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Public Assessment Report

Alvesco Takeda 40 Inhaler Alvesco Takeda 80 Inhaler

Alvesco Takeda 160 Inhaler

UK/H/5699/001-003/DC

PL 31752/0031-0033

Takeda GmbH

Alvesco Takeda 40 Inhaler UK/H/5699/001/DC Alvesco Takeda 80 Inhaler UK/H/5699/002/DC Alvesco Takeda 160 Inhaler UK/H/5699/003/DC

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Lay Summary

Alvesco Takeda 40 Inhaler Alvesco Takeda 80 Inhaler

Alvesco Takeda 160 Inhaler (ciclesonide)

This is a summary of the Public Assessment Report (PAR) for Alvesco Takeda 40, 80 and 160 Inhalers (PL 31752/0031-0033). Alvesco Takeda 40, 80 and 160 Inhalers will be referred to as Alvesco 40, 80 and 160 Inhalers throughout this report, for ease of reading. It explains how Alvesco 40, 80 and 160 Inhalers were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use these products. For practical information about using Alvesco 40, 80 and 160 Inhalers, patients should read the Patient Information Leaflet (PIL) or contact their doctor or pharmacist. What are Alvesco 40, 80 and 160 Inhalers and what are they used for? Alvesco 40, 80 and 160 Inhalers are the same as ‘Alvesco 40 Inhaler, 40 micrograms Pressurised inhalation, solution’, ‘Alvesco 80 Inhaler, 80 micrograms Pressurised inhalation, solution’, and ‘Alvesco 160 Inhaler, 160 micrograms Pressurised inhalation, solution’, respectively, which are already authorised. The company that owns these latter ‘reference products’ submitted applications for Alvesco 40, 80 and 160 Inhalers, using the reference products as bases for the grant of identical marketing authorisations (informed consent). Alvesco 40, 80 and 160 Inhalers are used to control persistent asthma in adult and adolescent patients (12 years old and more). How do Alvesco 40, 80 and 160 Inhalers work? Alvesco 40, 80 and 160 Inhalers contain the active substance ciclesonide, which is a corticosteroid. Ciclesonide helps a patient to breathe more easily by decreasing the symptoms of the asthma and by lessening the chances of an asthma attack. Ciclesonide is termed a ‘preventer’ medication; its effect builds up over a period of time, so these medicines needs to be taken every day, even when the patient is feeling well. How are Alvesco 40, 80 and 160 Inhalers used? Alvesco 40, 80 and 160 Inhalers are used by inhaling through the mouth into the lungs. It is important that a doctor, nurse or pharmacist shows the patient first how to use the Alvesco inhaler properly. A good technique will ensure that the patient is receiving the correct amount of these medicines into their lungs. Please read Section 3 of the PIL for detailed information on dosing recommendations, the route of administration, and the duration of treatment.


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The recommended dose of Alvesco is 160 micrograms once daily, which leads to asthma control in the majority of patients. This dose may be increased or decreased by the prescribing doctor. Alvesco 40, 80 and 160 Inhalers can only be obtained with a prescription.

What benefits of Alvesco 40, 80 and 160 Inhalers have been shown in studies? Alvesco 40, 80 and 160 Inhalers are considered identical to the previously granted marketing authorisations for ‘Alvesco 40 Inhaler, 40 micrograms Pressurised inhalation, solution’, ‘Alvesco 80 Inhaler, 80 micrograms Pressurised inhalation, solution’ and ‘Alvesco 160 Inhaler, 160 micrograms Pressurised inhalation, solution’, respectively, with the same benefits and risks. No new studies have been provided for Alvesco 40, 80 and 160 Inhalers, but reference is made to the studies for ‘Alvesco 40 Inhaler, 40 micrograms Pressurised inhalation, solution’, ‘Alvesco 80 Inhaler, 80 micrograms Pressurised inhalation, solution’ and ‘Alvesco 160 Inhaler, 160 micrograms Pressurised inhalation, solution’. What are the possible side effects from Alvesco 40, 80 and 160 Inhalers? Like all medicines, these medicines can cause side-effects, although not everybody gets them. For information about side-effects that may occur with using Alvesco 40, 80 and 160 Inhalers, please refer to the PIL or the Summaries of Product Characteristics (SmPCs) available on the Medicines and Healthcare products Regulatory Agency (MHRA) website. Why are Alvesco 40, 80 and 160 Inhalers approved? No new or unexpected safety concerns arose from these applications. It was, therefore, considered that the benefits of Alvesco 40, 80 and 160 Inhalers outweigh the risks, and the grant of these marketing authorisations was recommended. What measures are being taken to ensure the safe and effective use of Alvesco 40, 80 and 160 Inhalers? A Risk Management Plan (RMP) has been developed to ensure that Alvesco 40, 80 and 160 Inhalers are used as safely as possible. Based on this plan, safety information has been included in the SmPCs and the PIL for Alvesco 40, 80 and 160 Inhalers, including the appropriate precautions to be followed by healthcare professionals and patients. Known side-effects are continuously monitored. Furthermore, new safety signals reported by patients and healthcare professionals will be monitored and reviewed continuously as well. Other information about Alvesco 40, 80 and 160 Inhalers The Netherlands and the UK agreed to grant marketing authorisations for Alvesco 40, 80 and 160 Inhalers on 13 November 2014. The marketing authorisations in the UK were granted on 15 December 2014. For more information about taking Alvesco 40, 80 and 160 Inhalers, read the PIL, or contact your doctor or pharmacist.


