Summary Public Assessment Report

non-generics

Oxymetazoline Dr. Max 0.5mg/ml nasal spray Oxymetazoline hydrochloride

MT/0169/001/DC

Date: February 2015

Summary Public Assessment Report

non-generics

Oxymetazoline Dr.Max Nasal spray, solution

1 ml of nasal spray contains 0.5 mg oxymetazoline hydrochloride 1 dose (0.07 ml) contains 35 μg oxymetazoline hydrochloride.

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This is a summary of the public assessment report (PAR) for Oxymetazoline Dr.Max Nasal spray, solution. It explains how Oxymetazoline Dr.Max 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 Oxymetazoline Dr.Max Nasal spray, solution.

For practical information about using Oxymetazoline Dr.Max Nasal spray, solution, patients should read the package leaflet or contact their doctor or pharmacist.

What is Oxymetazoline Dr.Max Nasal spray, solution and what is it used for?

Oxymetazoline Dr.Max Nasal spray, solution is a medicine with ‘well-established use’. This means that the medicinal use of the active substance of Oxymetazoline Dr.Max Nasal spray, solution is well established in the European Union for at least ten years, with recognised efficacy and an acceptable level of safety. Oxymetazoline Dr.Max Nasal spray, solution is indicated for local and temporary relief of nasal congestion produced by rhinitis.

How does Oxymetazoline Dr.Max Nasal spray, solution work?

Oxymetazoline Dr.Max belongs to a group of medicines called sympathomimetics which acts producing local vasoconstriction and nasal decongestion.

How is Oxymetazoline Dr.Max Nasal spray, solution used?

The pharmaceutical form of Oxymetazoline Dr.Max Nasal spray, solution is nasal spray solution and the route of administration is nasally.

The recommended dose is one spray in each nostril, maximum 2 times per day.

It is not to be use for longer than 3 days without medical prescription.

It is not to be administered to children under the age of 12 years. Children could be especially prone to side effects. Instructions for the correct medicine administration

Before using this product for the first time, it is necessary to load the spray. For this purpose, the bottle is held away from the body, and the spray is pushed several times pointing down until pulverised liquid comes out.

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1. The protection cap of 2. The bottle is held 3. The bottle is aimed the bottle is removed. and the middle and into the nose and index fingers are put pressed. in the upper zone with the thumb underneath.

Nasal fluids should be eliminated before the application by blowing the nose.

After each use and before closing the bottle, the applicator should be cleaned with a clean and damp cloth.

The medicine can be obtained without a prescription.

What benefits of Oxymetazoline Dr.Max Nasal spray, solution have been shown in studies?

As Oxymetazoline is a well-known substance, and its use in the treatment of local and temporary relief of nasal congestion produced by rhinitis in adults and children over 12 years is well established, the applicant presented data from the scientific literature. The literature provided confirmed the efficacy and safety of Oxymetazoline in the treatment of local and temporary relief of nasal congestion produced by rhinitis in adults and children over 12 years

What are the possible side effects from Oxymetazoline Dr.Max Nasal spray, solution? The most common side effects with Oxymetazoline Dr.Max Nasal spray, solution (which may affect more than 1 in 10 people) are stinging, dryness and/or irritation of nasal mucosa or sneezing. Excessive or continued use may cause nasal congestion due to a rebound effect.

For the full list of all side effects reported with Oxymetazoline Dr.Max Nasal spray, solution, see section 4 of the package leaflet. Contraindications include taking antidepressants within the last 14 days, the use of other sympathomimetic decongestants, narrow-angle glaucoma (high fluid pressure inside the eye), recent neurosurgery (trans-sphenoidal hypophysectomy or other surgery exposing meninx),suffering from heart disease or circulatory system disease or a dry inflammation of the nasal mucous membrane with formation of crusts (rhinitis sicca).

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For the full list of contraindications, warnings and precautions see section 2 of the PL.

