Decentralised Procedure

Public Assessment Report

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze

Midazolam

DE/H/5442/001/DC

Applicant: Desitin Arzneimittel GmbH, Germany

Date: 14.03.2019

This module reflects the scientific discussion for the approval of Desiject 5 mg/ml Injektionslösung in einer Fertigspritze. The procedure was finalised on 13.12.2018.

TABLE OF CONTENTS

I INTRODUCTION ...... 4 II EXECUTIVE SUMMARY ...... 4 II.1 PROBLEM STATEMENT...... 4 II.2 ABOUT THE PRODUCT ...... 4 II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER ...... 4 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES ...... 4 III SCIENTIFIC OVERVIEW AND DISCUSSION ...... 5 III.1 QUALITY ASPECTS ...... 5 III.2 NON CLINICAL ASPECTS ...... 5 III.3 CLINICAL ASPECTS ...... 5 IV BENEFIT RISK ASSESSMENT ...... 9

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze, DE/H/5442/001/DC Public AR 2/9

ADMINISTRATIVE INFORMATION Name of the medicinal product in the Desiject 5 mg/ml Injektionslösung in einer Fertigspritze RMS Name of the drug substance (INN Midazolam name): Pharmaco-therapeutic group N03AE (ATC Code): Pharmaceutical form(s) and Solution for injection in pre-filled syringe; 5 mg/ml strength(s): Reference Number(s) for the DE/H/5442/001/DC Decentralised Procedure Reference Member State: DE Concerned Member States: Withdrawn: LU Legal basis of application: Art. 10(3) of Dir. 2001/83/EC Applicant (name and address) Desitin Arzneimittel GmbH Weg beim Jäger 214 22335 Hamburg Germany

Names and addresses of all proposed hameln rds a.s. manufacturer(s) responsible for Horná 36 batch release in the EEA 900 01 Modra Slovakia

Siegfried Hameln GmbH Langes Feld 13 31789 Hameln Germany

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze, DE/H/5442/001/DC Public AR 3/9

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Desiject 5 mg/ml Injektionslösung in einer Fertigspritze for the treatment of acute prolonged convulsive seizures lasting > 5 min (corresponding to early status epilepticus) in adults is approved.

II EXECUTIVE SUMMARY Problem statement N/A

About the product Midazolam is a short-acting benzodiazepine incorporating an imidazole ring fused in position 1, 2 which confers higher basicity and, hence, the capacity to form salts with hydrochloric, maleic or lactic acid that are readily water soluble with acceptable stability at pH 4 and below. It also contains fluorine at position 2 of the phenyl group. Midazolam is a potent sedative agent that requires titration and slow administration. Titration is strongly recommended to safely obtain the desired level of sedation according to the clinical need, physical status, age and concomitant medication.

Midazolam is currently indicated in adults for  conscious sedation (before and during diagnostic or therapeutic procedures with or without local anaesthesia)  anaesthesia (premedication before induction of anaesthesia, induction of anaesthesia and as a sedative component in combined anaesthesia)  sedation in intensive care units The same indications have been also approved for children, except that midazolam is not indicated for “induction of anaesthesia” and “as a sedative component in combined anaesthesia” in children. Different from these indications approved for the reference product, the indication proposed for “Desiject 5 mg/ml Injektionslösung in einer Fertigspritze” is "treatment of acute prolonged convulsive seizures lasting >5 min (corresponding to early status epilepticus) in adults”. In addition, the pharmaceutical form “pre-filled syringe” of the concerned generic product differs from that of the reference product, which is a solution for injection, infusion or rectal administration. All other parameters like active substance, strength and intramuscular route of administration are comparable to the reference product.

General comments on the submitted dossier This decentralised application in accordance with Art. 10(3) of Dir. 2001/83/EC as amended concerns a generic version of midazolam hydrochloride. The originator product is “Dormicum 5 mg/ml solution for injection” by Roche Pharma AG, authorised in Germany since 22nd December 1998 (German MA no. 41119.00.00). Hence, data protection has expired and generic successors can be licensed. With Germany as the Reference Member State in this Decentralized Procedure, Desitin Arzneimittel GmbH, Hamburg, Germany, is applying for the Marketing Authorisation of Desiject 5 mg/ml Injektionslösung in einer Fertigspritze in DE. LU was withdrawn.

General comments on compliance with GMP, GLP, GCP and agreed ethical principles The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. GMP active substance Regarding the statement on GMP for the active substance a statement/declaration is provided from the

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze, DE/H/5442/001/DC Public AR 4/9 manufacturer responsible for manufacture of the finished product and batch release situated in the EU.

III SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug Substance The active substance Midazolam is described in the European Pharmacopoeia. The quality of the drug substance Midazolam is controlled in compliance with the corresponding Ph. Eur. monograph. The suitability of the monograph to test the drug substance has been verified by EDQM and is documented by the issue of a certificate of suitability. The declared re-test period of the API is 5 years when stored in a double polyethylene bag in an aluminium bag placed in a fiberboard drum.

Drug Product The drug product is presented as a solution for intramuscular injection in a pre-filled syringe with 2 ml solution of Midazolam with a concentration of 5 mg/ml. Excipients are water for injections and sodium chloride as well as HCl for pH adjustment, all of which are of Ph. Eur. quality. Process validation has been performed on three pilot scale batches. Since a standard process is used, process validation data on production scale batches should be supplied post approval. Release and shelf-life specifications include the required tests relevant to this dosage form. The analytical test methods used for analysing drug product have been adequately described and validated. Stability data of pilot scale batches are presented up to 2 years at long term storage conditions, up to 1 year at intermediate storage conditions and up to 6 months at accelerated storage conditions. The storage conditions chosen for the stability studies are those of the general case. An alternative approach to determining water loss at reference relative humidity through calculation from higher relative humidity according to stability guideline ICH Q1A (R2) is applied. The stability results provided justify the proposed shelf life of 2 years. The need of the labelled storage condition “Keep the pre- filled syringe in the outer carton to protect from light” has been justified by results of photostability studies.

Non clinical aspects Pharmacological and toxicological properties of midazolam are generally considered well known. The non-clinical overview has been revised which is acceptable. The instructions on use of midazolam during pregnancy and lactation as well as the preclinical safety and fertility data have been revised in accordance with the more applicable instructions of “Buccolam” (EMEA/H/C/2267-IAIN/36) as indicated in the separately enclosed documents.

Environmental Risk Assessment (ERA) The applicant provided a Phase I ERA in accordance with the guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 Corr 2.). The PECsurface water has been calculated taking into account a refined market penetration factor Fpen, based on the incidence data for status epilepticus in Germany and the treatment regimen as per SmPC. The resulting PECsurface water is 0.000002 µg/l that is below the action limit of 0.01 µg/l. Hence, a Phase II assessment is not necessary. Furthermore, the applicant agreed to submit an experimental study on the n-octanol/water partition coefficient (logKow) as post-authorisation measure. A final conclusion on the environmental risk of midazolam cannot be drawn until the study on logKow has been provided to allow for the assessment of the PBT properties of midazolam.

Clinical aspects Pharmacokinetics The product being subject of this procedure is an aqueous solution in a pre-filled syringe and intended for i.m. application. Test and reference product contain the same substance in the same concentration. In addition, both products contain the same excipients in very similar quantity. Therefore, BE studies can be waived.

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze, DE/H/5442/001/DC Public AR 5/9

After intramuscular injection, absorption of midazolam from the muscle tissue is rapid and complete. Maximum plasma concentrations are reached within 30 minutes. The absolute bioavailability after intramuscular injection is over 90%. When midazolam is injected intravenously, the plasma concentration-time curve shows one or two distinct phases of distribution. The volume of distribution at steady state is 0.7-1.2 l/kg. 96-98 % of midazolam is bound to plasma proteins. Midazolam is almost entirely eliminated by biotransformation. Midazolam is hydroxylated by the cytochrome P4503A4 isozyme. The major metabolite alpha- hydroxymidazolam is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam. In healthy volunteers, the elimination half-life of midazolam is between 1.5 -2.5 hours. Midazolam is excreted mainly by renal route (60-80% of the injected dose) and recovered as glucuroconjugated alpha-hydroxymidazolam. The elimination half-life of alpha- hydroxy-midazolam is shorter than 1 hour. Midazolam is a derivative of the imidazobenzodiazepine group. The free base is a lipophilic substance with low solubility in water. The basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables midazolam to form water-soluble salts with acids. These produce a stable and well tolerated injection solution.

Pharmacodynamics The pharmacological action of midazolam is characterised by short duration because of rapid metabolic transformation. Midazolam has a sedative and sleep-inducing effect of pronounced intensity. It also exerts an anxiolytic, an anticonvulsant and a muscle-relaxant effect.

