Decentralised Procedure

Public Assessment Report

Silento / Pentoxyverin AL 1,35 mg/ml Lösung zum Einnehmen

Pentoxyverine

DE/H/4535-36/001/DC

Applicant: STADA Arzneimittel AG

Date: 15.08.2017

Reference Member State DE

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 ...... 4 III.1 Quality aspects...... 4 III.2 Non-clinical aspects...... 5 III.3 Clinical aspects ...... 6 IV. BENEFIT RISK ASSESSMENT ...... 8

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal Silento / Pentoxyverin AL product in the RMS 1,35 mg/ml Lösung zum Einnehmen

Name of the drug substance (INN Pentoxyverine name): Pharmaco-therapeutic group R05DB05 (ATC Code): Pharmaceutical form(s) and Oral solution, 2.13 mg/ml pentoxyverine hydrogen citrate strength(s): (corresponding to 1.35 mg/ml pentoxyverine)

Reference Number(s) for the DE/H/4535-36/001/DC Decentralised Procedure Reference Member State: DE DE/H/4535/001/DC: SK Concerned Member States: DE/H/4536/001/DC: LU, withdrawn STADA Arzneimittel AG Applicant (name and address) Stadastr. 2-18 D-61118 Bad Vilbel Names and addresses of all proposed STADA Arzneimittel AG manufacturer(s) responsible for batch Stadastr. 2-18 release in the EEA D-61118 Bad Vilbel

I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Silento / Pentoxyverin AL 1,35 mg/ml Lösung zum Einnehmen, in the treatment for short-term use for the treatment of dry cough, and in general, the duration of use must not exceed 2 weeks (see SmPC section 4.2), is approved.

II. EXECUTIVE SUMMARY II.1 Problem statement It is a generic application and the originator product is Pertix-Solo N Saft with the German application number: 6298063.00.00, registered since 25.05.1999; 21.3 ml Pentoxyverincitrate/10 ml. The dosage regimen, age classes and indication wording are adapted to this reference product. The marketing authorization holder is Boehringer Ingelheim Pharma GmbH & Co. KG.

II.2 About the product With Germany as the Reference Member State in this Decentralized Procedure, STADA Arzneimittel AG is applying for the Marketing Authorisations for Silento / Pentoxyverin AL 1,35 mg/ml Lösung zum Einnehmen in LU (for Pentoxyverin AL 1,35 mg/ml Lösung zum Einnehmen) and SK (for Silento 1,35 mg/ml Lösung zum Einnehmen). Pentoxyverine is an antitussive and belongs to the ATC-Code R05DB05. Pentoxyverine is a non- narcotic, centrally acting cough suppressant which has a specific effect on the cough reflex. It reduces the overstimulation of the cough centre and normalises its function. It is used for short-term use in the treatment of dry cough and the status is non-prescription.

II.3 General comments on the submitted dossier The clinical overview on the clinical pharmacology, efficacy and safety (with module 5) is adequate so far. The clinical overview refers to 27 publications up to year 2015.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles No clinical studies have been provided, because a waiver can be accepted as it is a solution with the same concentration of the active substance and the critical excipient sorbitol. The RMS has been assured that acceptable standards of GMP are in place for these product types at Stada Arzneimittel AG, Germany (site responsible for manufacture of bulk product, packaging, batch control and batch release). The RMS has accepted a copy of the current manufacturer authorisation as certification that acceptable standards of GMP are in place at this site. A new declaration of the Qualified Person of Stada Arzneimittel AG concerning GMP compliance for the active substance from the ASM has been provided. This QP declaration is accepted.

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Pentoxyverine hydrogen citrate is a known active substance which is covered by a Ph. Eur. monograph. The ASMF procedure is used. A Letter of Access has been provided. The applicant´s part of the current version of the ASMF is included in the quality dossier of the DCP procedure. Details of the manufacturing process are presented in the restricted part of the ASMF. The starting materials for the manufacture of the active substance have been re-defined and are acceptable. The ASMF has been revised accordingly. A new QP declaration has been provided. The structure of the active substance has been confirmed by the ASM. The active substance is specified and tested by the ASM according to the Ph. Eur. monograph for pentoxyverine hydrogen citrate. Additionally, residual solvents and several additional in-house impurities are specified. The analytical procedure of the ASM for residual solvents and for the additional in-house impurities are described and validated. The specification of the drug product manufacturer for the active substance is in line with the specification of the ASM. Compliant batch data of the ASM and the drug product manufacturer are provided. The compliant 18 long-term stability data at 25°C/60% RH and the compliant 6 months accelerated stability data at 40°C/75% RH justify the proposed retest period of 24 months.