The main safety concerns are vasodilation rebound effect, congestion and medicinal rhinitis, pregnancy and breastfeeding, usage of vasoconstrictor drugs, and usage in patients suffering from diabetes mellitus, hypertension, cardiovascular disease, glaucoma, prostatic enlargement and hyperthyroidism.

Why is Oxymetazoline Dr.Max Nasal spray, solution approved?

The Medicines Authority decided that Oxymetazoline Dr.Max Nasal spray, solution’s 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 Oxymetazoline Dr.Max Nasal spray, solution? A risk management plan has been developed to ensure that Oxymetazoline Dr.Max 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 Oxymetazoline Dr.Max 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. Routine pharmacovigilance is sufficient to monitor the effectiveness of the routine risk minimisation measures.

Other information about Oxymetazoline Dr.Max Nasal spray, solution The marketing authorisation for Oxymetazoline Dr.Max Nasal spray, solution was granted on 2nd January 2015. The full PAR for Oxymetazoline Dr.Max Nasal spray, solution can be found on the website http://mri.medagencies.org/human/ For more information about treatment with Oxymetazoline Dr.Max Nasal spray, solution, read the package leaflet http://mri.medagencies.org/Human/product-information or contact your doctor or pharmacist. This summary was last updated in 04-2015.

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CMDh/223/2005 February 2014

Public Assessment Report

Scientific discussion

Oxymetazoline Dr. Max 0.5mg/ml nasal spray, solution

Oxymetazoline hydrochloride

MT/0169/001/DC

Date: April 2015

This module reflects the scientific discussion for the approval of Oxymetazoline Dr. Max 0.5mg/ml nasal spray, solution. The procedure was finalised at 210. For information on changes after this date please refer to the module ‘Update’.

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I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Oxymetazoline Dr Max. 0.5mg/ml nasal spray solution from Dr.Max Pharma Limited.

 The product is indicated for Local and temporary relief of nasal congestion produced by rhinitis in adults and children over 12 years. A comprehensive description of the indications and posology is given in the SmPC.

This decentralised procedure concerns a bibliographical application based on article 10a of Directive 2001/83/EC for Oxymetazoline, under the trade name Oxymetazoline Dr Max. 0.5mg/ml nasal spray solution. With MT as the Reference Member State in this Decentralized Procedure, the following are the CMSs involved: PL, CZ, SK

The active substance of Oxymetazoline Dr. Max 0.5 mg/ml nasal spray, solution is oxymetazoline hydrochloride. Oxymetazoline hydrochloride was launched to the market in 1962 for the first time in Germany. Recognised efficacy and an acceptable level of safety have been proved during the 52 years of its use. Hence the applicant is using the ‘well-established medicinal use’ claim as referred to Article 10(a).

The efficacy and safety of the Oxymetazoline Dr. Max 0.5 mg/ml nasal spray, solution is demonstrated in detail in Modules 4 and 5 in the dossier. A detailed scientific bibliography addresses non-clinical and clinical characteristics of the drug product.

Oxymetazoline is a sympathomimetic amine of direct action which acts directly on α-adrenergic receptors. This causes vasoconstriction in nasal mucosa arteries, which at the same time reduces blood flow as well as nasal congestion. Intranasal administration of oxymetazoline solution causes local vasoconstriction which usually takes place from 5-10 minutes and persists for 5-6 hours, being gradually washed out during the next 6 hours.

Quality aspects

I.1 Introduction

Pharmaceutical Form Oxymetazoline Dr.Max is a solution for nasal use in plastic bottle with plastic spray pump and plastic cap.

The nasal solution contains 1 ml of nasal spray contains 0.5 mg oxymetazoline hydrochloride 1 dose (0.07 ml) contains 35 μg oxymetazoline hydrochloride.

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Excipient(s) with known effect: Benzalkonium chloride

Other Excipients Disodium phosphate anhydrous Sodium dihydrogen phosphate dihydrate Glycine Sorbitol Purified water.

