Public Assessment Report. Scientific discussion. Kaliumklorid "EQL Pharma" (Potassium chloride) DK/H/2662/001/DC. Date:

Transcription

1 CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Kaliumklorid "EQL Pharma" (Potassium chloride) DK/H/2662/001/DC Date: This module reflects the scientific discussion for the approval of Kaliumklorid "EQL Pharma". The procedure was finalised on For information on changes after this date please refer to the module Update.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Kaliumklorid EQL Pharma, from EQL Pharma. The product is indicated for: Hypokalaemia. Prevention of hypokalaemia in treatment with diuretics. A comprehensive description of the indications and posology is given in the SmPC. This decentralised procedure concerns a generic application claiming essential similarity with the reference product Kaleorid (MA number in the RMS Denmark: 04936) which has been registered in RMS by LEO Pharma A/S since The applicant has submitted a bioequivalence study in which the pharmacokinetic profile of the product is compared with the pharmacokinetic profile of the reference product Kaleorid, registered in Sweden. This generic product can be used instead of its reference product. The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC. II. II.1 QUALITY ASPECTS Introduction Kaliumklorid "EQL Pharma" prolonged-release tablet contains 750 mg potassium chloride. The film-coated prolonged-release tablets are opaque white to pearl white, oval 16x8 mm, plain tablet. Kaliumklorid "EQL Pharma" is packed in a HDPE bottle with a polypropylene screw cap in pack-sizes of 100 or 250 tablets. However, not all pack-sizes may be marketed. The excipients are Silica Colloidal Anhydrous, Ethylcellulose, Stearyl Alcohol, Hypromellose and Talc. Film-coating: Ethyl cellulose, Medium chain triglycerides, Oleic acid Compliance wih Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacture and assembly of this product prior to granting its national authorisation. II.2 Drug Substance There is a monograph for the active substance potassium chloride in Ph.Eur. A CEP (Certificate of suitability) has been granted for the active ingredient by EDQM (European Directorate for the Quality of Medicines & Health Care). The control tests and specifications for drug substance have been adequately drawn up. PAR Scientific discussion 2/6

3 II.3 Medicinal Product The development of the product has been described, the choice of excipients has been justified and their functions explained. A satisfactory batch formula has been provided for the manufacture of the product along with an appropriate account of the manufacturing process. Process validations have been carried out and the results are satisfactory. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis results have been presented from several batches of both strengths. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The shelf-life of three years without any special storage conditions when stored in HDPE container with a polypropylene screw cap is considered acceptable for the drug product. II.4 Discussion on chemical, pharmaceutical and biological aspects The chemical-pharmaceutical documentation in relation to the active substance and final product are of sufficient quality in view of the present European regulatory requirements. III. III.1 NON-CLINICAL ASPECTS Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of potassium chloride are well known. As potassium chloride 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. The non-clinical overview report refers numerous publications up to year The nonclinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Kaliumklorid EQL Pharma 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. IV. IV.1 CLINICAL ASPECTS Introduction Potassium chloride is a well-known active substance with established efficacy and tolerability. As potassium chloride is a widely used, well-known active substance, the applicant has not PAR Scientific discussion 3/6

4 provided additional studies (apart from a supportive bioequivalence study referenced below) and further studies are not required. Overview based on literature review is, thus, appropriate. The clinical report refers 11 publications up to The clinical overview on the clinical pharmacology, efficacy and safety is adequate. IV.2 Pharmacokinetics For this generic application, the MAH has submitted one bioequivalence study in which the pharmacokinetic profile of the test product Kaliumchlorid EQL Pharma is compared with the pharmacokinetic profile of the reference product <insert name, company and country of origin. Bioequivalence study To support the application the applicant has submitted 1 bioequivalence study (single-dose, 2- way crossover under fasting conditions, based on urinary excretion of potassium) with Kaliumklorid EQL 750mg (x8) prolonged release tablets by EQL Pharma which has been compared to Kaleorid 750mg (x8) prolonged release tablets, LEO from the Swedish market. 42 subjects participated in the study and 42 subjects completed the study and were analysed. Bioequivalence between the test and the reference product has been demonstrated. Results on Primary parameters analysed (Ae0-24 and Rmax) fall within the acceptance range of % for both methods of subtraction of baseline data of potassium excretion, and are within the acceptance range % for results calculated with initial values only (for re-assayed samples) and are within the acceptance range. Conclusion on bioequivalence studies: Based on the submitted bioequivalence study Kaliumklorid EQL Pharma is considered bioequivalent with Kaleorid. 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 Kaliumklorid EQL Pharma. Table 1: Summary of safety concerns Summary of safety concerns Important identified Hyperkalaemia risks a) in patients with renal insufficiency, untreated Addison s disease or severe electrolyte imbalance. b) in patients co-administered with ACE inhibitors, angiotensin-ii-receptor antagonists, ciclosporin, NSAIDs, β-blockers, heparin, digoxin, potassium sparing diuretics. Hypersensitivity Gastrointestinal ulcers Important potential risks Intentional or unintentional overdose of potassium chloride. Increased gastrointestinal adverse effects under coadministration with anticholinergics/antimuscarinics PAR Scientific discussion 4/6

5 Summary of safety concerns Missing information Use of potassium chloride in children The safety concerns are considered satisfactory. Table 2: Summary table of Risk Minimisation Measures Safety concern Hyperkalaemia a) in patients with renal insufficiency, untreated Addison s disease or severe electrolyte imbalance. b) in patients co-administered with ACE inhibitors, angiotensin-iireceptor antagonists, ciclosporin, NSAIDs, β-blockers, heparin, digoxin, potassium sparing diuretics. Routine risk minimisation measures SmPC sections 4.2, 4.3, 4.4, 4.5 & 4.8 Hypersensitivity SmPC sections 4.3 & 4.8 None Gastrointestinal ulcers SmPC sections 4.3, 4.4, 4.6 & None 4.8 Intentional or unintentional SmPC section 4.9 None overdose of potassium chloride. Increased gastrointestinal adverse effects under co-administration with anticholinergics/antimuscarinics SmPC sections 4.4 & 4.8 None Use of potassium chloride in children SmPC sections 4.2, 4.6 & 4.9 Additional risk minimisation measures None None The proposed risk minimisation measures are sufficient to minimise the risks of the product in the proposed indications. 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. The test consisted of: a pilot test with five participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. PAR Scientific discussion 5/6

6 VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Kaliumklorid "EQL Pharma" prolonged-release tablets contains 750 mg potassium chloride. Kaliumklorid EQL Pharma has a proven chemical-pharmaceutical quality and is a generic form of Kaleorid. Kaleorid is a well-known medicinal product with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. The MAH presented a risk management plan summarising the safety concerns. There are no additional pharmacovigilance or risk minimisation measures. Agreement between Member States was reached during a written procedure. There was no discussion in the CMDh. The Member States Concerned, on the basis of the data submitted, considered that essential similarity has been demonstrated for Kaliumklorid EQL Pharma with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on Kaliumklorid EQL Pharma was authorised in Denmark on According to the List of Union reference dates and frequency of submission of periodic safety update reports (PSURs), no routine PSURs are required for this product. The date for the first renewal will be There were no post-approval commitments made during the procedure. PAR Scientific discussion 6/6