Public Assessment Report. Scientific discussion. Propofol Hospira 10 mg/ml emulsion for injection/infusion. (Propofol) DK/H/2311/001/DC

Transcription

1 Public Assessment Report Scientific discussion Propofol Hospira 10 mg/ml emulsion for injection/infusion (Propofol) DK/H/2311/001/DC 18 September 2015 This module reflects the scientific discussion for the approval of Propofol Hospira. The procedure was finalised on 4 September 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 Propofol Hospira 10 mg/ml emulsion for injection/infusion, from Hospira UK Limited. The product is indicated for: Induction and maintenance of general anaesthesia in adults and children over 1 month. Sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults and children over 1 month. Sedation of ventilated patients over 16 years of age in the intensive care unit. A comprehensive description of the indications and posology is given in the SmPC. Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action of approximately 30 seconds. Recovery from anaesthesia is usually rapid. The mechanism of action, like all general anaesthetics, is poorly understood. However, propofol is thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAA receptors. This decentralised procedure concerns a generic application claiming essential similarity with the reference product Diprivan 10 mg/ml emulsion for injection/infusion which has been registered in Denmark by AstraZeneca A/S since The MAH has referred to the concept of a European Reference Product (ERP) in a number of Concerned Member States. The product referred to is Diprivan 10 mg/ml emulsion for injection/infusion from Denmark. The use of the European Reference Product is justified. The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Each ml of emulsion for injection/infusion contains 10 mg of propofol. Hence, each 20 ml vial contains 200 mg of propofol, each 50 ml vial contains 500 mg of propofol and each 100 ml vial contains 1000 mg of propofol. The product is a white or slightly off- white emulsion, having a milk-like appearance with no evidence of oiling-out of the emulsion and free from visible particulate. The product is packed in 20 ml, 50 ml or 100 ml Type I clear glass vials with bromobutyl rubber stoppers and aluminium seals in pack sizes of 1, 5, 10 or 20 vials per carton or tray. However, not all pack sizes may be marketed. The excipients are: Soya-bean Oil, Refined; Egg Phospholipids; Glycerol; Sodium Hydroxide and Water for Injections 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 manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. 2/7

3 II.2 Drug Substance The active substance propofol is described in the European Pharmacopoeia. Molecular structure: Propofol is sourced from two separate suppliers. The EDQM has certified that the quality of the active substance from the active substance manufacturers is adequately controlled by the Ph. Eur. monograph. Valid Certificates of Suitability have been provided for both manufacturers. The control tests and specifications for drug substance product are in line with the Ph. Eur. monograph for propofol. Additional stability studies have not been performed by the applicant. Reference is made to the stability data provided by the ASMs. No significant changes in any parameters have been observed. Based on the stability data presented, appropriate re-test periods have been set. II.3 Medicinal Product The drug product is an unpreserved, milky-white, isotonic oil in water emulsion for infusion or injection terminal sterilised in its intended container. The development of the qualitative and quantitative composition of the drug product has been adequately described, the choice of excipients has been justified and their functions explained. Acceptable process validation data have been provided for the manufacturing process of the proposed batch size. The drug product specifications cover appropriate parameters for this dosage form. The analytical methods and specifications for the drug product have been adequately drawn up. Suitable validation data of the analytical methods have been presented. Batch analysis has been performed on 4 batches of each fill size. The batch analysis results show that the finished products meet the proposed specification. The conditions used in the stability studies are according to the ICH stability guideline. The acceptable shelf-life/storage conditions are as follows: Shelf-life/storage conditions: 2 years. Do not freeze. Shelf-life after first opening: The product should be used immediately after first opening. Shelf-life after dilution: Chemical and physical in-use stability has been demonstrated for not more than 6 hours at 25 C. 3/7