I.2 Drug Substance

Drug Substance Active substance: Oxymetazoline Hydrochloride Chemical name: 3-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-6-(1,1-dimethylethyl)-2,4-dimethylphenol hydrochloride CAS Number: 2315-02-8

3.2.S.1.2 Structure

Molecular Formula: C16H25ClN2O Relative Molecular Mass: 296.8

Oxymetazoline hydrochloride is described by the Ph.Eur. It is white or almost white crystalline powder. The CEP (Certificate of suitability to the European Pharmacopoeia) procedure is followed for the drug substance; reference is made to a valid CEP. Data supporting the suitability of the drug substance have been provided by way of the CEP. One manufacturer is listed as possible source of Oxymetazoline HCl, with valid CEP and conforming to Ph.Eur. The provided CEP is the current version (EDQM database). The CEP includes a retest period of 3 years (if stored in a fibre drum or HDPE bottle lined with two interior polyethylene bags).

I.3 Medicinal Product

Drug Product

The finished product is formulated as nasal spray using well known excipients. Development studies are appropriate; the choice of excipients is justified and their functions explained. The manufacturing process is conventional and supported by data provided. The product specification includes relevant controls, and limits proposed are following ICH guidance or Ph. Eur. requirements. The control of

Summary PAR – non-generics 7/14 drug product is described in detail; validation of the analytical methods has been presented. The batch analysis results show that the finished products meet the specifications proposed. The container closure system is well described and conforms to relevant requirements. Stability studies of the final packaged product have been conducted in accordance with relevant guidelines. According to the stability results presented and in accordance to ICH guidance on stability testing, stability evaluation, and declaration of storage conditions, the proposed shelf life of 24 months for Oxymetazoline hydrochloride 0.5 mg/ml Nasal spray, solution in the intended container with the labelling statement of “Do not store above 30ºC”can be granted; the proposed in-use shelf-life of 30 days after first opening is acceptable.

II. NON-CLINICAL ASPECTS

Pharmacodynamic, pharmacokinetic and toxicological properties of Oxymetazoline are well known. As Oxymetazoline is a well-known active substance, no further studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate.

The non-clinical overview report refers 19 publications with the majority of publications dated prior to 2010.

II.1 Ecotoxicity/environmental risk assessment (ERA)

OXYMETAZOLINE DR. MAX 0.5MG/ML nasal spray is a well established use medicinal product. There is no reference product for this application. It therefore follows that OXYMETAZOLINE DR. MAX 0.5MG/ML will not be intended for generic substitution in the RMS and CMS. Therefore an environmental risk assessment is therefore deemed necessary in line with European Union (EU) guidance EMEA/CPMP/SWP/4447/00, 01 June 2006.

Oxymetazoline is expected to enter the water system after patient use and potentially could be spread on land from the disposal of sewage treatment plant sludge. Oxymetazoline does not enter the atmosphere based on its physical chemistry.

Local regulations supporting disposal of unused medicines should be followed by patients, doctors and pharmacies. Labelling of bulk containers for storage and disposal should follow the recommendations of the Safety Data Sheet. Based on the labelling criteria the active ingredient, Oxymetazoline, is not considered an environmental hazard and should not be labelled as such.

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Conclusions on studies: The concerned product OXYMETAZOLINE DR. MAX 0.5MG/ML nasal spray, solution is unlikely to represent a risk for the environment following its usage in patients as the estimated exposure (0.0007 μg/L) has been showed well below the established action limit 0.01 μg/L. Although no special disposal measures are warranted for OXYMETAZOLINE DR. MAX 0.5MG/ML nasal spray, solution based on calculation described above in order to enhance environmental protection, it was concluded to include the following general statement in the Summary of Product Characteristics (SPC) and Patient information leaflet (PIL): For SPC – “Any unused medicinal product or waste material should be disposed of in accordance with local requirements.” For PIL - “Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.”

III. CLINICAL ASPECTS

III.1 Introduction

III.2 Pharmacokinetics

No new data has been submitted by the applicant.

The pharmacokinetic profile of oxymetazoline is limited however the decongestant effects of the drug are well known together with its other effects both systemically and topically.

Absorption: Evidence related literature pharmacokinetic profile after oxymetazoline nasal instillation is limited. It has been shown, however, that this drug could be absorbed after topical nasal administration. Decongestant effects appear within 5-10 minutes, reaching a maximum after 6 hours.

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Its vasoconstrictor activity may last up to 12 hours. Absorption may occur from the nasal mucosa and systemic effects, mainly after the overdose or overuse.

Distribution and elimination: There is no information about distribution and elimination in humans. Metabolic studies in animals indicated that oxymetazoline is excreted in urine, appearing 30% of the dose unchanged after 72 hours. It also presents some elimination in faeces (10%). Its elimination half- life is 5-8 hours.

III.3 Pharmacodynamics

No new data has been submitted by the applicant.

After topical administration, oxymetazoline leads to a constriction of blood vessels decreasing mucosal blood flow and swelling of the mucosa, which produces a decongested nasal passage. This action is exerted on both the pre and post nasal mucosal capillaries. (Horie et al. 1995). The two activity profiles are discussed below:

Decongestant action:

The applicant has cited two papers (Corboz et al 2007 and Corboz et al 2008) to support the decongestant action of oxymetazoline. Both studies show favourable results when used as a decongestant.

The two publications of Corboz and colleagues show that capacitance vessels such as venous sinusoids of nasal area are regulated by α1 and 2-adrenergic receptors. Oxymetazoline direct causes vasoconstriction by norepinephrine release from sympathetic varicosities which, in turn act on the α- adrenoceptor effectors. The effect is a reduction of hyperaemia, of constriction sinusoids and of mucosal oedema, reducing the resistance to airflow and displaying decongestion without affecting blood pressure. Because blood flow is reduced from the glands to micro-vessels, a decrease in both the plasma exudates and nasal secretions is observed.

Similar work was developed by Brugel-Ribere et al. who carried out a study to establish the determinants of the collapse of the nasal valve region as a common cause of nasal obstruction. This was determined by calculating the cross-sectional area of the anterior part of the nose in 6 healthy subjects using acoustic rhinometry. These measurements were performed at baseline and after decongestion with oxymetazoline mucosa obtained.

Following administration of oxymetazoline, it was observed a drop of "compliance" nasal wall in the various areas that make up the space nasal valve area, medial part of the inferior turbinate and meatus region. The applicant concludes that the "compliance" nasal wall is due in part to the mucosal blood volume and the amount of vascular tissue, which varies in each of the three portions mentioned, increasing from the region to valvular middle meatus, which is the anatomical site where oxymetazoline exerts its action on nasal congestion.

Anti-inflammatory action

Beck-Speier et al studied the mechanisms of action of oxymetazoline related to inflammatory reactions and, more specifically, the effects exerted on the arachidonic acid metabolites. In these publications oxymetazoline showed not only a decongestant action traditionally described, but also exerts anti-inflammatory effects in the rhinitis course, which results, clinically, in a shortening of the duration of symptoms. In more detail, these authors suggest that oxymetazoline generates PGE2 production (prostaglandin E2, immunomodulatory agent) and 15-hydroxy-eicosatetraenoic acid (15 HETE, anti-inflammatory agent), also inducing depletion of leukotrienes A4 and B4 and 8 isoprostane, proinflammatory agents. Also, the inhibitory effect exerted by oxymetazoline on the activity of 5 and 15-lipoxygenase demonstrates the powerful nature of this drug inflammatory modulator.

Summary PAR – non-generics 10/14 Another relevant reference published by Westerveld et al showed that oxymetazoline is able to inhibit nitric oxide (NO) synthase. This effect has a high significance since nitric oxide plays a role in the genesis of inflammatory processes of the upper airway. Therefore, these authors conclude that oxymetazoline has a beneficial anti-inflammatory effect in inflammatory processes involving the upper airway.

The role of the active ingredient as an anti-inflammatory agent is also shown in Beck-Speier et al 2009 and 20006 and Westerveld et al. 2000. Hotovy et al 1961, Kuhnke 1961 and Miodek 1962 show that oxymetazoline is a potent vasoconstrictor with a long duration of action. These have all been cited and discussed by the applicant in the overview to show the pharmacodynamic effects of the active ingredient in the proposed indication and posology.

III.4 Clinical efficacy

The efficacy of intranasal oxymetazoline solution has been shown in many clinical trials, both controlled and non-controlled, in patients with nasal congestion in healthy subjects or patients affected with allergic or infectious rhinitis. Traverner D et al 1999 and Reinecke S et al 2005 are two of the main cited papers that discuss and show the efficacy of intranasal oxymetazoline solution. For instance, in Traverner D et al (a randomized, double-blind, crossover study a total of 20 subjects were tested the resistance of the nasal airway was measured by rhinomanometry), the effects of a single dose of oxymetazoline nasal spray on respiratory and nasal patency function, have been compared with placebo using three separate measuring systems in normal subjects. Additionally, nasal congestion symptoms were assessed using a visual analogue scale. The modifications shown by oxymetazoline were not depicted in patients taking placebo. Reinecke S et al was a prospective placebo controlled double blind study in 247 patients with acute rhinitis. In this case again oxymetazoline proved to be significantly superior to its placebo (saline).

The following studies: Voss et al 1973, Slodki et al 1965, Ekedahl C et al 1983 were also presented and discussed in light of the superiority of oxymetazoline over ephedrine and xylometazoline however this is beyond the scope of this application and its legal basis. Nonetheless, this is still evidence of the well established use of the active ingredient, its safety and efficacy.

Following a request from both the RMS and CMS at day 70 and 100 respectively the applicant has updated the clinical overview to include and discuss more bibliographic data discussing the efficacy and safety of oxymetazoline 0.5mg/ml nasal spray. A list of available products authorised in the EU with the same active, strength and form was also provided.

With respect to efficacy Akerlund A, 1999 discusses a dose range study confirming efficacy with the chosen strength of the proposed product (oxymetazoline 0.5mg/ ml). Slodki SJ 1965 compares oxymetazoline 0.5mg/ ml with ephineprine in two different pharmaceutical forms to show superiority (nasal drops and spray). In another comparative study the proposed product’s strength and formulation is compared to phenylephrine to determine superiority (Voss HE 2000). In another six studies which are discussed at a later stage of the procedure the proposed product and six products referred to in publications mentioned in the overview were presented to compare the total dose released at each nostril application. This comparison showed that with respect to posology the proposed product is in line with the guidance of the Martindale August 2010 and with respect to safety in terms of local tolerance it is safer since the maximum daily dose per nostril is less than that in the products which are available already on the EU market.

III.5 Clinical safety

Summary PAR – non-generics 11/14 In all of the referenced trials no serious adverse events were reported. In a trial (Graff et al 1999) performed in 35 patients with vasomotor rhinitis in which the position of the nasal mucosa was evaluated via rhinostereometry, the minimum transversal area via acoustic rhinostereometry and the nasal blockage as symptom via visual analogic scale, it was shown that topical administration of oxymetazoline during 10 days did not give way to rebound congestion. This is clinically important, since the recommendation of a 10 day limitation of topical nasal decongestants seems adequate.

A study in eight healthy volunteers made to investigate whether long-term use of oxymetazoline induces a rebound swelling of the nasal mucosa and whether the decongestion effect is altered during medication, concluded that rhinitis medica mentosa develops after 10 days, and rebound swelling after 30 days. (Ackerhans M et al 1994) The aim of this study was to investigate whether long-term use of oxymetazoline induces a rebound swelling of the nasal mucosa and whether the decongestion effect is altered during medication. Compared to the registrations before the start of medication, no rebound swelling was registered after 10 days. After 30 days, however, a rebound swelling was registered in all subjects (p < 0.001). All of them, then, also reported nasal stuffiness. The applicant discussed the study and concluded that it supports the recommendation that the drug should not be used over periods > 10 days.