Silento / Pentoxyverin AL 1,35 mg/ml Lösung zum Einnehmen, DE/H/4535-36/001/DC Public AR 4/8

Drug Product The drug product is a clear, colourless to yellowish oral solution which contains 2.13 mg/ml pentoxyverine hydrogen citrate (corresponding to 1.35 mg/ml pentoxyverine) as active substance. The oral solution is presented in a multi-dose bottle and is preserved with methyl parahydroxybenzoate and propyl parahydroxybenzoate. Propylene glycol, glycerol 85% and purified water are used as solvents. Sorbitol liquid (70%, non-crystallising) and saccharin sodium are used as sweetening agents. The buffer system consists of citric acid monohydrate and sodium citrate. Strawberry flavour is used for improving the compliance of the patients. The aim of the development of the drug product was to formulate a chemically and physically stable oral solution as a generic product of the reference medicinal product; i.e. with a formulation similar to the reference product. The development is briefly described. A comparison of the physico- chemical properties of the reference product and the test product has been conducted. The waiver regarding a BE study can be accepted from the quality point of view. The use of the preservatives at the chosen concentrations can be accepted in the generic product since the reference product contains the same preservatives in the same concentrations and since the generic product has the same patient groups and the same posology as the reference product. The drug product is filled in amber glass bottles (hydrolytic class type III) which are closed with a child-resistant screw cap. A measuring pipette and a measuring cup are provided with each package, permitting to dose the required volumes. The test according to Ph. Eur. 2.9.27 with the pipette and the measuring cup was compliant for each single dose volume stated in the SmPC. The efficacy of the antimicrobial preservation was confirmed according to Ph. Eur. 5.1.3 on the formulation intended for marketing and on a formulation containing only 90% preservatives. The manufacturing process and in-process controls are described. The manufacturing process has been validated with three full-scale production batches. The holding conditions of the bulk solution are described and justified. The release and shelf-life specification are provided. The analytical procedures are described and validated. The information concerning the container closure system and the measuring devices is regarded as sufficient. The measuring cup and the pipette comply with medical device directive 93/42/EEC. Due to the compliant 12 months long-term and intermediate stability data (at 25°C/60% RH and 30°C/65% RH) of three production-scale stability batches as well as due the compliant 6 months accelerated stability data (40°C/75% RH) of the stability batches, a shelf-life of 2 years of the finished drug product without temperature storage conditions is accepted. The in-use shelf-life of 12 months is accepted.

III.2 Non-clinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of pentoxyverine are well known. As pentoxyverine 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 refers 25 publications, including excerpts from standard text and reference books, up to year 2015. The non-clinical overview on pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

Environmental Risk Assessment (ERA) This is a generic application and consumption data for Germany were provided showing no increase. However, in Slovakia the active substance pentoxyverine is not on the market yet and consequently, an increase in consumption and environmental exposure is to be expected. Therefore, an ERA in accordance with the Guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 Corr 2) is deemed necessary. A Phase I PEC calculation was performed, resulting in a PECsurfacewater of 0.6 µg/l that exceeds the trigger of 0.01 µg/l for a Phase II environmental risk assessment. Furthermore, a logKow of 4.23 was cited that was calculated with EPISuite. However, a Phase II ERA has not been provided nor an experimentally derived logKow as indicated by the respective document on Questions and answers on 'Guideline on the environmental risk assessment of medicinal products for human use' (EMA/CHMP/SWP/44609/2010 Rev. 1.)

Silento / Pentoxyverin AL 1,35 mg/ml Lösung zum Einnehmen, DE/H/4535-36/001/DC Public AR 5/8

The applicant commits to provide an experimentally derived logKow (according OECD 117) as post- authorisation measure in order to complete the already submitted Phase I ERA. Based on the results of the completed Phase I ERA the performance of subsequent studies according to the EMA guideline EMEA/CHMP/SWP/4447/00 will be evaluated. The RMS agreed to the outlined commitment.

III.3 Clinical aspects Pharmacokinetics/Pharmacodynamics Absorption Following an oral dose, pentoxyverine is absorbed relatively quickly from liquid preparations in conjunction with a rapid onset of effect after 10 to 20 minutes. The peak plasma concentration is achieved within 2 hours (tmax between 0.5 and 2 hours). The absorption from liquid formulations is slightly faster than from tablets (mean t 0.9 vs. 1.2 h).

Distribution There is no human data available on tissue distribution. The distribution volume is approximately 10 l/kg. The extent of protein binding is unknown.

Biotransformation In vitro studies have shown that pentoxyverine is primarily metabolised via cytochrome P450 2D6, and to a lesser extent via P450 3A4, as well as hepatic esterases. A relevant effect on the CYP enzyme catalysed metabolism of simultaneously administered drugs is unlikely. The main metabolites that have been detected are N-desethyl pentoxyverine and 1-phenyl-cyclopentane carboxylic acid.

