Public Assessment Report UKPAR Desloratadine 0.5mg/ml Oral ... · Public Assessment Report . UKPAR . Desloratadine 0 ... The pharmaceutical form of Desloratadine is an oral solution

PAR Desloratadine 0.5mg/ml Oral Solution

PL 24668/0162

1

Public Assessment Report

UKPAR

Desloratadine 0.5mg/ml Oral Solution

(Desloratadine)

UK Licence No: PL 24668/0162

Caduceus Pharma Ltd.


PL 24668/0162

2

LAY SUMMARY

Desloratadine 0.5mg/ml Oral Solution

(desloratadine, oral solution, 0.5mg/ml)

This is a summary of the Public Assessment Report (PAR) for Desloratadine 0.5mg/ml Oral Solution (PL 24668/0162). It explains how Desloratadine 0.5mg/ml Oral 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 Desloratadine 0.5mg/ml Oral Solution. The product will be referred to as Desloratadine throughout the remainder of this PAR. For practical information about using Desloratadine, patients should read the package leaflet or contact their doctor or pharmacist. What is Desloratadine and what is it used for? Desloratadine is a ‘generic medicine’. This means that Desloratadine is similar to a ‘reference medicine’ already authorised in the European Union (EU) called Aerius 0.5 mg/ml oral solution (Merck Sharpe and Dohme Ltd, UK). ‘Aerius’ is also known by the product name ‘Neoclarityn’. Desloratadine relieves symptoms associated with allergic rhinitis (inflammation of the nasal passages caused by an allergy, for example, hay fever or allergy to dust mites) in adults, adolescents and children 1 year of age and older. These symptoms include sneezing, runny or itchy nose, itchy palate, and itchy red or watery eyes. Desloratadine is also used to relieve the symptoms associated with urticaria (a skin condition caused by an allergy). These symptoms include itching and hives. Relief of these symptoms lasts a full day and helps the patient to resume their normal daily activities and sleep. How does Desloratadine work? Desloratadine (the active ingredient in this medicine) belongs to a group of medicines called antihistamines. Desloratadine is an antiallergy medicine that does not make the patient drowsy. This medicine helps to control the patient’s allergic reaction and its symptoms. How is Desloratadine used? The pharmaceutical form of Desloratadine is an oral solution and the route of administration is via the mouth (oral). The patient must take this medicine exactly as their doctor or pharmacist has told them. The patient should check with their doctor or pharmacist if they are not sure. The recommended doses are: Children 1 year of age through to 5 years of age:

• 2.5ml (as marked on spoon) of oral solution once a day. Children 6 years of age through to 11 years of age:

• 5ml (one 5ml spoonful) of oral solution once a day


PL 24668/0162

3

Adults and adolescents 12 years of age and over: • 10ml (two 5ml spoonfuls) of oral solution once a day.

This medicine is for oral use. The patient should measure the dose using the spoon provided in the pack. The patient should swallow the dose of oral solution and then drink some water. This medicine can be taken with or without food. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment. Desloratadine can only be obtained with a prescription. What benefits of Desloratadine have been shown in studies? No additional studies were needed as Desloratadine is a generic medicine that is taken orally, as a solution, and contains the same active substance, in the same concentration, as the reference medicine, Aerius 0.5 mg/ml oral solution (Merck Sharpe and Dohme Ltd, UK). What are the possible side effects of Desloratadine? Because Desloratadine is a generic medicine, its benefits and possible side effects are taken as being the same as the reference medicine. For the full list of restrictions, see the package leaflet. For the full list of all side effects reported with Desloratadine, see section 4 of the package leaflet available on the MHRA website. Why was Desloratadine approved? It was concluded that, in accordance with EU requirements, Desloratadine has been shown to have comparable quality and to be comparable to Aerius 0.5 mg/ml oral solution (Merck Sharpe and Dohme Ltd, UK). Therefore, the MHRA decided that, as for Aerius 0.5 mg/ml oral solution (Merck Sharpe and Dohme Ltd, UK), the benefits are greater than their risk and recommended that it can be approved for use. What measures are being taken to ensure the safe and effective use of Desloratadine? A risk management plan (RMP) has been developed to ensure that Desloratadine 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 Desloratadine 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/healthcare professionals will be monitored/reviewed continuously. Other information about Desloratadine A Marketing Authorisation was granted in the UK on 12 October 2015. The full PAR for Desloratadine follows this summary. For more information about treatment with Desloratadine read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in November 2015.


