Public Assessment Report. Scientific discussion. Hydroxizin Alternova (hydroxyzine hydrochloride) Asp no : ,

Transcription

1 Public Assessment Report Scientific discussion Hydroxizin Alternova (hydroxyzine hydrochloride) Asp no : , This module reflects the scientific discussion for the approval of Hydroxizin Alternova. The procedure was finalised on For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: registrator@mpa.se Template version:

2 I. INTRODUCTION The application for Hydroxizin Alternova, 10 mg, 25 mg, film-coated tablet, is a generic application made according to Article 10(1) of Directive 2001/83/EC. The applicant, Alternova A/S applies for a marketing authorisation in Sweden through a National Procedure. The reference medicinal product chosen for the purposes of establishing the expiry of the data protection period is originator product Atarax, 10 mg and 25 mg, film-coated tablets authorised in SE since 1957, with UCB Nordic A/S as marketing authorisation holder. The reference product used in the bioequivalence study is Atarax, 25 mg, film-coated tablet from SE with UCB Nordic A/S as marketing authorisation holder. For approved indications, see the Summary of Product Characteristics. For recommendations to the marketing authorisation not falling under Article 21a/22 of Directive 2001/83 and conditions to the marketing authorisation pursuant to Article 21a or 22 of Directive 2001/83/EC to the marketing authorisation, please see section VI. II. II.1 QUALITY ASPECTS Drug Substance The structure of the drug substance has been adequately proven and its physico-chemical properties are sufficiently described. The manufacture of the drug substance has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents. The drug substance specification includes relevant tests and the limits for impurities and degradation products have been justified. The analytical methods applied are suitably described and validated. Stability studies confirm the retest period. II.2 Medicinal Product The medicinal product is formulated using excipients listed in section 6.1 in the Summary of Product Characteristics. The manufacturing process has been sufficiently described and critical steps identified. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies have been performed and data presented support the shelf life and special precautions for storage claimed in the Summary of Product Characteristics, sections 6.3 and /7

3 III. III.1 NON-CLINICAL ASPECTS Discussion on the non-clinical aspects Since this product has been shown to be essentially similar and refer to a product approved based on a full application with regard to preclinical data, no further such data have been submitted or are considered necessary. IV. IV.1 CLINICAL ASPECTS Pharmacokinetics Hydroxyzine has an oral bioavailability of approximately 80 % compared to intramuscular administration. Following an oral dose of hydroxyzine maximal plasma concentrations occur at approximately 2 hours. There are no restrictions with respect to food in the SPC of the originator. The terminal half-life is hydroxyzine is approximately 14 hours (7-20 h). Bioequivalence was evaluated in one single-dose, two-way crossover study conducted in 26 healthy volunteers, comparing Hydroxyzine, 25 mg, film-coated tablets, manufactured by Viminco A/S, Denmark, with Atarax, 25 mg, film-coated tablets under fasting conditions. The study was conducted at Arab Pharmaceutical Industry Consulting/Pharmaceutical Research Unit, Sweileh, Jordan between 6 th and 27 th August Blood samples were collected predose and up to 72 hours post-dose. The study design is considered acceptable. Plasma concentrations of hydroxyzine were determined with an adequately validated LC/MS/MS method. The use of an achiral analytical method is agreed. For AUC 0-t and C max the 90% confidence interval for the ratio of the test and reference products fell within the conventional acceptance range of %. Thus, bioequivalence has been demonstrated for the 25 mg strength. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median, range) for hydroxyzine, n=25. Treatment AUC 0-t ng*h/ml C max ng/ml t max Test ± ± ( ) Reference ± ± ( ) *Ratio (90% CI) ( ) ( ) - AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration t max time for maximum plasma concentration *calculated based on ln-transformed data Available data regarding linear kinetics is limited. The SmPC of the reference product suggests a slightly more than proportional increase in C max with increasing dose in the interval mg, although the dose-adjusted difference in C max is less than 25%. There are no signs of a less h 3/7

4 than proportional increase in AUC with increasing dose, which would be the case where a study with the lower strength would be necessary. Thus, the biowaiver for the lower strength can be accepted from a pharmacokinetic perspective. IV.2 Discussion on the clinical aspects 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. IV.3 Risk Management Plan The MAH has submitted a risk management plan, 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 Hydroxizin Alternova. Safety specification Summary table of safety concerns as approved in RMP Important identified risks Cardiac dysrhythmias / QT prolongation Convulsions Anticholinergic effect Interaction with alcohol Use in patients with moderate or severe renal impairment Use in patients with hepatic impairment Use in the elderly Use in patients with electrolyte imbalances Hypersensitivity Important potential risks Cerebrovascular events in patients with risk of stroke Missing information Use in children under 5 years of age Pharmacovigilance Plan Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed. Risk minimisation measures Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed. Summary of the RMP The MAH has satisfactory responded to the questions raised and updated the RMP accordingly. Issue is resolved The RMP is approved. 4/7

5 The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures. V. USER CONSULTATION A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference regarding content to Hydroxyzine EQL Pharma (DK/H/2313/001/DC) and the layout to Amiodaron Alternova 50 mg/ml solution for injection (assessed and accepted in Denmark 27 May 2014) for the plain package leaflet and Prednisolon Alternova 2.5 mg, 5 mg and 10 mg tablets (assessed and accepted in an IB-variation in Sweden 2121: ) for the fold-out package leaflet. The bridging report submitted by the applicant has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The benefit/risk ratio is considered positive and Hydroxizin Alternova, 10 mg, 25 mg, filmcoated tablet is recommended for approval. List of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment Area 1 Description The applicant has committed to place the next 3 manufactured batches on long-term, intermediate and accelerated stability and test multiple time points to further evaluate stability and the stability indicating properties of the method for detection of related substances. 1. Areas: Quality, Non-clinical, Clinical, Pharmacovigilance List of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC N/A 5/7

6 VII. APPROVAL Hydroxizin Alternova, 10 mg, 25 mg, film-coated tablet was approved in the national procedure on /7

7 Public Assessment Report Update 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) Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version: