical Practice (GCP). Amended SmPC Amended Patient Information Leaflet Amended labelling EXECUTIVE SUMMARY Scope of the variation Altyonz CFC-Free Inhaler 20 micrograms/actuation pressurised inhalation, solution was granted a Market Authorisation on 15 March 2017. In fulfilment of the Day 210 commitment, the Marketing Authorisation Holder has conducted a pharmacokinetic study and submitted the results for evaluation and acceptance. Consequentially, SmPC and PIL updates have also been submitted. SCIENTIFIC DISCUSSION Quality aspects N/A Non-clinical aspects N/A Clinical aspects Bioequivalence Study The results of the following bioequivalence study were submitted. A randomised, single dose, open label, two-treatment, two-period, two-sequence, crossover bioequivalence study comparing test product, Ipratropium Bromide hydrofluroalkane (HFA) pressurised metered dose inhaler (pMDI) 20 mcg per actuation (Cipla Limited) with the reference product, ATROVENT CFC-free 20 mcg per actuation (Boehringer Ingelheim Limited, UK), each administered as 2 puffs with an AeroChamber Plus valved holding chamber (VHC) in healthy, adult, male, human subjects under fasting conditions.


15

The subjects were administered (orally inhaled) a single dose (2 x 20 micrograms per actuation/puff; 40 micrograms) of either the test or the reference product with 240 mL of water as per the randomisation sequence, after at least a 10-hour overnight fast. Following an overnight fast of at least 10 hours, the dose was administered after high fat breakfast. Blood samples were collected pre-dose and up to 24 hours after each administration. The washout period between the treatment periods was 7 days. Pharmacokinetic (PK) parameters were measured from the plasma and statistically analysed. A summary of the PK results for ipratropium bromide are presented below. After 7 days but not more than 14 days from the last blood sample of the last treatment period, subjects underwent a post-study examination which included physical examination, well-being assessment, vital signs examination, Electrocardiogram (ECG) and laboratory evaluations. The per protocol population (PP) included data from all randomised subjects who satisfactorily completed the study without any major protocol violations (defined as any protocol violation which may affect the primary PK parameters) and for whom the primary PK parameters (Cmax and AUC0-t) were calculable. The PP population was the primary population for the comparisons. Results:

Pharmacokinetic parameters (geometric means, ratios and 90% confidence

intervals (CI)) for ipratropium bromide

Pharmacokinetic Parameters

Geometric Mean *(%)T/R 90% Confidence Interval Test (T) Reference (R)

Cmax(pg/ml) 68.65 73.61 93.31 87.21 – 99.83

AUC0-t(hr.pg/ml) 255.93 270.15 94.75 91.66 – 97.94

AUC0-∞(hr.pg/ml) 272.90 287.56 94.92 91.89 – 98.05 Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-∞ area under the plasma concentration-time curve from time zero to infinity hours *(%) T/R is ratio Test Geometric Least Square Mean/Reference Geometric Least Square Mean Ratios and 90% CI calculated from ln-transformed data

Conclusion of study The results for the primary variables indicated that the 90% confidence intervals test/reference ratio of geometric means for AUC0-t and Cmax for ipratropium bromide lie within acceptable bioequivalence limits. of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**)’. Thus, the data support the claim that the applicant’s test product is bioequivalent to, and thus therapeutically equivalent to, the reference product under fasting conditions, when administered via an AeroChamber Plus spacer device. Safety No new or unexpected safety concerns were raised during the bioequivalence study. Product information The applicant proposes changes to the section 4 of the SmPC and section 3 of the PIL to include reference to use of the Aerochamber Plus spacer device and instructions for its correct use. In addition, the product information has been updated with minor editorial changes. The proposed changes are acceptable. In accordance with Directive 2010/84/EU, the current version of the SmPC and PIL is available on the MHRA website. The current labelling is presented below.


16

The Marketing Authorisation Holder has submitted the text version only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed.


17


18

OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT Bioequivalence has been demonstrated between the applicant’s product and the reference product under fasting conditions, when administered via an Aerochamber Plus spacer device. The consequential and other proposed changes to the product information are acceptable. The benefit-risk balance of the product remains positive. RECOMMENDATION Based on the review of the data on safety and efficacy, the RMS considers that the Type II variation for Altyonz CFC-Free Inhaler 20 micrograms/ actuation pressurised inhalation, solution is approvable. Decision – Approved on 28 November 2018

public assessment report decentralised procedure altyonz ... · public assessment report...

Documents