Nidazea

Hauptinformation

  • Handelsname:
  • Nidazea 7,5 mg/g - Gel
  • Einheiten im Paket:
  • 25 g, Laufzeit: 54 Monate,30 g, Laufzeit: 54 Monate,40 g, Laufzeit: 54 Monate,50 g, Laufzeit: 54 Monate
  • Verschreibungstyp:
  • Arzneimittel zur wiederholten Abgabe gegen aerztliche Verschreibung
  • Verwenden für:
  • Menschen
  • Art der Medizin:
  • allopathic Droge

Dokumenten

Lokalisierung

  • Erhältlich in:
  • Nidazea 7,5 mg/g - Gel
    Österreich
  • Sprache:
  • Deutsch

Therapeutische Informationen

  • Therapiebereich:
  • Metronidazol
  • Produktbesonderheiten:
  • Abgabe durch eine (öffentliche) Apotheke

Weitere Informationen

Status

  • Quelle:
  • AGES
  • Zulassungsnummer:
  • 1-26532
  • Berechtigungsdatum:
  • 04-07-2006
  • Letzte Änderung:
  • 10-08-2017

Öffentlichen Beurteilungsberichts

PAR Metroxx 0.75% Gel / Metrosa 7.5mg/g Gel

UK/H/820/01

1

Public Assessment Report

Mutual Recognition Procedure

Nidazea 7,5 mg/g – Gel

AT/H/0859/001

Name in UK:

Metroxx 0.75% Gel

Metrosa 7.5mg/g Gel

Former Procedure Number:

UK/H/820/01

UK MA number: PL 13159/0006

Dr August Wolff GmbH & Co. KG

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Metroxx 0.75% Gel

Metrosa 7.5mg/g Gel

LAY SUMMARY

Austria, Belgium, Estonia, Germany, Finland, Hungary, Lithuania, Latvia and The

Netherlands have agreed to grant Marketing Authorisations to Dr August Wolff GmbH & Co.

KG for the medicinal product Metroxx 0.75% Gel/Metrosa 7.5mg/g Gel following

acceptance of the UK marketing authorisation. This is a prescription only medicine [POM]

used for the treatment of rosacea (redness in the face, sometimes together with raised areas of

the skin that contain pus).

The active ingredient, metformin, acts against some of the fungi and other organisms that can

affect the skin, and also, in patients suffering from rosacea, it can relieve the condition by

acting against the inflammation which happens when the condition becomes troublesome.

No new or unexpected safety concerns arose from these applications and it was decided that

the benefits of using Metroxx 0.75% Gel/Metrosa 7.5mg/g Gel outweigh the risks, hence the

UK marketing authorisation has been approved.

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TABLE OF CONTENTS

Page

Module 1: Information about initial procedure

Module 2: Summary of Product Characteristics

Module 3: Patient Information Leaflets

Module 4: Labelling

Module 5: Scientific Discussion

1. Introduction

2. Quality aspects

3. Non-clinical aspects

4. Clinical aspects

5. Overall conclusion, Risk-benefit assessment

and Recommendation

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Module 1

Information about initial procedure

Product Names

Metroxx 0.75% Gel

Metrosa 7.5mg/g Gel

Type of Application

Known active substance

Initial application

Bibliographic, Article 10.1(a)(ii)

Chemical Substance

Prescription only

Active Substance

Metronidazole

Form

Strength

0.75%w/w

MA Holder

Dr August Wolff GmbH & Co. KG

RMS

United Kingdom

CMS

Austria, Belgium, Estonia, Germany, Finland, Hungary,

Lithuania, Latvia and The Netherlands

Procedure Number

UK/H/820/01

Timetable

MRP Day 0: 27 January 2006

MRP Day 50: 18 March 2006

MRP Day 85: 22 April 2006

MRP Day 90: 27 April 2006

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Module 2

Summary of Product Characteristics

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1.

NAME OF THE MEDICINAL PRODUCT

Metrosa 7.5 mg/g Gel

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

1 g of gel contains 7.5 mg metronidazole.

Excipient: 30 mg propylene glycol / gram Gel

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Gel.

A smooth clear to turbid colourless to faintly yellow gel

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

For the topical treatment of Rosacea (inflammatory papulopustules rosacea related).

4.2

Posology and method of administration

Method of administration: Cutaneous use.

Adults and the elderly: Apply a thin film of the gel to the affected areas twice daily

for four weeks. Treatment may be continued for a further four weeks if necessary.

Use in children and adolescents: Not recommended as clinical trials have not been

undertaken.

4.3

Contraindications

Hypersensitivity to the active substance “metronidazole” or to any of the excipients

4.4

Special warnings and precautions for use

Avoid contact with the eyes. If contact should occur, wash out of the eyes carefully

with warm water.

Metrosa contains propylene glycol, which may cause skin irritation.

If a reaction suggesting local irritation occurs patients should be directed to use the

medication less frequently, discontinue use temporarily or discontinue use until

further instructions. Metronidazole is a nitroimidazole derivative and should be used

with care in patients with evidence of, or history of blood dyscrasia.

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Extensive exposure of treated sites to ultraviolet or strong sunlight should be avoided

during use of Metrosa. UV-radiation may inactivate metronidazol. The efficacy may

be reduced, but no phototoxicity was demonstrated by clinical results.

Unnecessary and prolonged use of this medication should be avoided.

4.5

Interaction with other medicinal products and other forms of interaction

In the case of oral metronidazole, there have been a small number of reports of a

disulfiram-like reaction if alcohol is taken concomitantly. Although the systemic

absorption of metronidazole from topical presentations is slight this interaction might

be seen.