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This summary was last updated in February 2015. The full PAR for Alvesco 40, 80 and 160 Inhalers follows this summary.


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Table of Contents

I Introduction Page 6 II Quality aspects Page 7 III Non-clinical aspects Page 8 IV Clinical aspects Page 8 V User consultation Page 9 VI Overall conclusion, benefit/risk assessment and

recommendation Page 10

Table of content of the PAR update

Page 17


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I Introduction Based on the review of the data on quality, safety and efficacy, the member states granted marketing authorisations for the medicinal products Alvesco 40, 80 and 160 Inhalers. These applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and the Netherlands as a Concerned Member State (CMS). Alvesco 40, 80 and 160 Inhalers are prescription-only medicines (POM), indicated to control persistent asthma in adults and adolescents (12 years and older). These applications were made under Article 10c of Directive 2001/83/EC, as amended. These applications cross-refer, and claim to be identical, to ‘Alvesco 40 Inhaler, 40 micrograms Pressurised inhalation, solution’ (PL 31752/0004), ‘Alvesco 80 Inhaler, 80 micrograms Pressurised inhalation, solution’ (PL 31752/0005) and ‘Alvesco 160 Inhaler, 160 micrograms Pressurised inhalation, solution’ (PL 31752/0006), which were originally granted to Altana Pharma AG (PL 20141/0004-0006) on 16 April 2004. The marketing authorisation holder subsequently underwent a change of ownership to the new marketing authorisation holder, Takeda GmbH, on 17 January 2008 (PL 31752/0004-0006). These medicinal products contain the active substance ciclesonide. Ciclesonide is an inhaled corticosteroid that exhibits low binding affinity to the glucocorticoid-receptor. Once orally inhaled, ciclesonide is enzymatically converted in the lungs to the principal metabolite (C21-des-methylpropionyl-ciclesonide), which has a pronounced anti-inflammatory activity and is thus considered as the active metabolite. No new data have been submitted and none are required for these simple applications, as the data are identical to those of the previously granted, cross-referred products.


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II Quality aspects II.1 Introduction These are simple, piggyback (informed consent) applications for Alvesco 40, 80 and 160 Inhalers submitted under Article 10c of Directive 2001/83/EC, as amended. The applications cross-refer to ‘Alvesco 40 Inhaler, 40 micrograms Pressurised inhalation, solution’ (PL 31752/0004), ‘Alvesco 80 Inhaler, 80 micrograms Pressurised inhalation, solution’ (PL 31752/0005) and ‘Alvesco 160 Inhaler, 160 micrograms Pressurised inhalation, solution’ (PL 31752/0006). Alvesco 40, 80 and 160 Inhalers contain the active substance ciclesonide at concentrations of 40 micrograms, 80 micrograms and 160 micrograms per actuation, respectively. The excipients present in Alvesco 40, 80 and 160 Inhalers are norflurane (HFA-134a) and anhydrous ethanol. The qualitative and quantitative composition of these excipients is identical to those of the respective cross-reference product. The inhalers each comprise a pressurised container made from aluminium that is sealed with a metering valve, mouthpiece and cap. The inhalers are available in sizes of 30, 60 and 120 metered actuations This packaging is identical to those of the cross-reference products. II.2 Drug Substance Ciclesonide The drug substance specification is identical to those of the cross-reference products and is acceptable. II.3 Medicinal Product Pharmaceutical development The drug products are non-aqueous metered dose inhalers, presented as ciclesonide in 40 micrograms/actuation, 80 micrograms/actuation and 160 micrograms/actuation strengths. These applications are direct copies of the dossiers for the cross-reference medicinal products and, therefore, the information provided here, including the formulation, is identical to that of the respective cross-reference products. Manufacture of the product The manufacture of the drug product together with in-process controls has been adequately described, and it is confirmed that this process is identical to that of the currently approved cross-reference products. With respect to Good Manufacturing Practice (GMP) certification, valid EU GMP certificates have been provided for both the finished product manufacturer, and batch release site. The certificates are acceptable and no further requests for inspection are requested during these procedures. The proposed manufacturing sites are consistent with those registered for the cross-reference products. Evidence of GMP compliance has been provided, which is identical to that of the cross-reference products.