Intranasal use of oxymetazoline may occasionally cause systemic sympathomimetic effects such us hypertension, nervousness, nausea, dizziness, headache, insomnia, palpitation, or reflex bradycardia. It may also cause transient burning, stinging, increased nasal discharge or dryness of nasal mucosa, and sneezing. Nevertheless, a number of clinical trials have shown that, generally, oxymetazoline is well tolerated in patients with acute or allergic rhinitis (Dorn et al 2003, Cherubino et al 1977, Leitch GB 1976)

Rebound congestion, characterised by chronic redness, swelling and rhinitis, frequently occurs with prolonged use and may result in overuse of the drug. (Graf et al. 1999, and 1994, Vaidyanathan et al. 2010, Aikman 1975)

Hummel et al, in a placebo-controlled, randomized, double-blind study performed in 36 subjects investigated the dose-related effects of oxymetazoline on olfactory function during the course of the spontaneously occurring cold. Oxymetazoline appeared to have neither negative nor major positive effects on intranasal chemosensory function. It is hypothesized that oxymetazoline needs to be applied locally to the area of the olfactory cleft in order to significantly improve olfaction during the course of the common cold.

The safety of oxymetazoline has been discussed in detail and is supported by a number of references which contain supportive data for the well established use of the active ingredient. The studies are performed using authorised presentations of oxymetazoline (namely Nasivin sanft 0.05% spray, Iladin nasal spray, Daphnlin nasal spray). The main side effects (tolerability, changes in olfactory function, and rebound congestion) have all been discussed and supported by adequate references and data from post marketing experience of other products containing the active.

The applicant has updated the clinical overview at day 105 and day 120 to include 5 studies of the particular product in question post marketing dated 2010 to 2013. The five studies support the proposed product’s safety profile despite the fact that in most of the studies presented are comparative studies with other decongestants. The product has been used in this particular strength and pharmaceutical form for a number of years and the discussion of the references provided show that there are no safety concerns.

III.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 Summary PAR – non-generics 12/14 identify, characterise, prevent or minimise risks relating to Oxymetazoline Dr.Max 0.5mg/ml nasal spray. The RMP version 1.0 was found to be acceptable.

Safety concern: Usage in patients suffering from diabetes mellitus, hypertension, cardiovascular disease, glaucoma, prostatic enlargement and hyperthyroidism. Areas requiring confirmation Proposed routine and additional Objectives or further investigation PhV activities

None Routine pharmacovigilance None proposed

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IV. 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 testing method included 22 participants during 3 rounds and the respondents were asked 16 questions. The test consisted of: a pilot test with 2 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability.

Conclusion

It was agreed that the user testing was successful.

V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

From the quality point of view, the benefit/risk ratio for the product is positive; the application is approvable. According to the stability results presented and in accordance to ICH guidance on stability testing, stability evaluation, and declaration of storage conditions, the proposed shelf life of 24 months for Oxymetazoline hydrochloride 0.5 mg/ml Nasal spray, solution in the intended container with the labelling statement of “Do not store above 30ºC”can be granted; the proposed in-use shelf-life of 30 days after first opening is acceptable.

The application contains an adequate review of published clinical data from 1965 to the present day hence fulfilling the criteria of use of the active ingredient for more than a decade from the first systematic and documented use in the community. The documentation submitted shows that there is still a degree of scientific interested in the use of the substance and the outcome of the studies mentioned is coherent. The data covers the pharmacodynamic effects, posology, safety and efficacy of the active and also takes account of pre- and post-marketing studies in the published literature provided.

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Oxymetazoline Dr. Max 0.5 mg/ml nasal spray, solution in the treatment of local and temporary relief of nasal congestion produced by rhinitis in adults and children over 12 years, is approvable.

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