Oral metronidazole has been reported to potentiate the effect of warfarin and other

coumarin anticoagulants, resulting in a prolongation of prothrombin time. The effect

of topical metronidazole on prothrombin is not known.

4.6

Pregnancy and lactation

Metrosa should not be used if pregnant or if breast-feeding.

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been

performed.

4.8

Undesirable effects

The adverse effects by cutaneous use are only local.

Uncommon (>1/1000, <1/100) there are skin and subcutaneous tissue disorders like

dryness, peeling, or itching.

4.9

Overdose

Overdosage is not to be expected with this preparation. Any excess gel may be

removed by washing with warm water. Appropriate gastric emptying may be used, if

considered necessary, should accidental ingestion occur.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Chemotherapeutics for topical use

ATC Code: D06BX01

Metronidazole is a 5-nitroimidazole derivative with activity against anerobic protozoa

and bacteria, due probably to an interference with DNA by a metabolite of the

metronidazole.

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The precise mode of action of metronidazole in Rosacea is not known. It has been

suggested that it has an anti-inflammatory effect due to an anti-oxidant activity

affecting neutrophil cell function, or that it acts as a parasiticide towards Demodex

folliculorum.

5.2

Pharmacokinetic properties

The gel is applied topically for its local action.

In humans, systemic absorption of 1g gel with 7.5mg metronidazole after topical

application is low (1% of oral dose). Quantifiable serum levels are in the range 25-66

ng/ml and c

is < 5 % of that observed after a 30 mg oral dose (41 ng/ml vs. 850

ng/ml); t

is prolonged, 5.98 hours compared to 0.97 hours orally.

5.3

Preclinical safety data

Single dose studies in mouse and rat by oral, intraperitoneal and intravenous routes

show a low order of toxicity. Repeat dose studies (oral and intravenous) in mouse, rat,

dog, and monkey indicate a no-effect level of 75 mg/kg/day.

Reproductive studies showed no evidence of embryotoxicity or teratogenicity in

mouse, rat and rabbit (oral and intravenous). Reversible male infertility was observed

in rats treated with 400 mg/kg/day.

Metronidazole is mutagenic in bacteria and fungi, but is regarded as non-genotoxic in

mammalian species.

No phototoxic or photogenotoxic effects were seen in studies in Chinese hamster lung

cells.

Carcinogenicity studies in mouse and rats showed an increased incidence of tumour,

but recent epidemiological studies in human showed no increased cancer risk.

No local dermal toxicity (irritation, sensitisation) was seen in guinea pigs.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Phenoxyethanol

Propylene glycol

Hypromellose

Purified water

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

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54 months. Shelf life after first opening is 1 month.

6.4

Special precautions for storage

Do not store above 25

C. Do not refrigerate or freeze.

6.5

Nature and contents of container

Aluminium tube, fitted with a polyethylene (HDPE) screw cap.

Pack sizes: 25g, 30g, 40g, or 50g.

Not all pack sizes are marketed.

6.6

Special precaution for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Dr. August Wolff GmbH & Co. KG Arzneimittel

Sudbrackstrasse 56, 33611 Bielefeld, Germany

e-mail: info@wolff-arzneimittel.de

8.

MARKETING AUTHORISATION NUMBER

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

10.

DATE OF REVISION OF THE TEXT

04/2006

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Module 3

Patient Information Leaflets

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Metrosa 7.5 mg/g Gel

Metronidazole

Read all of this leaflet carefully before you start using this medicine.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them,

even if their symptoms are the same as yours.

If any of the side effects gets serious, or if you notice any side effects not listed in this

leaflet, please tell your doctor or pharmacist.

In this leaflet:

What Metrosa is and what it is used for

Before you use Metrosa

How to use Metrosa

Possible side effects

How to store Metrosa

Further information

1.

WHAT METROSA IS AND WHAT IT IS USED FOR

Metrosa is an antiinflammatory gel to be applied on the skin.

Metrosa is used for the treatment of rosacea (redness in the face, sometimes together with

additional pustules) when the condition suddenly gets worse, and the inflammation becomes

troublesome.

Metronidazole acts against some of the fungi and other organisms that can affect the skin,

and also, in patients suffering from rosacea, it can relieve the condition by acting against the

inflammation which happens when the condition becomes troublesome.

2.

BEFORE YOU USE METROSA

Do not use Metrosa

if you are hypersensitive (allergic) to Metronidazole or any of the other ingredients listed

below

Take special care with Metrosa

Do not let the gel come into contact with the eyes. If it does, wash the gel carefully out of the

eyes with warm water.

Use Metrosa with care if you suffer or suffered in the past from blood dyscrasia.

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Do not go out into strong sunlight, or use UV lamps while you are using this product. Avoid

prolonged and unnecessary use of this medicine.

Use in children and adolescents

Metrosa should not be used in children and adolescents.

Using other medicines

Using Metrosa could interfere with drugs used to thin the blood (anticoagulants) such as

warfarin and coumarin. Contact your doctor for advice if you are taking medicines to thin

your blood, or if you suffer for any other blood disorders.

Please tell your doctor or pharmacist if you are taking or have recently taken any other

medicines, including medicines obtained without a prescription.

Using Metrosa with food and drink

Food and meals can be consumed with only one exception: It is best not to take alcohol while

using the gel, as there is a very small possibility of a reaction that might you feel sick or

nauseous.

Pregnancy and breast-feeding

You should not use the gel if you are pregnant or if you are breast-feeding. If you are, or

think you may be, pregnant, or wish to breast-feed, please make sure your doctor knows of

this immediately.

Driving and using machines

You are allowed to drive and use machines since there are no effects known on the ability to

drive.

