Hinnangu kokkuvõte

15.10.2015 anti müügiluba Divapharma GmbH ravimile Neo-Angin Salvia 1.2mg/0.6mg/5.9mg, losengid (suhkruvaba).

Müügiluba taotleti kui olemasoleva müügiloa laiendust rahvusliku protseduuri kaudu.

Tegemist on käsimüügiravimiga.

Neo-Angin Salviat kasutatakse täiskasvanutel ja üle 6 aasta vanustel lastel suuõõne ja neelu antiseptikaks. Ravimi toimeained on 2,4-diklorobensüülalkohol, amüülmetakresool ja levomentool. Neo-Angin Salvia kuulub ravimite rühma, mida nimetatakse teisteks kurguhaiguste raviks kasutatavateks preparaatideks.

Ravimile anti müügiluba, kuna Neo-Angin Salvia kasutamisest oodatav kasu ületab võimalikud riskid.

Alljärgneva avaliku hinnanguaruande on koostanud Ravimiamet. CMDh/223/2005 February 2014

Public Assessment Report

Scientific discussion

NEO-ANGIN CHERRY NEO-ANGIN SALVIA

2,4-dichlorobenzyl alcohol Amylmetacresol Levomenthol

National

Date: 04.01.2016

This module reflects the scientific discussion for the approval of Neo-Angin Cherry & Neo- Angin Salvia. The procedure was finalised at 15. October 2015. For information on changes after this date please refer to the module ‘Update’.

PAR Scientific discussion 2/9

I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the State Agency of Medicines has granted a marketing authorisation for Neo-Angin Cherry & Neo-Angin Salvia lozenge 0,6 mg+1,2mg+5,9mg, from DIVAPHARMA GmbH. The product is indicated as an antiseptic for the oral cavity and throat. A comprehensive description of the indications and posology is given in the SmPC.”

The marketing authorisation has been granted pursuant to Article 10a well-established use application of Directive 2001/83/EC as amended using purely national procedure.

II. QUALITY ASPECTS

II.1 Introduction

Neo-Angin sugar-free lozenges contain the following active ingredients: 2,4-dichlorobenzyl alcohol 1.2 mg Amylmetacresol 0.6 mg Levomenthol 5.9 mg Neo-Angin Cherry lozenges are round, red, biconvex, slightly transparent lozenges with a diameter of about 20 mm. The excipients are isomalt, tartaric acid, Cherry-flavour, Peppermint oil, Ponceau 4R (E 124) and Indigotin (E 132) Neo-Angin Salvia lozenges are round, honey-coloured, biconvex, slightly transparent lozenges with a diameter of about 20 mm. The excipients are isomalt, tartaric acid, Sage oil, Peppermint oil, Ponceau 4R (E 124), Quinoline yellow (E 104) and Patent blue V (E131). Lozenges are packed into blister strips aluminium foil and transparent PVC- PVdC foil.

II.2 Drug Substance

2,4-dichlorobenzyl alcohol Dichlorobenzyl alcohol is an antiseptic used chiefly as an ingredient of lozenges in the treatment of minor infections of the mouth and throat. The substance consists of white or slightly yellow crystals. Data on the quality and manufacture of the active substance were provided using the Active Substance Master File (ASMF) procedure with additional data in the marketing authorization dossier. An official monograph for Dichlorobenzyl alcohol is recently valid in Ph. Eur. 2,4-Dichlorobenzyl alcohol has no asymmetrical C-atom, hence it has no potential isomerism. It is freely soluble in acetone, methanol and ethanol, insoluble in water. Due to the production process applied (hard-boiling) and pharmaceutical form obtained (lozenge for oromucosal administration) polymorphism and particle size distribution are not critical quality attributes of the drug substance. Due to the simple structure of the API only one step synthesis following the synthesis step is used and accepted. The suitability of applied specifications has been demonstrated and the absence of any impurity with structural alert properly addressed. 2,4-dichlorobenzyl alcohol is packed in double lined poly bags and stored in HDPE drums with pilfer proof sealing. The re-test period of 36 months with no restrictions in storage conditions has been approved for the drug substance.