Clinical efficacy Different from the reference medicinal product Dormicum the proposed indication for the intended product Desiject 5 mg/ml Injektionslösung in einer Fertigspritze is acute prolonged convulsive seizures lasting > 5 min (corresponding to early status epilepticus) in adults. Prolonged convulsive seizures lasting longer than 5 minutes represent a medical emergency and failure to achieve control of seizures is associated with significant morbidity and mortality. Benzodiazepins are generally accepted as treatment of first choice in convulsive SE and intravenous lorazepam became widely regarded as optimal first-line treatment [e.g. Leitlinie für Diagnostik und Therapie in der Neurologie. Status epilepticus im Erwachsenenalter, 2012; Meierkord, 2010]. In Germany intravenous clonazepam and intravenous/rectal diazepam are also approved for initial treatment of SE in adults. In the emergency setting the intravenous route of benzodiazepines is the most suitable, reliably delivering adequate quantities of active substance as fast as possible, however, obtaining an intravenous line in a convulsing patient can be very challenging. In order to allow for treatment that does not require IV access or administration by trained medical staff, rectal diazepam is approved in adults and children for treatment of SE, further oromucosal midazolam is approved in children (aged 3 months to < 18 years) for the treatment of prolonged, acute, convulsive seizures. The main study submitted in support of the newly proposed epilepsy indication for intramuscular midazolam is the RAMPART trial (Silbergleit, 2012), a randomized, active controlled, double-blind, non-inferiority clinical trial in children and adults treated by paramedics in the pre-hospital setting for seizures lasting longer than 5 minutes. Beyond published information relating to the Rampart study, the applicant has evaluated the trial protocol, statistical analysis plan and extensive data listings of this study and provided further comprehensive analyses thereof (including analyses by age groups and by actual study drug treatment with/without rescue medication), hereby corroborating the robustness of the Rampart study. In the Rampart study, the primary efficacy endpoint, i.e. absence of seizures at the time of arrival in the emergency department without rescue therapy, was reached by 73.4% (329 of 448) subjects in the IM midazolam group compared to 63.4% (282 of 445) in the IV lorazepam group (absolute difference: 10 percentage points in favour of IM midazolam, 95% confidence interval: 4.0-16.1; P<0.001 for both non-inferiority and superiority). Whereas these numbers seem to imply superiority of IM midazolam to IV lorazepam, there are some uncertainties pertaining to the use of an autoinjector in the Rampart study as well as the fixed sequence of the study drug administration which preclude conclusion of superiority of IM midazolam.

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze, DE/H/5442/001/DC Public AR 6/9

As the positive results regarding IM midazolam found in the Rampart trial are considered to be dependent to a considerable extent from the possibility of fast IM administration of midazolam, which was accelerated by means of usage of an autoinjector, the Rampart study results can not readily be extrapolated to IM administration of midazolam from a vial containing midazolam solution. Nevertheless, compared to administration via autoinjector the use of the intended prefilled syringe is also considered to allow for a relatively fast intramuscular drug administration, such that a possible time delay without autoinjector is considered very low. Further, with regard to a possible bias due to the fixed sequence of study drug administration, sensitivity analyses performed by the applicant provided reassurance, that the conclusion of non- inferiority of IM-midazolam to IV-lorazepam still holds when different time to administration between IV and IM group is taken into account. It is therefore concluded that IM midazolam is at least non-inferior compared to IV lorazepam in early SE in adults.

Efficacy by age group The study was not powered for evaluation by age subgroups nevertheless, efficacy results regarding non-older adults were also rather clearly in favor of IM midazolam. Although in older adults responsiveness to study treatment was lower in both treatment groups, the respective results were numerically also in favor of IM midazolam and the respective difference was of a similar magnitude as the overall study results for all ages combined. Of the submitted supportive studies only the Clemency (2015) study evaluated IM midazolam in the adult SE population. Similar success rates for pre-hospital seizure cessation for IV diazepam, IV midazolam or IM midazolam were reported, however, the study was a retrospective chart review. Across the 4 prospective, controlled supportive trials studying IM midazolam in SE, a shorter time to study drug administration and seizure cessation after IM midazolam compared to respective control treatment was described, however all of these 4 trials were unblinded and were performed exclusively in children. The contribution of the supportive studies, which were unblinded or a retrospective chart review, to proof of efficacy within different age groups in the now claimed epilepsy indication is thus limited.