Important information about some of the ingredients of Metrosa

Propylene glycol may cause skin irritation. Should this occur, stop using the medicine and

consult your doctor.

3.

HOW TO USE METROSA

Metrosa gel is for cutaneous use only.

Unless your doctor has told you differently, apply a 2 - 3 cm line of gel to the affected areas

and rub it gently into the skin. Use the gel twice each day, for up to four weeks.

Always use Metrosa exactly as your doctor has told you. You should check with your doctor

or pharmacist if you are not sure.

If you use more Metrosa than you should

If you apply too much of the gel, simply wipe off the excess with a clean tissue. The gel is for

use on the skin only. If you, or anyone else, should accidentally swallow a quantity of the gel,

tell your doctor at once, or go to the nearest hospital casualty department.

If you forget to use Metrosa

If you forget to use the gel, then use it as soon as you remember, unless the next application

is due within about two or three hours, in which case omit the forgotten dose.

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If you stop using Metrosa

If you stop using the gel, contact your doctor or pharmacist.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4.

POSSIBLE SIDE EFFECTS

Like all medicines, Metrosa can cause side effects, although not everybody gets them.

Uncommonly (between one and ten per 1000 treated patients), you may notice

dryness

peeling or

itching

after using the gel. If this should become troublesome, stop using the gel and tell your doctor.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist.

5.

HOW TO STORE METROSA

Keep out of the reach and sight of children.

Do not use Metrosa after the expiry date which is stated on the tube. The expiry date refers to

the last day of that month.

Do not store above 25 °C. Do not refrigerate or freeze the gel.

Use within 1 month of first opening.

6.

FURTHER INFORMATION

What Metrosa contains

The active substance is Metronidazole

1 g of gel contains 7.5 mg metronidazole

The other ingredients are phenoxyethanol, propylene glycol, hypromellose, and purified

water.

What Metrosa looks like and contents of the pack

It is made available as a collapsible aluminium tube containing 25 g, 30 g, 40 g or 50 g of the

gel (not all pack sizes will be market at time).

Marketing Authorisation Holder and Manufacturer

Dr. August Wolff GmbH & Co. KG Arzneimittel

Sudbrackstraße 56, D-33611 Bielefeld, Germany

Phone: +49 (0)521 8808-05; Fax: +49 (0)521 8808-334

E-Mail: info@wolff-arzneimittel.de

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This medicinal product is authorised in the Member States of the EEA under the

following names:

Estonia, Germany, Hungary, Latvia, Lithuania: Metrosa 7.5 mg/g Gel

Austria, Belgium, Finlandia, The Netherlands: Nidazea 7.5 mg/g Gel

United Kingdom:

Metroxx 0.75 % Gel

This leaflet was last approved in 04/2006

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Module 4

Labelling

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Metrosa 7.5 mg/g Gel

Metronidazole

1 g of gel contains 7.5 mg metronidazole

Other ingredients: Propylene glycol, hypromellose, phenoxyethanol, purified water

Contains propylene glycol - Read the package leaflet before use

25 g

30 g

40 g

50 g

Cutaneous use

Read the package leaflet before use

Keep out of the reach and sight of children

Avoid contact with the eyes

Expiry date:

Store below 25 °C and do not freeze or refrigerate

Dr. August Wolff GmbH & Co. KG Arzneimittel

Sudbrackstraße 56, 33611 Bielefeld, Germany

Marketing authorisation number: (national number)

Lot:

Medicinal product subject to medical prescription

Braille (Metrosa):

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

Metrosa 7.5 mg/g Gel

Metronidazole

1 g of gel contains 7.5 mg metronidazole

Other ingredients: Propylene glycol, hypromellose, phenoxyethanol, purified water

Contains propylene glycol - Read the package leaflet before use

25 g

30 g

40 g

50 g

Cutaneous use

Read the package leaflet before use

Keep out of the reach and sight of children

Avoid contact with the eyes

Expiry date:

Store below 25 °C and do not freeze or refrigerate

Dr. August Wolff GmbH & Co. KG Arzneimittel

Sudbrackstraße 56, 33611 Bielefeld, Germany

Marketing authorisation number: (national number)

Lot:

Medicinal product subject to medical prescription

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Scientific discussion during the initial procedure

1.

INTRODUCTION

1.1

RECOMMENDATION

Based on the review of the data on quality, safety and efficacy, the reference member

state (RMS) considered that the application for Metroxx 0.75% Gel in the treatment of

acute exacerbations of acne rosacea, could be approved. A national marketing

authorisation was granted on 15 November 2004.

1.2

EXECUTIVE SUMMARY

Problem statement

These mutual recognition applications consider a bibliographic application for

Metroxx 0.75% Gel.

The product was granted a marketing authorisation in the UK on 15 November 2004.

With the UK as the Reference Member State in this Mutual Recognition Procedure

(MRP), the Marketing Authorisation Holder, Dr August Wolff GmbH & Co. KG, is

applying for marketing authorisations for Metroxx 0.75% Gel in Estonia, Germany,

Hungary, Latvia and Lithuania.

Regarding patient user testing and harmonisation of the PIL, as far as the UK is

concerned these will be completed within 12 months. As far as the individual member

states in the MRP are concerned, a timetable will be agreed in discussion with each of

the individual concerned member states (CMSs) to meet the requirements of that

CMS.

About the product

Metroxx 0.75% Gel contains the well-established active substance, metronidazole, in

a topical gel formulation and is for the treatment of acute exacerbations of acne

rosacea.

Metronidazole has been used clinically for more than 40 years. It is a 5-nitroimidazole

derivative, with activity against anaerobic protozoa and bacteria, due probably to an

interference with DNA by a metabolite of metronidazole.