Amylmetacresol Amylmetacresol is a phenolic antiseptic used chiefly as an ingredient of lozenges in the treatment of minor infections of the mouth and throat. The substance is a clear or almost clear liquid or a solid crystalline mass, colourless or slightly yellow when freshly prepared, which darkensduring storage. PAR Scientific discussion 3/9

The drug substance is practically insoluble in water, very soluble in acetone and ethanol (96%), soluble in ether and in fixed and volatile oils. Amylmetacresol has no asymmetrical C-atom, hence it has no potential isomerism. Due to the production process applied (hard-boiling) and pharmaceutical form obtained (lozenge for oromucosal administration) polymorphism and particle size distribution are not critical quality attributes of the drug substance. The Ph. Eur. monograph for amylmetacresol is valid since January 2011 and the API manufacturer possesses the valid CEP No. R0-CEP 2012-343-Rev 01. According to the valid CEP the re-test period of the substance is 4 years if stored in amber glass bottle with polypropylene cap placed in a corrugated box.

Levomenthol (-)-Menthol is an organic compound made synthetically or obtained from different mint oils. It occurs as colourless, acicular or prismatic shiny crystals. It is practically insoluble in water and very soluble in ethanol (96%) and in light petroleum, freely soluble in fatty oils and in liquid paraffin, very slightly soluble in glycerol. Levomenthol is the levo isomer of racementhol. The main form of menthol occurring in nature is (−) menthol, which is assigned the (1R,2S,5R) configuration. Levomenthol has cooling, analgesic and secretoytic properties causing a local anaesthetic effect, and is widely used to relieve minor throat irritation. The Ph. Eur. monograph for levomenthol is valid since January 1989 and the API manufacturer possesses the valid CEP No. R1-CEP 2004-100-Rev 01. No re-test period or container-closure system is fixed on the current CEP. Based on the data provided levomenthol is packaged and hermetically sealed in mono-layer plastic bags which are further packaged into cardboard boxes. No re-test period could be approved due to the unavailability of sufficient stability data. Therefore full analysis of the API has to be performed before levomenthol is incorporated in the production process of the medicinal product.

II.3 Medicinal Product

The drug products are manufactured by Klosterfrau Berlin GmbH (Germany) as conventional lozenges and packed in transparent PVC/PVdC aluminium foil. The manufacturer is responsible for the production of the finished product, packaging and batch control. DIVAPHARMA GmbH (Germany) is responsible for batch release. The compositions of the medicinal products are similar with the previously authorised Neo-Angin (sugar free) lozenges. It differs mainly in appearance and flavour of the solid dosage form. The excipients are well known and widely used in the pharmaceutical industry. The production process has been defined in sufficient detail and appropriate specifications are in place to ensure a product of constant quality. The analytical methods are described and validated. Batch analysis data from the proposed production site have been provided demonstrating compliance with the release specification. Container closure system and the applied specifications of its components are considered satisfactory. The lozenges complied with the appropriate specifications when stored for 48 months at 25°C/60% RH and 12 months at 30°C/65% RH. Crystallization of lozenges was observed in some batches after 6 months at 40°C/75% RH. According to CPMP/QWP/609/96, the restriction in storage conditions has been implemented as “Do not store above 30°C. Store in the original package to protect from moisture”. The 48 months shelf-life period has been approved.

III. NON-CLINICAL ASPECTS

III.1 Introduction

Based on the available pre-clinical data it can be concluded that the combination of 2,4-dichlorobenzyl alcohol, amylmetacresol, and levomenthol, i.e. Neo-Angin shows a good benefit-risk profile. This conclusion can be further supported by many years of clinical experience using this 'traditional' antiseptic combination of “well-established medicinal use”.

PAR Scientific discussion 4/9

III.2 Pharmacology

Pharmacological studies in animals have demonstrated antiseptic effect of 2,4-dichlorobenzyl alcohol and amylmetacresol as well as their combination. Consequently, the reduction of pathogenic microorganisms in the mouth and throat results in an improvement of the infectious and inflammatory status. In addition, the cooling effect of levomenthol on skin and mucous membranes exerts anaesthetic and analgesic actions contributing to relieve of pain.

