CMDh/223/2005 February 2014

Public Assessment Report

Scientific discussion

Orinox HA 1 mg/ml nasal spray, solution (Xylometazoline hydrochloride)

LV/H/0177/001/DC

Date: September 2019

I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Orinox HA 1 mg/ml nasal spray, solution, from Dr. Max Pharma s.r.o., Czech Republic.

The product is indicated for symptomatic treatment of nasal congestion caused by sinusitis or rhinitis.

A comprehensive description of the indications and posology is given in the SmPC.

With Latvia as RMS in the Decentralised procedure, Dr. Max Pharma s.r.o. applied for the marketing authorisations for Orinox HA 1 mg/ml nasal spray, solution in CMS: Czech Republic, Slovakia, Poland and Romania.

The marketing authorisation has been granted pursuant to Article 10(a) of Directive 2001/83/EC- well established use application.

II. QUALITY ASPECTS

II.1 Introduction

Orinox HA 1 mg/ml nasal spray, solution is clear, colourless, sterile solution. 1 ml of solution contains 1 mg xylometazoline hydrochloride. One spray (140 µl) contains 0.140 mg xylometazoline hydrochloride. 10 ml of solution is filled into HDPE bottles with a nasal pump spray.

Excipients are purified sea water, potassium dihydrogen phosphate, sodium hyaluronate, purified water.

The State Agency of Medicines of Latvia has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for Orinox HA 1 mg/ml nasal spray, solution 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 marketing authorization.

II.2 Drug Substance

Xylometazoline hydrochloride

Chemical name: 2-(4-tert.-butyl-2,6-dimethylbenzyl)-2-imidazoline monohydrochloride

IUPAC name 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]-4,5-dihydro-1H-imidazole hydrochloride

Other names: 1H-Imidazole,2-[[4-(1,1-dimethylethyl)-2,6-dimethylphenyl]-methyl]-4,5-dihydro- monohydrochloride

Structure:

PAR Scientific discussion 2/12

Molecular formula: C16H25ClN2

Rel. mol. Mass: 280.8

The active substance xylometazoline hydrochloride is described in the European Pharmacopeia – monograph No 01/2008:1162. The Ph. Eur. certificate of suitability (CEP) procedure is used for the drug substance.

The details on manufacture, specification, analytical methods and packaging material were reviewed by the European Directorate for the Quality of Medicines (EDQM) in assigning the CEP for both drug substance manufacturers.

The specifications of the drug substance are not submitted from both active substance manufacturers, but according to the submitted batch data, one active substance manufacturer additionally to Ph. Eur. requirements controls the residual solvents – benzene, toluene, isopropanol and acetone and the other active substance manufacturer additionally to Ph. Eur. requirements controls the pH, heavy metals, chromatographic purity – sum of all impurities and residual solvents – DMF, isopropyl alcohol and toluene.

The CEP contains information about container closure system for both active substances.

Drug product manufacturer has provided requested compiled active substances specification and references to the analytical methods.

II.3 Medicinal Product

Pharmaceutical development The aim of the formulation development was to develop a stable, sterile, isotonic aqueous solution of xylometazoline hydrochloride, intended for nasal application, as a nasal spray in strength xylometazoline hydrochloride 1 mg/ml. The development of the product has been described, the choice of excipients is justified and their functions explained.

Manufacture of the product The drug product is manufactured as sterile products by sterile filtration followed by aseptic filling into pre-sterilized bottles closed with the pump system, an appropriate and validated (where necessary) in-process control tests are applied. The manufacturing process is adequately described. The used in-process controls and the performed validation studies are considered as sufficient to guarantee an appropriate quality of the drug product. Process validation data are presented for commercial scale batches.

Product specification The release and shelf-life specifications of the drug product are provided, and the non-compendial analytical procedures are described and validated. Certificates of analysis are provided for three batches. The batch analysis results show that the drug product meets the established specification.

Stability of the product PAR Scientific discussion 3/12

The conditions used in the stability studies are according to the ICH stability guideline requirements. After evaluation of updated stability data, the trend for increase of Impurity A amount under intermediate and accelerated storage conditions was observed, therefore, temperature storage conditions were introduced (Store below 25°C). The proposed shelf-life of 36 months is considered acceptable.

An in-use stability of 6 months is claimed. This is supported by experimental data gained with a product in the beginning of storage period and towards to the end of the claimed shelf-life.

Since no batch produced with APFPLUS® spray pump system is available at the moment, the Applicant commits to put first produced batch with the APFPLUS® spray pump system in inverted orientation on stability study (long term and accelerated storage conditions) to confirm proposed shelf life irrespective to the orientation of the product.

II.4 Discussion on chemical, pharmaceutical and biological aspects

Based on the submitted dossier, the member states consider that Orinox HA 1 mg/ml nasal spray, solution has a proven chemical and pharmaceutical quality. Sufficient controls have been laid down for the active substance and the finished product.