Orally, metronidazole is active against anaerobic protozoa such as Entamoeba

histolytica, Giardia intestinalis and Trichomonas vaginalis. Most obligate anaerobes

are susceptible to metronidazole, such as Clostridium spp., and some facultative

anaerobes, such as Campylobacter (Helicobacter) spp. It has also been used locally in

the form of suppositories and pessaries.

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The development programme

The objective of the development programme was to formulate a robust, stable,

acceptable aqueous gel formulation of metronidazole 0.75% that was easily applied,

non-sticky and left no visible film after application.

General comments on compliance with GMP, GLP, GCP and agreed ethical

principles

No new preclinical studies were conducted, which is acceptable given that the legal

basis for this application was Article 10.1(a)(ii) of Directive 2001/83/EC, a

bibliographic application.

No clinical studies were conducted, which is acceptable given that the legal basis for

this application was Article 10.1(a)(ii) of Directive 2001/83/EC, a bibliographic

application.

The RMS has been assured that acceptable standards of GMP are in place for these

product types at all sites responsible for the manufacture and assembly of this product

prior to granting its national authorisation.

For manufacturing sites within the community, the RMS has accepted copies of

current manufacturer authorisations issued by inspection services of the competent

authorities as certification that acceptable standards of GMP are in place at those sites.

2.

QUALITY ASPECTS

2.1

INTRODUCTION

This is a standard abridged application for a topical gel, containing metronidazole

0.75%w/w as the active ingredient. The application has been made under Article

10.1(a)(ii) of Directive 2001/83/EC, as amended, supplemented by clinical data.

The product is intended for topical administration in the treatment of acute

exacerbations of acne rosacea. Metroxx Gel is intended to be applied as a thin film to

the affected areas twice daily for 4 weeks, continuing for a further 4 weeks, if

clinically necessary.

The applicant already has UK Marketing Authorisations for identical preparations

Skinola Gel PL 13159/0001 (granted 28 July 1995) and Metrosa Gel 0.75% PL

13159/0004 (granted 7 June 1999). Metrosa Gel was approved as a piggy-back to

Skinola Gel.

2.2

DRUG SUBSTANCE

The drug substance has been used in granted topical preparations, including the

applicant’s own products, Skinola Gel and Metrosa Gel.

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General Information

Nomenclature

rINN:

Metronidazole

Compendial name:

Metronidazole (Ph.Eur)

Chemical Name:

2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethanol.

Structure

Molecular Formula:

Molecular Weight:

171.2

General Properties

Appearance: White or yellowish, crystalline powder.

Solubility: Slightly soluble in water, in acetone, in alcohol and in methylene chloride.

Melting Point: 159˚C to 163˚C.

Manufacture

Manufacturers

Description of Manufacturing Process and Process Controls

Control of Materials

Controls of Critical Steps and Intermediates

These are covered by the EDQM Certificate of Suitability.

Characterisation

Elucidation of Structure and Other Characteristics

This is covered by the EDQM Certificate of Suitability.

Impurities

This is covered by the EDQM Certificate of Suitability. The Certificate states that

water is used in the last step of synthesis.

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Control of drug substance

Specification

Analytical Procedures

Validation of Analytical Procedures

Batch Analyses

Justification of specification

The drug substance is tested in accordance with the Ph.Eur. monograph. Certificates

of Analysis from both the drug substance manufacturer and the finished product

manufacturer (Dr August Wolff GmbH and Co, Arzneimittel) have been provided. No

analytical validation data are supplied. This is acceptable as Ph.Eur. methods are used.

Reference Standards or Materials

Metronidazole Ph.Eur. CRS is used as primary reference standard; working standards

are validated against this primary reference standard. This is satisfactory.

Container/closure system

The drug substance is packed in sealed double PE bags and placed in fibreboard

drums.

Stability

Stability data for six batches of metronidazole stored at 40

C/75%RH for 6 months

and seven batches stored at 25

C/60%RH for up to 60 months have been provided.

These data show no significant changes in appearance, identification, melting range,

assay and impurities in the batches tested under accelerated or long-term conditions

and demonstrate that the drug substance is stable for up to 60 months when stored at

C/60%RH. Based on these data, the re-test period of 60 months is satisfactory.

Literature references have been provided for photo stability studies performed, which

indicate that metronidazole is photolabile and should be protected from direct

sunlight.

2.3

MEDICINAL PRODUCT

Description and composition of the drug product

Smooth clear to turbid, colourless to faintly yellow gel.

Composition:

Ingredients

Quantity

Reference

Standard

Function

Metronidazole

0.75%w/w Ph.Eur.

Active

Phenoxyethanol

Ph.Eur.

Preservative

Propylene glycol

Ph.Eur.

Vehicle

Methylhydroxypropyl cellulose

4000

Ph.Eur.

Thickener

Purified water

Ph.Eur.

Vehicle

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The gel is contained in collapsible aluminium tubes, with a sealing band and is fitted

with a polyethylene cap.

Pharmaceutical Development

The aim of the development programme was to formulate an aqueous gel that was

easily applied, non-sticky and left no visible film after application. Very little

development pharmaceutics data is provided. According to the expert most of the

formulation requirements were obtained by use of well-recognised excipients.

The function of each excipient has been explained and justification given for its

choice - hypromellose 400 (viscosity adjuster), propylene glycol (humectant),

phenoxyethanol (preservative) and purified water (vehicle). Three preservative

efficacy systems were considered before selection of the final preservative. BP

preservative efficacy tests showed adequate preservative efficacy for all three

preservative systems. Phenoxyethanol was chosen because it is well tolerated and has

a low allergising potential.