III.3 Pharmacokinetics

There are only few data available concerning the pharmacokinetic features of orally applied 2,4- dichlorobenzyl alcohol, amylmetacresol, and levomenthol. After intestinal absorption, primary aromatic alcohols like 2,4-dichlorobenzyl alcohol are partly oxidised. The compound is metabolised into 2,4-dichloro-benzoic acid, which can finally be converted into benzoic acid. The metabolites are excreted renally. According to early investigations in rats receiving 250 mg amylmetacresol per gavage, it was suggested that amylmetacresol is rapidly absorbed already in the stomach. The compound is probably partly metabolised like other cresols (methyl-substituted phenols) into carbonic acids. After sulphation or glucuronisation both the unchanged amylmetacresol and its derivatives are eliminated by urinary excretion. As levomenthol is a lipophilic monoterpene, it is assumed to be rapidly absorbed and distributed in almost all tissues. The metabolism of levomenthol mainly takes place in the liver. Investigations in rats could show that the compound is rapidly converted into p-menthan- 3,8-diol and 3,8-dihydroxy-p- menthan-7-carbonic acid by oxidation finally resulting in glucuronides. In rats, the glucuronides show a considerable enterohepatic recirculation. The study using radiolabelled levomenthol in rats also revealed that 78% of an orally administered dose is excreted within a period of 48 h in equal amounts in both urine and faeces. Only levomenthol glucuronides could be detected, whereas unchanged levomenthol was not excreted. In rabbits, about 50% of orally ingested levomenthol was excreted as glucuronides, whereas in dogs a considerable oxidation and a reduced excretion of only 5% bound to glucuronic acid were reported.

III.4 Toxicology

Studies analysing the acute toxicity of the orally administered Neo-Angin lozenges showed LD50 values of more than 20 g/kg bw in rats and 8 g/kg in dogs. The investigations were performed with the former product "Neo-Angin Pastillen". Higher doses were not applicable. Histopathological examination of all organs of both species revealed no structural changes.

III.5 Ecotoxicity/environmental risk assessment (ERA)

Following the valid guideline, the assessment of potential risks to the environment is a step-wise, phased procedure, consisting of two phases. The test can be finalised, when the data show that an environmental risk can be excluded or when the risk is identified and sufficiently characterised. The first phase (Phase I) estimates the exposure of the environment to the drug substance in the aquatic compartment. The calculated predicted environmental concentration (PECSurface water) for each active substance of Neo-Angin Cherry & Salvia. Neo-Angin Cherry & Salvia are below the action limit of 0.01 μg/L. There are no other environmental concerns apparent regarding the use of Neo-Angin Cherry & Salvia lozenges. The medicinal products are unlikely to represent a risk for the environment following the prescribed usage in patients. It is not required to perform a further environmental risk assessment according to phase II.

PAR Scientific discussion 5/9

III.6 Discussion on the non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of 2,4-dichlorobenzyl alcohol, amylmetacresol and levomenthol are well known. As these are widely used, well-known active substances, the applicant has not provided additional studies and further studies are not required.

IV. CLINICAL ASPECTS

IV.1 Introduction

2,4-dichlorobenzyl alcohol, amylmetacresol, and levomenthol are well-known active substances with established efficacy and tolerability. Neo-Angin Cherry & Salvia sugar-free lozenges are used for the disinfection of mouth and throat. The acute respiratory illness (common cold) is the most frequent disease in man. Colds are caused by viruses and affect most people several times per year. The viruses cause an inflammation of the mucous membranes of the respiratory tract, mostly in the upper airways as nose, mouth, throat and voice box. Accordingly, the predominant symptoms beside the decreased general well-being and reduced capability are a sore throat and trouble swallowing. Any viral cold bears the risk of complication, e.g. a bacterial secondary infection. 2,4-dichlorobenzyl alcohol and the phenol derivative amylmetacresol antiseptics are characterised by their broad bactericidal action against the most pathogens of the oral cavity that cause throat infections. They are also fungicidally active. They are frequently used in these quantities since the 1930s. The dosage of 1.2 mg 2,4-dichlorobenzyl alcohol and 0.6 mg amylmetacresol are historically derived. Levomenthol, is used for its cooling, analgesic and secretolytic properties, which cause a local anaesthetic effect and thus an alleviation of the inflammation symptoms. The applicant has submitted four clinical studies to assess efficacy of the Neo-Angin lozenge in the short-term relief of sore throat (controlled studies DPK-03 and DPK-04, in vivo pilot study and in vivo study). The content of the SPC approved during the national procedure is in accordance with Neo-Angin sugar-free lozenges.