The following post-approval commitment was made:

 The applicant commits to put first produced batch with the APF pump system in inverted orientation on stability study (long term and accelerated storage conditions) to confirm proposed shelf life irrespective to the orientation of the product.

III. NON-CLINICAL ASPECTS

III.1 Pharmacology

Pharmacological properties of xylometazoline are well known. As xylometazoline is a widely used, well-known active substance, the Applicant has not provided additional studies and further studies are not required.

The Applicant has provided review of literature data of xylometazoline pharmacology describing primary, secondary pharmacodynamics and safety pharmacology.

Xylometazoline is a topical sympathomimetic vasoconstrictor. It is structurally and pharmacologically related to other imidazoline derivatives such as oxymetazoline, tetrahydrozoline (tetryzoline), tramazoline and naphazoline. Xylometazoline has a high affinity to alpha-adrenergic receptors. Its affinity for α2-adrenoreceptors and α1-adrenoreceptors is almost equal. Xylometazoline activation of α1- and α2-adrenoreceptors results in constriction of pre-capillary arterioles and post-capillary venules in the nasal mucosa. Extracellular fluid that contributes to congestion and rhinorrhea is reduced as a result of the blood flow reduction to the nasal mucosa capillary bed. In additional, vasoconstriction from α1-adrenoreceptor activation reduces the blood volume in the mucosa and the mucosal volume.

Xylometazoline exerts little to no effect on beta-adrenergic receptors. In vivo, xylometazoline has a rapid onset of action (about 5-10 minutes) and the vasoconstrictive effect lasts up to 10 hours (8-12h).

III.2 Pharmacokinetics

PAR Scientific discussion 4/12

No specific pharmacokinetic non-clinical studies have been conducted to support this application. It is considered acceptable for well-established use application.

Relatively little data is available on pharmacokinetic studies in animals and humans.

After intra-nasal administration of 14C-xylometazoline the majority of radioactivity remained in and around the site of application. A part of radioactivity was absorbed into the tissues and in the same pattern of the intravenous administration.

III.3 Toxicology

No specific toxicology studies have been conducted in support of this application. It is considered acceptable for well-established use application.

Studies on mutagenicity did not reveal any genotoxic potential of xylometazoline. Xylometazoline tested negative in the Ames test and the micronucleus-test in mice.

There are no published carcinogenicity studies for xylometazoline. Carcinogenic studies with the closely related imidazoline derivative tramazoline over a period of two years showed no evidence of a carcinogenic risk in rats.

Xylometazoline did not show foetotoxic effects either in mice or in rats in doses up to 7.5 mg/kg/day. Some data in rats indicates intrauterine growth retardation or embryotoxicity following exposition to xylometazoline at doses above the recommended therapeutical doses for humans. Three studies investigating the use of xylometazoline during pregnancy found some indication of slightly higher rates of congenital disorders.

Xylometazoline caused a dose-dependent cilio-inhibitory effect on in vitro rat tracheal cilia.

The impurity profile of the drug product was considered acceptable. There are no significant differences between relevant physical and chemical parameters for the proposed product and products available on the market many years. Excipients used in the proposed product are well known, well tolerated and clinically safe.

III.4 Ecotoxicity/environmental risk assessment (ERA)

An environmental risk assessment has been completed based on CHMP Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use (EMEA/CHMP/SWP/4447/00) adopted by CHMP 01 June 2006. The Predicted Environmental Concentration (PECSURFACE WATER) has been calculated for xylometazoline hydrochloride 1 mg/ml based on a maximum daily human dose of 3 sprays per nostril per day. The guideline states that if the PEC SURFACE WATER is below 0.01 μg/L, then the product is unlikely to represent a risk for the environment. The PECSURFACE WATER value for xylometazoline hydrochloride 1 mg/ml is 0.0027 μg/L. This calculated surface water concentration is far below the action limit 0.01 μg/L and it is therefore assumed that the medicinal product is unlikely to represent a risk for the environment following its prescribed usage in patients.

IV. CLINICAL ASPECTS

IV.1 Introduction

PAR Scientific discussion 5/12

In accordance to Article 10 (a) of Directive 2001/83/EC, instead of results of pharmacological or clinical trials bibliographical scientific literature is provided.

No new efficacy data are presented for this application and none are required. The Applicant has provided a bibliographic review of clinical trials published in the literature confirming the efficacy and safety of xylometazoline hydrochloride as nasal decongestant in the acute rhinitis or sinusitis.

