Public Assessment Report. Scientific discussion MINOXIDIL AT/H/0638/ /DC. Date:

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1 CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Alocutan 20 mg/ml Spray zur Anwendung auf der Haut, Lösung, Alocutan 50 mg/ml Spray zur Anwendung auf der Haut, Lösung MINOXIDIL AT/H/0638/ /DC Date: This module reflects the scientific discussion for the approval of Alocutan 20 mg/ml Spray zur Anwendung auf der Haut, Lösung and Alocutan 50 mg/ml Spray zur Anwendung auf der Haut, Lösung. The procedure was finalised at For information on changes after this date please refer to the module Update. 1

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Alocutan 20 mg/ml Spray zur Anwendung auf der Haut, Lösung and Alocutan 50 mg/ml Spray zur Anwendung auf der Haut, Lösung from Dermapharm AG. Alocutan 20 mg/ml Spray zur Anwendung auf der Haut, Lösung is indicated for the treatment of female-pattern hair loss. Alocutan 50 mg/ml Spray zur Anwendung auf der Haut, Lösung is indicated for the treatment of male-pattern hair loss (androgenetic alopecia) A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 10(3) of Directive 2001/83/EC ( hybrid application ). As a peripheral vasodilator, minoxidil increases the microcirculation to hair follicles. Minoxidil stimulates vascular endothelial growth factor (VEGF) which is probably responsible for the increased capillary permeability and hence shows a high metabolic activity which can be observed during the anagen phase. II. QUALITY ASPECTS II.1 Introduction Alocutan is a cutaneous spray, solution, which is presented in a 60 ml white HDPE bottle. II.2 Drug Substance The active substance in Alocutan is minoxidil. The specification of the active substance meets the current scientific requirements. The adequate quality of the active substance has been shown by submitting the appropriate control data. The stability of the active substance has been tested under ICH conditions. The results of the stability studies support the established retest-period. II.3 Medicinal Product Alocutan contains the following excipients: Ethanol 96% (v/v) propylene glycol purified water. Alocutan 20 mg/ml Spray zur Anwendung auf der Haut, Lösung 2

3 Excipient with known effect: 199 mg/ml propylene glycol. Alocutan 50 mg/ml Spray zur Anwendung auf der Haut, Lösung. Excipient with known effect: propylene glycol 509 mg/ml. The development of the products has been sufficiently made and deemed appropriate. The usage of all the excipients has been described. The release specification includes the check of all parameters relevant to this pharmaceutical form. Appropriate data concerning the control of the finished product support the compliance with the release specifications. The packaging of the medicinal product complies with the current legal requirements. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SmPC, with a shelf life of 30 months. Special storage conditions are: Do not freeze. The shelf-life after first opening is 6 weeks. The pharmaceutical quality of Alocutan has been adequately shown. II.4 Discussion on chemical, pharmaceutical and biological aspects Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics. III. NON-CLINICAL ASPECTS Pharmacodynamic, pharmacokinetic and toxicological properties of minoxidil are well known. As minoxidil is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. III.1 Ecotoxicity/environmental risk assessment (ERA) Since Alocutan 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.2 Discussion on the non-clinical aspects The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. 3

4 IV. IV.1 CLINICAL ASPECTS Introduction The indications claimed are in accordance with the innovator products, Regaine. Minoxidil is a widely used and long-standing, well-known active substance. According to the Note for Guidance no bioequivalence study is required. Consequently, no further studies were required for this application and the applicant provided none. IV.2 Pharmacokinetics According to Appendix 2 of the BE-Guideline a waiver of the need to provide equivalence data may be acceptable in the case of topical solutions. The justification for not performing a clinical study is based on the development of a formulation having the same qualitative and quantitative composition concerning the active substance, an essentially similar composition of excipients and essentially similar pharmaceutical properties and was considered acceptable. IV.3 Pharmacodynamics Minoxidil belongs to the following ATC-Code: D11AX01 The exact mechanism of action by which minoxidil stimulates hair growth is not fully known. However, minoxidil may stop hair loss in androgenetic alopecia by: increasing the diameter of the hair shaft, stimulating hair growth in the anagen phase, extending the anagen phase, shortening the telogen phase, whereby the anagen phase is reached more quickly. As a peripheral vasodilator, minoxidil increases the microcirculation to hair follicles. Minoxidil stimulates vascular endothelial growth factor (VEGF) which is probably responsible for the increased capillary permeability and hence shows a high metabolic activity which can be observed during the anagen phase. IV.4 Clinical efficacy and safety The indications claimed are in accordance with those of the reference product, Regaine. No new efficacy or safety data have been submitted and none are required for this application. 4