IV.2 Pharmacokinetics

2,4-Dichlorobenzyl alcohol After intestinal absorption, primary aromatic alcohols are partly oxidised; 2,4- dichlorobenzyl alcohol is catabolised to 2,4-dichlorobenzoic acid. Dechlorination can virtually be excluded. Analogous to benzoic acid, 2,4-dichlorobenzoic acid is renally excreted either as acid or as glycine conjugate.

Amylmetacresol Amylmetacresol is quickly absorbed and excreted again. Methyl-substituted phenols, i.e. the cresols, are partially oxidised to the corresponding carboxylic acids and renally excreted as glucuronide (p- cresol). This way of catabolism seems also probable in this case besides direct sulphation and glucuronidisation. Both the unaltered amylmetacresol and its derivatives are subsequently eliminated via urine excretion.

Levomenthol Levomenthol is quickly absorbed and probably distributed in almost all tissues of the body. Levomenthol is metabolised mainly in the liver. Experiments with rats could demonstrate that levomenthol is rapidly metabolised to p-menthan-3,8-diol and 3,8-dihydroxy-p-menthane-7-carboxylic acid, which are finally oxidised to glucuronides. There are indications of an involvement of the hepatic cytochrome-P450 system. Only limited data are available on the pharmacokinetics of levomenthol.

Special clinical trials on the pharmacokinetics and bioavailability of the three active substances of Neo-Angin sugar-free are not available or not known.

PAR Scientific discussion 6/9

IV.3 Pharmacodynamics

2,4-Dichlorobenzyl alcohol and amylmetacresol are active against the most frequent pathogens resident in the mucous membrane of mouth and throat (Gram positive and Gram negative bacteria as staphylococci, pneumococci and fusobacteria). The antiseptic action of essential oils is known from literature. The individual components and the combination both show a growth inhibition of a broad spectrum of various microorganisms. The bactericidal effect is based on the destruction of the cellular membrane of the bacteria, which is probably achieved by interactions of the active substances with the lipids of the cellular membrane. It is also possible that the synthesis of proteins or nucleic acids in the pathogen is inactivated by damage to the enzymes of their basic metabolism. In vitro trials it has been demonstrated that 2,4-dichlorobenzyl alcohol have antibacterial has a distinct antiseptic effect. Levomenthol Essential oils are known to have disinfectant properties which have been demonstrated in numerous clinical trials. Levomenthol causes stimulation of the cold receptors of skin and mucous membrane. Peripheral vessels first react with contraction and then with dilatation. Levomenthol is frequently used for the treatment of typical symptoms of cold, like rhinitis and cough. The main action of levomenthol is the cooling effect after application on skin or mucous membrane. Levomenthol causes both cold and heat receptors stimulation. The pain relieving effect is achieved by a levomenthol-induced inhibition of the neural impulses in the dorsal horn region, which originate in the nocireceptors in skin. In this place, the afferent fibres enter the spinal marrow through the dorsal root. Pain-relieving effect of levomenthol is demonstrated in several experiments.

IV.4 Clinical efficacy

Two efficacy, tolerability and dosage proving studies: GCP conforming, multicentric, placebo- controlled, randomised double-blind studies were conducted in 1994/5 (DPK-03 and DPK-04, Schneeweiss). DPK-03: randomised, placebo-controlled, double-blind study in adult patients with “Acute Respiratory Disease (ARD)”. The therapeutic efficacy of Neo-Angin® lozenges in acute, uncomplicated conditions of the upper respiratory tract can be regarded as established. DPK-04: double-blind, placebo-controlled, randomised, multi-centre Phase IV study. Efficacy and tolerability of DPK-04 (Neo-Angin® lozenges) as compared to placebo in sore throat were assessed. The treatment with Neo-Angin® lozenges can be regarded as superior to placebo and as safe and well tolerable.