IV.2 Pharmacokinetics

The effect of xylometazoline hydrochloride nasal spray starts within 5-10 minutes after administering and lasts for several hours. There is only minimum systemic absorption of xylometazoline when it is used in the recommended dose and route of administration. With intranasal administration, the absorbed amount can be sufficient to some extent to induce systemic effects, e.g. on the central nervous system and cardiovascular system. There are no available data from pharmacokinetic studies in humans. The Applicant has presented an adequate summary of the known pharmacokinetics of xylometazoline. There are no published data on systemic human pharmacokinetics of xylometazoline after nasal application.

IV.3 Pharmacodynamics

Xylometazoline hydrochloride is a direct acting sympathomimetic adrenergic alpha-agonist used to induce systemic vasoconstriction, thereby decreasing nasal congestion. The sympathomimetic action of xylometazoline hydrochloride constricts the smaller arterioles of the nasal passages, producing a prolonged decongesting effect. Xylometazoline is an imidazoline derivative. It is a compound with high affinity to α-adrenergic receptors but has little to no effect on the ß-adrenergic receptors. Its affinity for α2-receptors is almost the same as for α1-receptors. It has been reported to behave as a selective α2-antagonist and as a typical α1-agonist. It constricts the dilated nasal blood vessels and reduces oedema, thereby decongesting the mucosa of nose and pharynx. As it allows for improved ventilation in the upper respiratory tract, it reduces the risk of complications, e.g. the accumulation and colonisation of secretions.

IV.4 Clinical efficacy

Topical decongestants including xylometazoline hydrochloride and systemic decongestants have been used to treat nasal congestion associated with the common cold for many years. Short-term use of xylometazoline in the alleviation of nasal congestion is well-established. Xylometazoline possesses a rapid decongestant effect, with a decrease in nasal airflow resistance and increase of inspiratory flow.

In terms of efficacy, xylometazoline has been well established for more than 50 years. Efficacy in most of the studies has been based on subjective assessment of nasal breathing, reduction in swelling of nasal mucosa measured by rhinostereometry and assessment of nasal resistance measured by rhinomanometry. All studies demonstrated the efficacy and suitability of xylometazoline hydrochloride in the granted indications.

Xylometazoline hydrochloride 1.0 mg/ml is indicated in adults and adolescents aged 12 and older. The dose in adults and adolescents 12 years of age and older is 1 spray of xylometazoline 1 mg/ml nasal spray into each nostril up to 3 times daily.

The dose recommendations made in the SPC are based on xylometazoline hydrochloride pharmacokinetic properties and are in accordance with other xylometazoline hydrochloride containing products that are available on the European market.

PAR Scientific discussion 6/12

IV.5 Clinical safety

After intranasal administration, xylometazoline hydrochloride seldom produces significant systemic adverse effects. Topical nasal decongestants are poorly absorbed from the nasal mucosa and therefore normally do not have the systemic effects reported for oral decongestants. Depending on whether central or peripheral α-adrenergic receptor stimulation predominates, systemic overdose of imidazole- derivates may result in central nervous system depression or stimulation. In case of prolonged use or overdose, the following cardiovascular or central nervous may occur: increase of arterial pressure and heart rate; cerebral hyper-reactivity resulting in insomnia, hallucinations and anxiety; increase of thyroid function and glycaemia; and increase in intraocular pressure. Nausea has rarely been reported.

Intranasal use of xylometazoline hydrochloride has been associated with a number of local side effects. The most relevant adverse side effects are slight transient irritations (burning sensation or dryness) of the nasal mucosa. Long-term use can cause nasal stuffiness (rhinitis medicamentosa) and tolerance to the effect. Rhinitis medicamentosa is a term used specifically to refer to a condition which occurs with persistent overuse of topical nasal decongestants. Overuse of these drugs may result in rebound congestion, nasal hyperreactivity, tolerance, and histologic changes of the nasal mucosa. Therefore, xylometazoline hydrochloride generally should not be used for longer than 5 days.

IV.6 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 Orinox HA 1 mg/ml nasal spray, solution.

- Summary table of safety concerns as approved in RMP

Routine risk minimisation and pharmacovigilance is suggested and no additional risk minimisation and pharmacovigilance activities are proposed by the Applicant, which is endorsed.

Pharmacovigilance System The Applicant has submitted a signed Summary of the Applicant'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.

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.

PAR Scientific discussion 7/12

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.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the benefit risk assessment is considered positive and application for Orinox HA 1 mg/ml nasal spray, solution for symptomatic treatment of nasal congestion caused by sinusitis or rhinitis is approvable.

The decentralised procedure was finalised on July 20, 2019.

CMDh/233/2011 June 2014

Summary Public Assessment Report

non-generics

Orinox HA 1 mg/ml nasal spray, solution (Xylometazoline hydrochloride)

LV/H/0177/001/DC

PAR Scientific discussion 8/12

Date: September 2019

PAR Scientific discussion 9/12

Summary Public Assessment Report

non-generics

Orinox HA 1 mg/ml nasal spray, solution Xylometazoline hydrochloride

This is a summary of the public assessment report (PAR) for Orinox HA 1 mg/ml nasal spray, solution. It explains how Orinox HA 1 mg/ml nasal spray, solution was assessed and its authorisation recommended as well as its conditions of use. It is not intended to provide practical advice on how to use Orinox HA 1 mg/ml nasal spray, solution.