Clinical safety The safety profile of midazolam i.m. in the currently approved sedative and anaesthetic indications is well established. The main adverse effects relevant to the now claimed epilepsy indication include cardiorespiratory adverse events (respiratory depression, apnoea, respiratory arrest and/or cardiac arrest, hypotension, bradycardia, vasodilating effects), anterograde amnesia, and paradoxical reactions. In the established indications, precautions are required for patients with impaired respiratory function or cardiovascular instability and adults over 60 years of age, as life-threatening cardio-respiratory incidents are more likely in these patient groups. With respect to the newly sought epilepsy indication, the most relevant safety information is provided by the Rampart study (as published by Silbergleit, 2012). In this study 443 ITT subjects actually received IM midazolam and 297 received IV lorazepam. In general a similar safety profile for the IM midazolam group compared to the IV lorazepam group was described in the Rampart study. The treatment groups including all ages combined were similar with respect to need for endotracheal intubation (14.1% of subjects with IM-midazolam and 14.4% with IV- lorazepam), recurrence of seizures (11.4% and 10.6%, respectively), and occurrence of hypotension (2.7 and 2.9%, respectively); hospitalization and ICU-admission tended to be less frequent with IM- midazolam; injection/application site reactions were rare, but tended to be slightly more frequent with IM-midazolam (0.9% and 0.5%, respectively).

With regard to safety in older adults, there appeared a clear trend towards higher proportions of patients with AEs (71.7% vs. 55.9%), SAEs (50.0% vs. 38.2%) and AEs leading to ETI (37.0% vs. 23.5%) in in the active midazolam compared to the active lorazepam group (without rescue medication; comparable results were found in respective patients who additionally received rescue medication as well as in the analyses of related AEs/SAEs/AEs, leading to ETI). The proposed midazolam dose for acute prolonged convulsive seizures (> 5min) in (non-older) adults of 10 mg midazolam i.m. is in line with the posology used in the Rampart trial in adults. 10 mg is

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze, DE/H/5442/001/DC Public AR 7/9 within the approved dose range of midazolam solution in the hitherto approved indications as a sedative and anaesthetic. Based on the known safety profile of midazolam in older patients in the established indications and respective recommendations of lower midazolam doses, the safety findings of the Rampart study in older adults, as well as similar approaches in older SE patients for authorized benzodiazepines, the applicant’s proposal to start treatment in older patients with 5 mg IM midazolam and to repeat this treatment if required (adding up to a total dose of 10 mg midazolam as used in the Rampart study) is therefore considered a reasonable approach.

No new safety concerns arose from the submitted supportive studies.

Legal Status Medicinal product subject to medical prescription, which may not be renewed.

User Testing Besides the Status epilepticus indication claimed in the current DCP, the tested PL also contains the established midazolam indications. Nevertheless, readability of this more extensive and complicated PL has been demonstrated. Compared to the intended PL, the tested PL further differed with regard to the pharmaceutical form, i.e. instead of the intended solution for injection in a pre-filled syringe, the pharmaceutical form of the tested PL is a solution for injection (in a vial). However, as the intended route of injection as well as administration site (i.m. injection into the mid-outer thigh) are the same and the medicinal product is administered by medical professionals only, the difference in pharmaceutical form of tested and intended PL is not considered to constitute a problem regarding readability by patients. Overall, the test methodology follows the guidelines of the European commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009;Update of Directive 2001/83/EC as amended by Directive 2004/27/EC/Guidance concerning consultations with target patient groups for the packet leaflet, May 2006). During both main test rounds, 100% of participants were able to locate the correct information, and 100% of participants were able to answer all questions correctly. The general impression of the PL (content, language and layout) was mainly positive. In conclusion the user test is considered acceptable.

Summary Pharmacovigilance system The Applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

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 Desiject 5 mg/ml Injektionslösung in einer Fertigspritze.

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze, DE/H/5442/001/DC Public AR 8/9

Summary of safety concerns The Applicant provided the following summary of safety concerns:

Summary of safety concerns Important identified risks  None Important potential risks  None Important missing information  None

Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account: • PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. • For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. • In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

IV BENEFIT RISK ASSESSMENT Bioequivalence of the intended midazolam 5 mg/ml solution with reference product Dormicum 5 mg/1 ml can be concluded. The benefit-risk profile of the intended Desiject 5 mg/ml in a prefilled syringe in the indication of acute prolonged convulsive seizures lasting > 5 min (corresponding to early status epilepticus) in adults is considered positive. The application is approved. For intermediate amendments see current product information.

Desiject 5 mg/ml Injektionslösung in einer Fertigspritze, DE/H/5442/001/DC Public AR 9/9