4 III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of propofol are well known. As propofol is a widely used and well-known, the MAH has not provided additional studies and none are required. An overview based on a literature review is therefore appropriate. The non-clinical overview report refers 52 publications up to year The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Propofol Hospira 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. CLINICAL ASPECTS IV.1 Introduction Propofol is a well-known active substance with established efficacy and tolerability. As propofol is a widely used, well-known active substances, the MAH has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. The clinical overview report refers 88 publications up to year The clinical overview on the clinical pharmacology, efficacy and safety is adequate. IV.2 Pharmacokinetics This medicinal product is an emulsion for injection/infusion. No bioequivalence studies have been presented in support of the application. According to the bioequivalence guideline (CPMP/EWP/QWP/1401/98 Rev. 1), this dosage form is not normally qualified for a biowaiver but may be considered eligible for a biowaiver provided that a) the product is not designed to control release or disposition and b) the method and rate of administration is the same as the currently approved product. For the two points the composition of the applied and approved products should be the same qualitatively and quantitatively in addition to having very similar physicochemical properties. Biowaiver of Propofol Hospira is acceptable based on similar physico-chemical characteristics of the Hospira product and the Diprivan brand leader product. 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 Propofol Hospira. 4/7

5 Table 1. Summary table of safety concerns as approved in RMP Summary of safety concerns Important identified risks Important potential risks Missing information Misuse of propofol Reduced clearance in patients with impaired cardiac, respiratory, renal or hepatic function and to hypovolaemic or invalid patients Bradycardia (at times severe) and asystole Seizures in patients with epilepsy Patients with disorders of lipid metabolism Propofol infusion syndrome Hypotension Airway obstruction Oxygen desaturation Severe cardiovascular depression in children Involuntary movements Postoperative unconsciousness Growth of micro-organisms Off-label use for sedation in children under 16 years of age Use in children/neonates (potential for significantly reduced clearance and overdose) Use in pregnancy Table 2. Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP Safety concern Routine risk minimisation measures Important identified risks Misuse of propofol Warning in SmPC Section 4.4 None Reduced clearance in patients with impaired cardiac, respiratory, renal or hepatic function and to hypovolaemic or invalid patients Warning in SmPC Section 4.4 None Bradycardia (at times severe) Warning in SmPC Section 4.4 None and asystole Seizures in patients with Warning in SmPC Section 4.4 None epilepsy Patients with disorders of lipid Warning in SmPC Section 4.4 None metabolism Propofol infusion syndrome Warning in SmPC Section 4.4 None Hypotension Warning in SmPC Section 4.4 None Airway obstruction Warning in SmPC Section 4.4 None Oxygen desaturation Warning in SmPC Section 4.4 None Severe cardiovascular Warning in SmPC Section 4.4 None depression in children Important potential risks Involuntary movements Warning in SmPC Section 4.4 None Postoperative unconsciousness Warning in SmPC Section 4.4 None 5/7 Additional risk minimisation measures

6 Growth of micro-organisms Warning in SmPC Section 4.4 None Off-label use for sedation in Warning in SmPC Section 4.4 None children under 16 years of age Missing information Use in children/neonates Warning in SmPC Section 4.4 None (potential for significantly reduced clearance and overdose) (&Pharmacokinetic data in Section 5.2) Use in pregnancy Warning in SmPC Section 4.6 None The above safety concerns are agreed upon with no additional pharmacovigilance or risk minimisation measures. 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 4 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 Propofol Hospira 10 mg/ml emulsion for injection/infusion has a proven chemical-pharmaceutical quality and is a generic form of Diprivan. Diprivan is a well-known medicinal product with an established favourable efficacy and safety profile. Since both the reference and current product are intended for parenteral use, no bioequivalence study is deemed necessary. The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Propofol Hospira with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 4 September Propofol Hospira was authorised in Denmark on 18 September According to the List of Union reference dates and frequency of submission of periodic safety update reports (PSURs), the PSUR submission cycle is 5 years. The first data lock point for Propofol Hospira is 7 November The date for the first renewal will be: 4 September /7

7 The following post-approval commitments have been made during the procedure: The MAH commits to update the PI in accordance with the core safety profile of propofol, if necessary. This update should be submitted via the appropriate variation within 2 months from the finalisation of NO/H/PSUR/0009/002. 7/7