The final formulation was compared to Metrogel (Sandoz, UK) in an in-vitro

diffusion test, using nude mouse kin membrane. The applicant has provided details of

the methods used and the results provided show that the two products have similar

characteristics.

The formulation for all clinical trial batches is claimed to be the same as that proposed

in this application.

No specific studies were performed to investigate the compatibility between the

product and container as the applicant considered that water-based cellulose gel and

other ingredients were not aggressive to collapsible Al tubes that are internally coated

with epoxy resin. A similarly packaged product, Neutratop has been marketed in the

UK since 1999 with no compatibility problems.

Manufacture

Manufacturers

Batch release is carried out at Dr August Wolff GmbH & Co KG Arzneimittel,

Sudbrackstrasse 56, 33611 Bielefeld, Germany. This site has been approved for use in

granted topical preparations marketed in the UK.

Batch formula

A satisfactory manufacturing formula is provided for a production batch size. No

overages are included or required.

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Description of manufacturing process and process controls

The equipment used are stated. All manufacturing equipment are cleaned and checked

for cleanliness before use. A satisfactory description is provided on the manufacturing

method. The resultant gel is sampled and after QC release filled into tubes, sealed and

packaged.

In-process controls during manufacture include checks on the complete dissolution of

metronidazole crystals and checks for absence of lumps and undispersed aggregates

of methylhydroxypropyl cellulose. Before filling, the tests for release according to the

finished product specification are carried out. After filling the product is tested again

for appearance, identity and microbiological purity. Controls applied are considered

satisfactory.

Control of critical steps and intermediates

There are no critical steps in the manufacturing process.

Process validation and/or evaluation

No specific process validation data are provided for this product. According to the

applicant the manufacturing process is relatively standard and manufacture of an

aqueous cellulose type gel is claimed to be without any technical difficulties. The

manufacturer has also claimed to have several years of manufacturing experience of

the product. In-process controls ensure the complete dissolution of the drug and

incorporation of hypromellose in the solution mix.

In addition, the applicant has committed to providing data from the first production-

scale batches produced and has provided a copy of the formal validation programme

to be followed for production-scale batches. It includes satisfactory checks during the

preparation of solution, suspension, and final gel. During filling, checks are made of

viscosity, fill weight, active and preservative assays, and microbial testing. The

equipment to be used for production scale batches will be comparable to that used for

pilot scale batches.

Overall the data provided is acceptable.

Control of excipients

All added ingredients comply with their respective Ph.Eur monographs. Certificates

of Analysis have been provided for all excipients showing compliance with their

respective Ph.Eur. monographs. The dosage form manufacturer performs full testing

to Ph.Eur. for purified water, hypromellose and phenoxyethanol. Propylene glycol is

tested for identity (A-D), appearance, relative density and refractive index by the

dosage form manufacturer, with all other test results taken from the supplier.

Excipients of human and animal origin

None of the materials used in the manufacture of the product are of human or animal

origin. Supporting certification is provided.

PAR Metroxx 0.75% Gel / Metrosa 7.5mg/g Gel

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24

Control of drug product

Specifications

The finished product specification is satisfactory. Controls on microbiological quality

are in line with Ph.Eur. requirements and are satisfactory.

Analytical procedures

Validation of analytical procedures

Analytical methods used have been satisfactorily described. Methods are general

pharmacopoeial procedures or BP/Ph.Eur.

Batch analysis

Batch analytical data are provided for three consecutive pilot scale batches. All

batches comply with the proposed specification.

The finished product specification was changed during the national assessment. In

view of this, the applicant provided additional batch analysis data for three batches.

Justification of specifications

Satisfactory justifications are given for the specifications proposed.

Reference standards or materials

The reference standards used are Metronidazole Ph.Eur CRS, 2-methyl-5-

nitroimidazole BPCRS or Ph.Eur CRS. Phenoxyethanol complies with BP/Ph.Eur.

requirements. A satisfactory Certificate of Analysis is provided for the in-house

reference sample.

Container closure system

Collapsible aluminium tubes with epoxy-phenol resin combination as internal

protective lacquer (TU 25/N 48169/H) and white polyethylene (HDPE) screw cap.

The lower end of the tubes is coated internally with a sealant lacquer. Manufacturers

of the various components are stated. The internal tube lacquer complies with FDA

requirements for resinous and polymeric coatings which may be safely used as food

contact surfaces for packaging of food products. The sealant lacquer also complies

with FDA requirements for materials suitable for food contact use. The HDPE screw

cap complies with Ph.Eur. and EC requirements. Suppliers/manufacturers

specifications for the packaging materials have been submitted and are all

satisfactory.

Pack size: 25g, 40g and 50g.

Stability

Shelf-life: 54 months; Storage conditions: Do not store above 25C. Do not refrigerate

or freeze the gel. In-use shelf-life: 1 month.

PAR Metroxx 0.75% Gel / Metrosa 7.5mg/g Gel

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Stability data are provided for batches filled into the proposed immediate packaging

material. Drug substance used in all finished product batches was from one batch.

Samples have been stored at 25C/60% RH for over 60 months.

The proposed shelf-life and storage proposals are generally satisfactory. The applicant

has also provided results from preservative efficacy testing for two batches, which

show compliance with the current Ph.Eur requirements for preservative efficacy. The

applicant has committed to putting the first three production-scale batches on ICH

follow-up stability studies.

In-use stability data satisfactorily supports the in-use shelf life of 1 month for this

product.

Regional Information

The process validation plan for 3 full-scale production batches is outlined and is

satisfactory.

A copy of the EDQM Certificate of Suitability is provided.

The applicant has confirmed that the product complies with current CPMP-CVMP

requirements on minimising the risk of transmitting animal spongiform agents via

human and medicinal products. Supporting declarations are also provided by

manufacturers of active and excipients.