5 IV.5 Risk Management Plan The MAH has submitted an updated risk management plan (Version number 1.1), 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 Alocutan. - Summary table of safety concerns as approved in RMP Important identified risks Angioedema and hypersensitivity reactions Cardiovascular adverse reactions (including palpitations, heart rate increased, chest pain, hypotension, hypertension, dizziness and peripheral oedema) Important potential risks Interaction with peripheral vasodilators Missing information Safety of use in children and adolescents under 18 years Safety of use during pregnancy and breast-feeding - Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP Safety Concern Angioedema and hypersensitivity reactions Routine Risk Minimisation Measures Important Identified Risks SmPC: - Section 4.3: Contraindication for patients with hypersensitivity to the active substance - Section 4.8: Hypersensitivity and angioedema are listed as adverse reaction Additional Risk Minimisation Measures None proposed Cardiovascular adverse reactions (including palpitations, heart rate increased, chest pain, hypotension, hypertension, dizziness and peripheral oedema) SmPC: - Section 4.4.: Treatment with Minoxidil should not take place in patients with signs of cardiovascular disease or cardiac arrhythmias or in hypertensive patients, including patients on treatment with antihypertensives. The patient should discontinue the product and consult a doctor None proposed 5

6 Safety Concern Routine Risk Minimisation Measures if a reduction in blood pressure is detected (see section 4.8), or if one or more of the following manifestations occur: chest pain, accelerated heartbeat, asthenia or dizziness, sudden unexplained weight gain, swollen hands or feet, persistent redness or irritation of the scalp. Inadvertent ingestion can cause severe cardiovascular adverse reactions. This product must therefore be kept out of the reach of children. - Section 4.8: Tachycardia palpitations, hypertension, hypotension, dizziness, peripheral oedema and chest pain listed as adverse reactions - Section 4.9: Description of cardiovascular adverse reactions as symptoms of intoxication/overdose. Additional information regarding the treatment of intoxication: Clinically significant tachycardia can be controlled with β-blockers and oedema with diuretics. An excessive decrease in blood pressure can be treated by intravenous infusion of physiological saline solution. Sympathomimetics such as adrenaline and noradrenaline are to be avoided due to their cardiotonic effect. Additional Risk Minimisation Measures Interaction with peripheral vasodilators Important Potential Risks SmPC: - Section 4.5.: Although not clinically proven, there is a theoretical possibility that absorbed minoxidil may potentiate orthostatic hypotension in patients concomitantly taking peripheral vasodilators. - Section 4.8: Hypotension listed None proposed 6

7 Safety Concern Data on the safety of use in children and adolescents under 18 years Safety of use during pregnancy and breast-feeding Routine Risk Minimisation Measures as adverse reaction Missing Information SmPC: - Section 4.2: The safety and efficacy of <Invented name> in children and adolescents below 18 years have not been established. No data are available. SmPC: - Section 4.3: 20 mg/ml cutaneous solution: Contraindication for pregnant women and breast-feeding mothers. 50 mg/ml cutaneous solution: Contraindication in woman due to occasional signs of cosmetically distressing, reversible, facial hair growth during treatment. - Section 4.6: 20 mg/ml cutaneous solution: Description of known risks in animals and contraindication for use. 50 mg/ml cutaneous solution: <Invented name> 50 mg/ml is indicated for use in male patients only and must not be used by pregnant women and breastfeeding mothers. Additional Risk Minimisation Measures None proposed None proposed IV.6 Discussion on the clinical aspects The clinical overview on the clinical pharmacology, efficacy and safety is adequate. 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 German. 7

8 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. A full user test has been performed for Alocutan 20 mg/ml Spray zur Anwendung auf der Haut, Lösung. The test consisted of: two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. A bridging report for the second strength, Alocutan 50 mg/ml Spray zur Anwendung auf der Haut, Lösung on this user test was considered acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The pharmaceutical quality of Alocutan has been adequately shown. No new non-clinical or clinical concerns have been identified. The benefit/risk relation is considered positive. 8

9 Public Assessment Report Update Alocutan 20 mg/ml Spray zur Anwendung auf der Haut, Lösung, Alocutan 50 mg/ml Spray zur Anwendung auf der Haut, Lösung MINOXIDIL AT/H/0638/ /DC This module reflects the procedural steps and scientific information after the finalisation of the initial procedure. 9

10 Procedure number* Scope Product Information affected Date of end of procedure Approval/ non approval Summary/ Justification for refuse *Only procedure qualifier, chronological number and grouping qualifier (when applicable) 10