Elimination The elimination half-life in adults is 2 hours (mean half-life t1/2 = 2.3 hours). The half-life found for adults corresponds to that of the estimated value of approximately 2 to 3 hours deduced from the duration of action (5 to 6 hours), while in neonates the elimination appears to be greatly delayed.

The proposed waiver for own clinical studies can be accepted, as it is a solution with the same concentration of the active substance and the critical excipient sorbitol. (More details see quality part (dissolution profiles).

Clinical efficacy No own studies have been provided. The waiver is accepted, as it is a solution with the same concentration of the active substance and the same critical excipient sorbitol as the originator product (Pertix-Solo N Saft).

Declaration of the applicant: According to the most recent version of the CHMP ”Guidance on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev. 1/corr**): “A waiver of the need to provide equivalence data may be acceptable in the case of solution, e.g. eye drops, nasal sprays or cutaneous solutions, if the test product is the same type of solution (aqueous or oily), and contains the same concentration of then same active substance as the medicinal product currently approved. Minor differences in the excipient composition may be acceptable if the relevant pharmaceutical properties of the test product and the reference product are identical or essentially similar.” Pentoxyverine 30 mg/ml liquid drops and Pentoxyverin 2.13 mg/ml syrup have been developed as generic medicinal products with reference to Silomat® gegen Reizhusten, Pentoxyverin Tropfen and Silomat® gegen Reizuhusten, Pentoxyverin Saft and have identical formulations with respect to both the active agent and the excipients. There is only a minor difference in the kind of the flavouring.

Qualitative properties of Pentoxyverine 30 mg/ml liquid drops and Pentoxyverine 2.13 mg/ml syrup have further been compared with those of Silomat® gegen Reizhusten, Pentoxyverin Tropfen and Silomat® gegen Reizhusten, Pentoxyverine Saft. There are no relevant differences in the pharmaceutical quality of the corresponding product.

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The applicant seeks approval for the indication:  For short-term use for the treatment of dry cough.  In general, the duration of use must not exceed 2 weeks (see SmPC section 4.2) This indication is accepted as the wording is in line with the reference product. The posology and method of administration is in line with the reference, too.

Pentoxyverine is an antitussive and belongs to the ATC-Code R05DB05. Pentoxyverine is a non- narcotic, centrally acting cough suppressant which has a specific effect on the cough reflex. It reduces the overstimulation of the cough centre and normalises its function.

Clinical safety N/A

Legal Status In Germany, the product is not under prescription and is a pharmacy medicine.

User Testing The lowest RI rating (finding + understanding) of any requested information was 19/20 (95.0%) for question no. 5, 7 and 14. Even the additionally tested diagram for the application chapter was well understood. This test result meets the corresponding success criteria of the “Guideline on the readability of the labelling and package leaflet of medicinal products for human use”, Annex, 2009 [1]: “A satisfactory test outcome for the method outlined above is when the information requested within the package leaflet can be found by 90% of test participants, of whom 90% can show that they understand it. That means to have 16 out of 20 participants able to find the information and answer each question correctly and act appropriately”. From the RMS’s point of view, the testing can be accepted and the test is assessed as positive. A proportion of 99.1% (317 out of 320) of the requested information was found, only 0.9% was not found. A proportion of 100.0% (320 out of 320) of the requested information was understood. Altogether 317 out of 320 (99.1%) of all requested information were found and understood correctly.

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 applicant 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 Pentoxyverincitrate.

- Summary of safety concerns as accepted Summary of safety concerns Important identified risks  Occurrence of seizures and respiratory depression in infants  Use in patients with increased sensitivity to anticholinergic effects (e.g. patients with glaucoma or benign prostatic hyperplasia)  Effect on the central nervous system (e.g. sedation and respiratory depression)  Reduction of psychomotor performance when taken concomitantly with alcohol  Use during breastfeeding Important potential risks None

Silento / Pentoxyverin AL 1,35 mg/ml Lösung zum Einnehmen, DE/H/4535-36/001/DC Public AR 7/8

Missing information  Use in patients with renal insufficiency  Use in elderly patients  Use in pregnancy  The effect on fertility

There are no additional risk minimisation measures.

An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

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. • For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

IV. BENEFIT RISK ASSESSMENT It is a generic application with a BE waiver applied for, because it is a solution with the same qualitative and quantitative composition of the active substance and there are no differences in the critical excipients. The indication wording and dosage regime is in line with the reference product. From the quality, non-clinical and clinical efficacy point of view the application is approvable and the benefit-risk assessment is positive. The application is approved. For intermediate amendments see current product information.

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