Clinical module

Protocol Dr August Wolff/01: A double-blind, double-dummy study has been

undertaken to compare the effectiveness of 0.75% metronidazole gel and tetracycline

in the treatment of papulo-pustular rosacea. The study was carried out during

September 1993-March 1999. Three batches of the metronidazole gel (Skinola Gel)

have been used. In response to a question during the national assessment,

confirmation was provided that Skinola Gel is the same as the product proposed for

marketing.

Protocol 05: A comparative study of cutaneous levels of metronidazole after topical

application in normal volunteers has been sponsored by the applicant. The study was

designed to compare the percutaneous penetration of the applicant’s formulation with

MetroGel (Sandoz, UK). The study was a double-blind study using a single

investigator. Twenty-four normal subjects were used and subjects were randomly

allocated to four groups of 6 individuals. The test and reference products were applied

to the flexor aspect of the forearms, one to each arm. Approximately 0.1g of gel was

rubbed into the skin. After 30 minutes, samples of the stratum corneum and full

thickness skin were removed from six subjects and repeated at 1, 2 and 4 hours for the

remaining groups of six subjects. The levels of metronidazole in tissue samples were

determined by an HPLC method. The HPLC method with detection at 324nm has

been adequately described and validated.

Protocol CSL 03: Metronidazole gel 0.75% and the gel base with four other topical

formulations have been tested in 102 healthy volunteers, to assess their irritancy and

sensitisation potential. The study was a single centre; double blind study and was

PAR Metroxx 0.75% Gel / Metrosa 7.5mg/g Gel

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26

designed as a repeat insult patch test investigation consisting of six applications over a

15-day irritancy phase and a challenge on day 22 to determine irritancy. All six

products were tested under occlusion using a 12-mm aluminium Finn chamber on

Scanpor tape.

Protocol CSL 04: A single-centre, double-blind randomised study to determine the

photo toxicity potential of metrondazole gel and base formulation in 12 normal

volunteers.

Batch numbers and batch sizes of all batches used in the clinical trials have been

provided and batch analytical results for these are satisfactory.

Quality Overall Expert

The Quality Expert has appropriate qualifications and has provided a satisfactory

report.

2.4

PHARMACEUTICAL CONCLUSION

It is recommended that a product licence should be granted.

3.

NON-CLINICAL ASPECTS

3.1

INTRODUCTION

This is a standard abridged application for Metroxx Gel containing 0.75%w/w of the

active ingredient metronidazole and submitted under Article 10.1a(ii) of Directive

2001/83/EC.

The proposed formulation is intended for topical application, in the treatment of acute

exacerbations of acne rosacea for up to 8 weeks. The applicant has marketing

authorisations in the UK for similar topical products, namely Skinola Gel

(PL13159/0001) and Metrosa Gel 0.75% (PL13159/0004).

Expert report

A pharmaco-toxicological Expert Report has been supplied. This consists of a critical

review of the toxicology of metronidazole with reference to published literature. The

pharmacology of metronidazole is also briefly discussed. Unfortunately, the published

literature has not been submitted in support of this application.

3.2

DISCUSSION ON THE NON-CLINICAL ASPECTS

Metronidazole, a 5-nitro-imidazole derivative, is an antimicrobial medicine with

activity against anaerobic bacteria and protozoa. The pharmacology and toxicology of

metronidazole are well established, and have been adequately reviewed by the

Expert.

The source of active ingredient has been previously used in other UK medicinal

products and impurities are controlled according to a previously granted drug master

file and do not raise any safety concerns.

PAR Metroxx 0.75% Gel / Metrosa 7.5mg/g Gel

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27

The main concern with this type of application is whether systemic absorption of

metronidazole is considerably higher than other marketed metronidazole

formulations. Apparently, there are no preclinical pharmacokinetic data with topically

applied metronidazole. In monkeys, metronidazole (1mg/kg) applied to vagina was

extensively absorbed systemically (bioavailability was 73%). However, in humans,

systemic absorption of 1g metronidazole 0.75% applied to the skin was very low

(approximately 1% of that seen after an oral dose) such that serum concentrations of

metronidazole were in the range 25-66ng/ml and C

was 20% of that observed after

a 30mg oral dose (41ng/ml vs 850ng/ml).

Metronidazole is extensively metabolised by the liver. One of its two major

metabolites, namely 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (the

hydroxy metabolite) has 30-65% of the biological activity of the parent drug and a

longer elimination half-life than the parent compound. It is not known whether this

active hydroxy metabolite is formed following topical administration of

metronidazole. However, in view of the low systemic absorption of parent drug when

applied to human skin, plasma levels of the active hydroxy metabolite, if formed, are

unlikely to be of safety concern.

Considering the low systemic concentrations of metronidazole anticipated with the

proposed formulation, the existing safety margins are unlikely to be eroded with this

new topical formulation at the proposed dose regimen and there are no preclinical

objections to grant a Marketing authorisation for Metroxx Gel.

3.3

CONCLUSION

There are no preclinical objections to grant of a Marketing Authorisation for Metroxx

Gel.

4.

CLINICAL ASPECTS

4.1

INTRODUCTION

This is an abridged standard licensing application of metronidazole gel for cutaneous

use regarding the treatment of acute exacerbations of acne rosacea. It is submitted

under Article 10.1a(ii) of Directive 2001/83/EC. The application is based on reference

to bibliography and supplementary clinical studies with this particular gel.

Background

Metronidazole is an antimicrobial drug with high activity against anaerobic bacteria

and protozoa.

Indications

For the treatment of acute exacerbations of acne rosacea

Assessor's comment

This indication is appropriate.