PL 24668/0162

4

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


PL 24668/0162

5

I INTRODUCTION The Medicines and Healthcare products Regulatory Agency (MHRA) granted Caduceus Pharma Ltd, a Marketing Authorisation for the medicinal product Desloratadine (PL 24668/0162) on 12 October 2015. The product is a prescription-only medicine (POM) indicated for the relief of symptoms associated with allergic rhinitis and urticaria. The application was submitted under Article 10.1 of Directive 2001/83/EC, as amended, as a generic application. The reference medicinal product marketed in the EU for more than 10 years is Aerius 5 mg film-coated tablets which was authorised by the centralised procedure on 15 January 2001 (EU/1/00/160/001-003); whereas the reference medicinal product for purpose of demonstrating equivalence is Aerius 0.5 mg/ml oral solution which was also authorised by the centralised route on 23 April 2007. Aerius 5 mg film-coated tablets and Aerius 0.5 mg/ml oral solution belong to the same global marketing authorisation (GMA), so the legal basis is acceptable. ‘Aerius’ is also known by the product name ‘Neoclarityn’. Desloratadine is a non-sedating, long-acting histamine antagonist with selective peripheral H1-receptor antagonist activity. After oral administration, desloratadine selectively blocks peripheral histamine H1-receptors because the substance is excluded from entry to the central nervous system. No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of an originator product that has been licensed for over 10 years. No new clinical data have been submitted and none are required for applications of this type. A bioequivalence study was not necessary to support this application as both test and reference products are oral solutions at the time of administration. No new or unexpected safety concerns arose during the review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Desloratadine outweigh the risks and a Marketing Authorisation was granted.


PL 24668/0162

6

II QUALITY ASPECTS II.1 Introduction Each ml of oral solution contains 0.5mg desloratadine. Other ingredients consist of the following pharmaceutical excipients; liquid sorbitol (non-crystallizing), propylene glycol, citric acid monohydrate, sodium citrate, hypromellose 2910, sucralose, disodium edetate, tutti frutti and purified water. The finished product is packed into amber (Type III) glass bottles with a white polypropylene child-resistant screw closure having a multi-ply polyethylene-faced liner. The bottles are packed into a cardboard carton together with a measuring spoon marked for doses 2.5 ml and 5 ml or an oral measuring syringe of a final volume of 5 ml marked in graduations of 0.5ml. The product is available in pack sizes of 50 ml, 60 ml, 100 ml, 120 ml and 150 ml bottles. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. II.2. Drug Substance INN: Desloratadine Chemical names:

Structural formula:

Molecular formula: C19H19ClN2 Molecular mass: 310.8 g/mol Appearance: A white to off-white crystalline powder. Solubility: Soluble in methanol, dichloromethane and isopropyl alcohol. Desloratadine is the subject of a European Pharmacopoeia monograph. Synthesis of the active substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant Certificates of Analysis. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Appropriate proof-of-structure data have been supplied for the active substance. All potential known impurities have been identified and characterised. Satisfactory certificates of analysis have been provided for all working standards. Batch analysis data are provided that comply with the proposed specification.


