CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Colecalciferol Fresenius 14.400 I.E./ml Tropfen zum Einnehmen, Lösung COLECALCIFEROL AT/H/0578/001/DC Date: 21.12.2016 This module reflects the scientific discussion for the approval of Colecalciferol Fresenius 14.400 I.E./ml Tropfen zum Einnehmen, Lösung. The procedure was finalised at 30.11.2016. For information on changes after this date please refer to the module Update. 1
I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Colecalciferol Fresenius 14,400 IU/ml oral drops, solution, from Fresenius Kabi Austria GmbH. The product is indicated for: - Prevention and treatment of vitamin D deficiency - Treatment of rickets - As an adjunct to a specific therapy for osteoporosis in patients at risk of vitamin D deficiency A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. Vitamin D regulates the calcium- and phosphate balance. Cholecalciferol and to an even greater extent its hydroxylation products induce the formation of a calcium transport protein in the mucous membrane of the small intestine. This leads to increased absorption of calcium and phosphate from the intestine. In the kidneys vitamin D stimulates the reabsorption of calcium and phosphate. A vitamin D deficiency leads to rickets in the growing organism and osteomalacia in adults. II. QUALITY ASPECTS II.1 Introduction Colecalciferol Fresenius is presented as oral drops, solution. The clear, colourless to slightly yellowish oily solution is available in 15 ml brown glass bottles (type III), containing 12.5 ml, with dropper applicator, screw cap and tamper evident ring made of polyethylene. II.2 Drug Substance The active substance in Colecalciferol Fresenius is cholecalciferol (vitamin D 3 ). 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 Colecalciferol Fresenius contains the following excipients: - Medium chain triglycerides 2
The development of the product 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 2 years when stored below 30 C and stored in the original package to protect from light. The shelf-life after first opening of the container is10 months. The pharmaceutical quality of Colecalciferol Fresenius 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 Cholecalciferol are well known. As Cholecalciferol is a widely used, well-known active substance, the applicant has not provided additional studies. Overview based on literature review is, thus, appropriate. III.1 Ecotoxicity/environmental risk assessment (ERA) Since Colecalciferol Fresenius 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. IV. IV.1 CLINICAL ASPECTS Introduction This is a generic product; therefore, new clinical studies are generally neither required nor submitted. 3
No bioequivalence study has been performed. IV.2 Pharmacokinetics The active pharmacological ingredient is cholecalciferol, known as vitamin D, which is widely used in Europe with a well-characterised safety profile. It has a well-established medicinal use in the meaning of Commission Directive 2001/83/EC, with recognised efficacy and an acceptable level of safety. Colecalciferol Fresenius is identical to its reference medicinal product Oleovit D3 Tropfen, which has been approved in Austria on 11 March 1960. Since there is no risk of bioinequivalence between identical medicinal products. a bioequivalence study has not been considered necessary. IV.3 Pharmacodynamics Cholecalciferol belongs to the following ATC code: A11CC05, in the group of vitamin D and analogues. Abundant data on cholecalciferol s clinical pharmacodynamics are available in the public literature. The applicant has not provided additional studies and further studies are not required. IV.4 Clinical efficacy / clinical safety No new efficacy or safety data have been submitted and none were required for this generic application. IV.5 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 Colecalciferol Fresenius 14.400 I.E./ml Tropfen zum Einnehmen, Lösung. Summary of safety concerns as approved in RMP version 1.3 with data lock point 28.07.16; date of final sign off 28.11.2016 4
Summary of pharmacovigilance activities Additional pharmacovigilance requirements are not considered necessary. Routine pharmacovigilance activities are considered sufficient at the moment. Summary of risk minimisation measures 5
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- If applicable: Table of Ongoing and Planned Additional Pharmacovigilance Studies / Activities in the Pharmacovigilance Plan as approved in RMP not applicable IV.6 Discussion on the clinical aspects The clinical overview on the clinical pharmacology, efficacy and safety is adequate. 13
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. 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. The test consisted of: a pilot test with 3 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The pharmaceutical quality of Colecalciferol Fresenius has been adequately shown. There are no non-clinical or clinical concerns. The benefit/risk relation is considered positive. 14
Public Assessment Report Update Colecalciferol Fresenius 14.400 I.E./ml Tropfen zum Einnehmen, Lösung COLECALCIFEROL AT/H/0578/001/DC This module reflects the procedural steps and scientific information after the finalisation of the initial procedure. 15
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) 16