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Dose & dose schedule

Adults and the elderly: Apply a thin film of the gel to the affected areas twice daily

for four weeks. Treatment may be continued for a further four weeks if necessary.

Use in children: Not recommended.

Toxicology

This has been assessed separately. An increased number of tumours have been

reported in studies with high doses of metronidazole in rats and mice. The issue of

carcinogenicity in animal studies is discussed in the toxicology assessment.

Clinically, this subject has also been reviewed. There appears to be no evidence to

date to substantiate an increased risk of cancer in humans.

4.2

PHARMACOKINETICS

The gel is applied topically for its local action. There is limited data on absorption

using a 0.75% gel. The five studies reviewed in this application show that use of 1g of

gel (7.5mg metronidazole) topically results in blood levels ranging from undetectable

to about 1% of the C

seen from oral dosing.

4.3

PHARMACODYNAMICS

The precise mode of action of metronidazole in acne rosacea is not known. It has been

suggested that it has an anti-inflammatory effect due to an anti-oxidant activity

affecting neutrophil cell function, or that it acts as a parasiticide towards Demodex

folliculorum.

4.4

CLINICAL EFFICACY

The applicant has submitted a critical review of thirty-two published studies and

clinical trials. Copies of these publications are provided.

One double-blind, placebo-controlled study conducted in Sweden, involving 81

patients, showed that topical metronidazole at a concentration of 1% in a cream base

was effective topical therapy for rosacea. Another double-blind study comprising 51

patients, compared 1% metronidazole cream with systemic oxytetracycline; although

both groups demonstrated a high degree of improvement there was no difference

between the two groups.

Another, double-blind, placebo-controlled study investigated 59 subjects treated for

9 weeks with metronidazloe 0.75% gel or base alone. Statistically significant

reductions in erythema and global improvement were seen in the metronidazole group

compared with placebo. However, selective measurements of telangiectasia showed

no improvements with either metronidazole or placebo.

Another double-blind study consisting of 33 patients compared 0.75% metronidazole

gel versus tetracycline treatment over a 9-week period. There was no statistically

significant difference between the two groups. However, the study was relatively

PAR Metroxx 0.75% Gel / Metrosa 7.5mg/g Gel

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29

small with only 16 patients in treatment group and does not show clear improvement

of the rosacea by both treatments.

In another double-blind, randomised study had two treatment groups: (A) topical

metronidazole 0.75% gel BID (plus oral placebo tetracycline) or (B) oral tetracycline

500mg (plus gel base BID). Treatment period was 9 weeks with a 3-week follow-up

period. Seventy-four subjects were recruited and 64 were available for per-protocol

analysis of efficacy. Assessments were at weeks 0, 3, 6, 9 and 12 (follow-up). The

primary efficacy variable was defined as the total number of inflammatory lesions.

The results of each of the two centres and the combined findings are summarised in

table 1 below.

Table 1 Mean total number of inflammatory lesions

Treatment A

Treatment B

Cardiff

Gdansk

Combined

Cardiff

Gdansk

Combined

Week 0

42.05

75.00

56.30

38.29

64.38

49.57

Week 3

22.60

40.00

30.06*

17.13

30.06

23.81*

Week 6

13.44

14.14

13.75*

8.38

16.21

12.44*

Week 9

9.71

9.29

9.52*

6.50

9.86

8.31*

Week 12

8.69

10.71

9.63*

4.70

8.14

6.71*

* p<0.001 for difference from Week 0

Both treatments showed significant improvement (p<0.001), with the most rapid

improvement occurring during the first 3 weeks, at which stage the tetracycline group

was significantly better than metronidazole (p<0.05), although this difference

disappears at weeks 6 and 9. At follow-up the metronidazole group remains much the

same but there is continued improvement in the tetracycline group with a significant

difference at twelve weeks (p<0.01).

One study took a different approach of using topical metronidazole 0.75% gel in

combination with tetracycline initially to control the rosacea, and then continuing with

BID application of gel to maintain control. The study was in two parts, an open

portion initially in which 113 patients were enrolled and treated with a combination of

oral tetracycline plus topical metronidazole 0.75% gel. Successfully treated patients

(88) were entered into the second part of the study which was randomised, double-

blind, placebo controlled comparing metronidazole 0.75% gel BID with the gel base

(placebo) in a long term (6 month) follow-up. The rationale was to cease oral

tetracycline as soon as remission occurred to avoid the risk of systemic complications

and adverse events from the use of long term systemic antibiotics. The primary

criteria for assessing efficacy were again inflammatory lesion counts. The results are

summarised in table 2 below.

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30

Table 2 Summary of response to treatment with topical Metronidazole 0.75%

Gel or Placebo

Metronidazole

Placebo

Week 12

Week 24

Week 12

Week 24

% Patients Relapsing

% Patients free of Inflammatory

Lesions

Mean No. of Inflammatory

Lesions

3.3**

% Erythema rated as 0 or Mild

* p<0.05

** p<0.01 at both 12 and 24 weeks

The results of this maintenance treatment study showed that metronidazole 0.75% gel

significantly prolonged the disease-free interval and minimised recurrence.

Assessor’s comments

The results of the studies presented show that this formulation of topical

metronidazole 0.75% gel is probably as effective as oral tetracycline in the treatment

of rosacea.

4.5

CLINICAL SAFETY

In general, the incidence of dermatological reactions is low. The applicant has

provided a review with reference to the published clinical trials. The commonest

events are erythematous rash and localised skin reactions. In reports of three studies,

the irritancy and sensitisation potential of Metroxx gel was examined by the standard

repeat insult technique in 102 subjects. Metroxx was shown to be non-irritant with a

moderate potential for sensitisation. Photosensitivity potential was studied in 12

healthy volunteers using the standard technique and the results showed no evidence of

phototoxicity.