Study A 03085: for quantitative determination of the microbial count reduction by the monosubstances of Neo-Angin compared to their combination, an in vitro study on the basis of the method handbook of the DGHM [Deutsche Gesellschaft für Hygiene und Mikrobiologie; German Society for Hygiene and Microbiology] (2001) was carried out. Efficacy of the test sample Neo-Angin sugar-free lozenges was compared to the solutions of the individual active substances (2,4-dichlorobenzyl alcohol, amylmetacresol and levomenthol) on various test pathogens. Combination of active substances, in particular at the traditional quantities, is necessary and reasonable for achieving a high level of efficacy.

Study A 03086: in-vivo study was intended to prove if and to what extent the specific pharmaceutical form is effective in reducing the microbial count of the oral flora. This study is based on the previously conducted in-vitro tests (test report by Hygiene Nord GmbH A 03085, dated 18 Feb. 2004), in which the test sample was found to be bactericidal and fungicidal. A highly significant reduction in microbial count of approximately one power of ten was achieved for the first hour. The study, conducted in healthy subjects with a distinct physiological oral flora, provides impressive evidence of the antiseptic effect of Neo-Angin sugar-free lozenges, which persists for two to five hours after application.

PAR Scientific discussion 7/9

The data listed here confirm good and broad efficacy with high safety and excellent tolerability of use for the area of application of Neo-Angin lozenges, namely acute infections of the pharynx.

IV.5 Clinical safety

The critical evaluation of decades of experience with the drug formulation Neo-Angin, the scientific experiments of the past on the lack of mutagenicity in animal experiments and the extremely rare and non-serious adverse events in the current clinical trials and the clinical trials DPK-03 and DPK-04 conducted in 1994 all indicate the safety of this preparation. Neo-Angin sugar-free lozenges – as almost all medicines - should only be taken during pregnancy and lactation after consulting a doctor. Infants should not suck on lozenges due to the risk of aspiration. There are no principal considerations against a use in children aged 6 and up, however children must be able to suck lozenges controlled. Publications on interactions with other drugs or on effects on reactivity are not available or are unknown in the observed period.

IV.6 Risk Management Plan

Neo-Angin contains as active substances 2,4-dichlorobenzyl alcohol, amylmetacresol, levomenthol. These substances are well known since many years, the risk/benefit-ratio is positive; the product is sold without prescription. There is no Risk Management Plan in place.

IV.7 Discussion on the clinical aspects

The clinical efficacy and safety of the combination preparation Neo-Angin can be assumed on the basis of bibliographical data and the results from own clinical studies and in vitro experiments, which were conducted according to the “Standard methods of the DGHM for the testing of chemical disinfection procedures”. The data listed there confirm good and broad efficacy with high safety and excellent tolerability of use for the area of application of Neo-Angin lozenges, namely acute infections of the pharynx. It can be assumed that a quick and lasting reduction of all relevant microorganisms can be achieved if used as directed in two hour intervals. The results from presented clinical trials DPK-03 and DPK-04 indicate that immediately after manifestation of the first disease symptoms, local antiseptic therapy is indicated in order to prevent bacterial secondary infections facilitated by virogenetic disease. Serious side effects that could have required termination of the study did not occur. Tolerability was good.

V. USER CONSULTATION

The composition of the new flavour Neo-Angin sugar-free Cherry lozenges is based on the already approved marketing authorisation of Neo-Angin sugar-free lozenges. The only difference between these two kinds of lozenges is the amount of levomenthol (5,9 mg versus 5,72 mg) and the composition of excipients (aroma: cherry flavour or sage oil instead of star anise oil, colorant: addition of indigotine (cherry) or quinoline yellow / patent blue (salvia)). In consequence, the wording of the SPC, package leaflet and the labelling of the outer and inner packaging of Neo-Angin Cherry & Salvia is identical to the one of the already approved product information of Neo-Angin sugar-free in Estonia. The only difference in wording is the addition of the flavour name and the changed composition. These slight changes in the SPC, package leaflet and the labelling of the outer and inner packaging will not affect the readability of the product information. Therefore, a consultation with target patient groups is not necessary.

PAR Scientific discussion 8/9

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Based on preclinical and clinical data, a very good benefit-risk profile can be attributed to the combination of 2,4-dichlorobenzyl alcohol, amylmetacresol and levomenthol, with the benefit clearly outweighing the risks it carries. This conclusion is further supported by the decades of positive clinical experience with the active substance combination of Neo-Angin, as a drug with a “well-established medicinal use”.

PAR Scientific discussion 9/9