PL 24668/0162

7

Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with food. Appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging. II.3. Medicinal Product Pharmaceutical Development The objective of the development programme was to formulate a safe, efficacious, oral solution containing 0.5mg desloratadine per ml of oral solution that was comparable in performance to the originator product Aerius 0.5 mg/ml oral solution (Merck Sharpe and Dohme Ltd, UK). A satisfactory account of the pharmaceutical development has been provided. Comparative impurity profiles have been provided for the proposed and originator products. All excipients comply with their respective European Pharmacopoeia monographs with the exception of sucralose which complies with The United States Pharmacopeia (USP) and the tutti frutti flavour which is controlled to a suitable in-house specification. In addition, confirmation has been provided that the tutti frutti flavour complies with EU regulation EC/1334/2008. Satisfactory Certificates of Analysis and batch analysis have been provided for all excipients. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Manufacture of the product 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 and shown satisfactory results. The process validation protocol to be followed for full-scale production batches has been provided and is satisfactory. Finished Product Specification The finished product specification proposed is acceptable. Test methods have been described and have been adequately validated. Batch data have been provided that comply with the release specifications. 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 18 months for the unopened bottle with the storage conditions ‘Do not freeze. Store in the original package.’ The in-use shelf life of the product is 2 months after first opening. II.4 Discussion on chemical, pharmaceutical and biological aspects This application is satisfactory from a pharmaceutical viewpoint.


PL 24668/0162

8

III NON-CLINICAL ASPECTS III.1 Introduction As the pharmacodynamic, pharmacokinetic and toxicological properties of desloratadine are well-known, no new non-clinical studies are required and none have been provided. An overview based on the literature review is, thus, appropriate. The MAH’s non-clinical expert report 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 Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.3 Pharmacokinetics Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.4 Toxicology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.5 Ecotoxicity/environmental risk assessment (ERA) Since Desloratadine is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.6 Discussion on the non-clinical aspects No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of a reference product that has been licensed for over 10 years. There are no objections to the approval of this application from a non-clinical viewpoint. IV CLINICAL ASPECTS IV.1 Introduction In line with the CPMP guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), the test product is to be administered as an aqueous oral solution containing the same active substance concentration as the approved reference medicinal product. No bioequivalence data have been submitted with this application and none are required for this application. No new efficacy or safety studies have been performed and none are required for this type of application. A comprehensive review of the published literature has been provided by the applicant, citing the well-established clinical pharmacology, efficacy and safety of desloratadine. Based on the data provided, Desloratadine can be considered bioequivalent to the reference product Aerius 0.5 mg/ml oral solution (Merck Sharpe and Dohme Ltd, UK). IV.2 Pharmacokinetics In line with the CPMP guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), the test product is to be administered as an aqueous oral solution containing the same active substance concentration as the approved reference medicinal product. No bioequivalence data have been submitted with this application and none are required for this application. IV.3 Pharmacodynamics No new pharmacodynamic data were submitted and none were required for an application of this type.


PL 24668/0162

9

IV.4 Clinical efficacy No new efficacy data were submitted and none were required for an application of this type. IV.5 Clinical safety No new safety data were submitted and none were required for this application. IV.6 Risk Management Plan (RMP) The marketing authorisation holder (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 Desloratadine. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below: Summary table of safety concerns:

Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns. IV.7 Discussion on the clinical aspects No new clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of a reference product that has been licensed for over 10 years. A bioequivalence study was not necessary to support this application as both test and reference products are aqueous oral solutions at the time of administration. The grant of a marketing authorisation is recommended for this application.


PL 24668/0162

10

V User consultation The package 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 PIL 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 The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with desloratadine is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.


PL 24668/0162

11

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website. The following text is the approved label text for Desloratadine, no label mock-ups have been provided. In accordance with medicines legislation, the product shall not be marketed in the UK until approval of the label mock-ups has been obtained:


PL 24668/0162

12


PL 24668/0162

13


PL 24668/0162

14


PL 24668/0162

15


PL 24668/0162

16


PL 24668/0162

17


PL 24668/0162

18

The approved labelling for Desloratadine for own label supplier (OLS) Actavis is presented below:


PL 24668/0162

19

Documents

Public Assessment Report UKPAR Desloratadine 0.5mg/ml Oral ... · Public Assessment Report . UKPAR . Desloratadine 0 ... The pharmaceutical form of Desloratadine is an oral solution