For practical information about using Orinox HA 1 mg/ml nasal spray, solution, patients should read the package leaflet or contact their doctor or pharmacist.

What is Orinox HA and what is it used for?

Orinox HA 1 mg/ml nasal spray, solution is a medicine with ‘well-established use’. This means that the medicinal use of the active substance of Orinox HA is well established in the European Union for at least ten years, with recognised efficacy and an acceptable level of safety.

Orinox HA 1 mg/ml nasal spray, solution is used for symptomatic treatment of nasal congestion with a running nose due to common cold or sinusitis.

How does Orinox HA work?

Orinox HA 1 mg/ml nasal spray, solution belongs to the group of medicines for the treatment of nasal diseases, sympathomimetics. It contains xylometazoline hydrochloride, which helps constricting blood capillaries in your nose thereby reducing the swelling of the nasal mucosa.

How is Orinox HA used?

The pharmaceutical form of Orinox HA is nasal spray, solution and the route of administration is nasal use.

Posology

Dosage depends on the sensitivity of the individual patient and clinical effect.

Adults and adolescents (≥12 years) The dose in adults and adolescents older than 12 years is 1 spray into each nostril, up to 3 times daily.

Paediatric population Orinox HA 1 mg/ml nasal spray, solution should not be used children younger than 12 years. Other pharmaceutical strengths may be more appropriate for administration to this population.

Duration of treatment Xylometazoline should not be used for longer than 5 days. Use can be repeated after the treatment was interrupted for several days.

Method of administration The medicinal product is intended for nasal use.

PAR Scientific discussion 10/12 Before the first application, it is necessary to spray a few times (5 times) in the air, to achieve a uniform dose. If the product is not used for several days at least one test spray in the air should be done in order to achieve a uniform dose.

The medicine should be used after blowing one’s nose.

After application, the pump should be carefully wiped with dry and clean paper tissue and the protective cap should be put. For hygienic reasons and to avoid spreading of infections, each spray bottle should be used by only one person.

Please read section 3 of the PL for detailed information on dosing recommendations, the route of administration, and the duration of treatment.

The medicine can be obtained without a prescription.

What benefits of Orinox HA have been shown in studies?

As xylometazoline hydrochloride is a well-known substance, and its use in symptomatic treatment of nasal congestion with a running nose due to common cold or sinusitis is well established, the applicant presented data from the scientific literature. The literature provided confirmed the efficacy and safety of xylometazoline hydrochloride in the symptomatic treatment of nasal congestion with a running nose due to common cold or sinusitis.

What are the possible side effects from Orinox HA?

The following side effects have been recorded:

Common (may affect up to 1 in 10 people)  headache  temporary and mild irritation symptoms, such as stinging or dryness of the nasal mucosa and/or throat  sneezing  nausea

Uncommon (may affect up to 1 in 100 people)  sensation of a “blocked” nose (after the effect of the medicine has ended)  nose bleeding

Rare (may affect up to 1 in 1,000 people)  dizziness  irregular and rapid heart beat  increase in blood pressure  transient visual disorders  systemic allergic reactions such as angioedema, rash, pruritus

Very rare (may affect up to 1 in 10,000 people)  nervousness  insomnia  arrhythmia  tachycardia

Orinox HA 1 mg/ml nasal spray, solution should be stopped using and medical help should be sought immediately if there are any of the following which may be signs of an allergic reaction: PAR Scientific discussion 11/12

 difficulty breathing or swallowing  swelling of the face, lips, tongue or throat  severe itching of the skin, with red rash or raised bumps

Why is Orinox HA approved? The State Agency of Medicines of Latvia decided that Orinox HA 1 mg/ml nasal spray, solution benefits are greater than its risks and recommended that it be approved for use.

What measures are being taken to ensure the safe and effective use of Orinox HA?

A risk management plan has been developed to ensure that Orinox HA 1 mg/ml nasal spray, solution is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Orinox HA 1 mg/ml nasal spray, solution, including the appropriate precautions to be followed by healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore, new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously as well.

Other information about Orinox HA

The marketing authorisation for Orinox HA 1 mg/ml nasal spray, solution was granted on 28.08.2019.

The full PAR for Orinox HA 1 mg/ml nasal spray, solution can be found on the website https://mri.cts-mrp.eu/Human/Product/Details/57694 . For more information about treatment with Orinox HA 1 mg/ml nasal spray, solution, read the package leaflet (link)or contact your doctor or pharmacist.

This summary was last updated in 09-2019.

PAR Scientific discussion 12/12