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None of the excipients contain materials of animal or human origin. Finished Product Specification The finished product specifications are identical to the cross-reference medicinal products, for both the shelf-life and release acceptance parameters. Stability of the product The proposed shelf-lives of 1 year for a 30 actuation presentation and 3 years for the 60 and 120 actuation presentations are acceptable. These are identical to those of the cross-reference products. Alvesco 40, 80 and 160 Inhalers do not require any special storage conditions, which is identical to that of the cross-reference products. II.4 Discussion on chemical, pharmaceutical and biological aspects The quality data for these applications are consistent with those previously assessed for the marketing authorisations for ‘Alvesco 40 Inhaler, 40 micrograms Pressurised inhalation, solution’ (PL 31752/0004), ‘Alvesco 80 Inhaler, 80 micrograms Pressurised inhalation, solution’ (PL 31752/0005) and ‘Alvesco 160 Inhaler, 160 micrograms Pressurised inhalation, solution’ (PL 31752/0006) and, as such, have been judged to be satisfactory. The grant of marketing authorisations is recommended. III Non-clinical aspects As these are abridged applications, submitted under Article 10c of Directive 2001/83/EC, as amended, no new non-clinical data has been supplied and none are required. The grant of marketing authorisations is recommended. IV Clinical aspects As these are abridged applications, submitted under Article 10c of Directive 2001/83/EC, as amended, no new clinical data have been supplied and none are required. Risk Management Plan (RMP) The applicant has submitted an 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 Alvesco 40, 80 and 160 Inhalers. A summary of safety concerns and risk minimisation measures, as approved in the RMP, are listed below:


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Summary table of safety concerns Summary of safety concerns

Important identified risks

None

Important potential risks

Local oropharyngeal adverse events Paradoxical bronchospasm Hypothalamic-pituitary-adrenal (HPA) axis effects Decreased bone density Effects on growth in children Eye disorders (cataract, lens opacities and glaucoma) Use in patients with underlying pulmonary infection (tuberculosis, viral, fungal or bacterial) Immediate or delayed hypersensitivity reactions Psychiatric Events Interactions with potent CYP3A4 inhibitors

Missing information Experience in pregnancy and lactation Use in patients with severe hepatic impairment

Summary table of risk minimisation measures Routine Pharmacovigilance and routine risk minimisation is proposed for all safety concerns, which is considered acceptable.

The grant of a marketing authorisation is recommended. V User consultation A User Testing report is provided from 9 July 2006 based upon the readability testing of the leaflet for the cross-reference products. The PIL of the cross-reference products was evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC.


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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. As the proposed leaflet for the current applications will be identical to that of the cross-reference products, upon this basis an additional User Testing report is not required. VI Overall conclusion, benefit/risk assessment and recommendation The quality of these products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The applicant’s products are identical to the cross-reference products. The benefit/risk assessment is, therefore, considered to be positive. The Summaries of Product Characteristics (SmPCs), Patient Information Leaflet (PIL) and labelling are satisfactory, in line with current guidelines and consistent with the cross-reference products. In accordance with Directive 2012/84/EU, the current approved UK versions of the SmPCs and PIL for these products are available on the MHRA website. The currently approved labels are listed below:


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Labelling text for Alvesco 40 Inhaler


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Labelling for Alvesco 80 Inhaler


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Labelling text for Alvesco 160 Inhaler


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Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II variations, PSURs, commitments)

Scope Product

information affected

Date of start of the procedure

Date of end of procedure

Approval/ non approval

Assessment report attached Y/N (version)

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