Skin penetration compared with Metrogel was examined by using the skin surface

biopsy (skin snipping) technique to remove five successive samples following

application of Metroxx and Metrogel in 24 subjects. All analyses were blind. Small

differences were detected indicating that Metroxx seemed to penetrate the stratum

corneum at a greater rate.

Assessor’s comment

It would appear that the absorption of Metroxx is faster than that of Metrogel

preparation. However, the average dose applied to the face is less than 4mg

metronidazole daily. Even if this was absorbed in total, blood levels would still be

very low compared with the doses of up to 2g daily orally, where the absorption is

known to approach 100%. Therefore, topical usage can be said to provide a wide

therapeutic margin of safety.

PAR Metroxx 0.75% Gel / Metrosa 7.5mg/g Gel

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31

4.6

DISCUSSION

Metronidazole has been used in clinical practice in the UK for well over 30 years. It

has a recognised efficacy and acceptable safety profile. Topical metronidazole has

been licensed for the treatment of rosacea for more than 10 years in a number of

countries including the UK, USA and France.

With regards to current application, sufficient clinical information has been

submitted. When used as indicated, Metroxx Gel 0.75% has a favourable benefit-to-

risk ratio. The hazard associated with Metroxx Gel appears to be low and acceptable

when considered in relation to its therapeutic benefits.

Expert report

A satisfactory Clinical Expert Report has been submitted with appropriate CV.

4.7

CONCLUSION

Marketing authorisation may be granted on medical grounds.

PAR Metroxx 0.75% Gel / Metrosa 7.5mg/g Gel

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32

5.

OVERALL CONCLUSION, RISK-BENEFIT ASSESSMENT AND

RECOMMENDATION

QUALITY

The important quality characteristics of Metroxx 0.75% Gel/Metrosa 7.5mg/g Gel is

well defined and controlled. The specifications and batch analytical results indicate

consistency from batch to batch. There are no outstanding quality issues that would

have a negative impact on the benefit/risk balance.

NON-CLINICAL

Considering the low systemic concentrations of metronidazole anticipated with the

proposed formulation, the existing safety margins are unlikely to be eroded with this

topical formulation.

CLINICAL

Metronidazole has been used in clinical practice in the UK for well over 30 years. It

has a recognised efficacy and acceptable safety profile. Topical metronidazole has

been licensed for the treatment of rosacea for more than 10 years in a number of

countries including the UK, USA and France.

No new or unexpected safety concerns arise from this application.

RISK-BENEFIT ASSESSMENT

The quality of the product is acceptable and no new preclinical or clinical safety

concerns have been identified. The hazard associated with Metroxx 0.75%

Gel/Metrosa 7.5mg/g Gel appears to be low and acceptable when considered in

relation to its therapeutic benefits. The risk-benefit assessment is therefore considered

to be favourable.

RECOMMENDATION

Based on the review of the data on quality, safety and efficacy, it was considered that

the application for Metroxx 0.75% Gel/Metrosa 7.5mg/g Gel in the treatment of

rosacea, could be approved for use as described in the Summary of Product

Characteristics.

33/34

Public Assessment Report

Update

Nidazea 7,5 mg/g – Gel

AT/H/0859/001

This module reflects the procedural steps and scientific information after the finalisation of the

initial procedure.

34/34

Procedure number*

Scope

Product Information

affected

Date of end of

procedure

Approval/

non approval

II/012

Revision of the SPC and PL

16/12/2009

Approved

R/001

Renewal of Marketing Authorisation

18/06/2015

Approved

UK/H/0820/001

AT/H/0859/001

Transfer of RMS

06/03/2018

Approved

*Only procedure qualifier, chronological number and grouping qualifier (when applicable)

Packungsbeilage: zusammensetzung, kinische angaben, nebenwirkungen, wechselwirkungen, dosierung, schwangerschaft, stillzeit

PACKUNGSBEILAGE

GEBRAUCHSINFORMATION: INFORMATION FÜR ANWENDER

Nidazea 7,5 mg/ g - Gel

Wirkstoff: Metronidazol

Lesen Sie die gesamte Packungsbeilage sorgfältig durch, bevor Sie mit der Anwendung dieses

Arzneimittels beginnen, denn sie enthält wichtige Informationen.

Heben Sie die Packungsbeilage auf. Vielleicht möchten Sie diese später nochmals lesen.

Wenn Sie weitere Fragen haben, wenden Sie sich an Ihren Arzt oder Apotheker.

Dieses Arzneimittel wurde Ihnen persönlich verschrieben. Geben Sie es nicht an Dritte weiter.

Es kann anderen Menschen schaden, auch wenn diese die gleichen Beschwerden haben wie Sie.

Wenn Sie Nebenwirkungen bemerken, wenden Sie sich an Ihren Arzt oder Apotheker.

Dies gilt auch für Nebenwirkungen, die nicht in dieser Gebrauchsinformation

angegeben sind. Siehe Abschnitt 4.

Was in dieser Packungsbeilage steht:

Was ist Nidazea und wofür wird es angewendet?

Was sollten Sie vor der Anwendung von Nidazea beachten?

Wie ist Nidazea anzuwenden?

Welche Nebenwirkungen sind möglich?

Wie ist Nidazea aufzubewahren?

Inhalt der Packung und weitere Informationen

1.

WAS IST NIDAZEA UND WOFÜR WIRD ES ANGEWENDET?

Nidazea ist ein anti-entzündliches Gel zum Auftragen auf die Haut.

Nidazea wird angewendet zur Behandlung von Rosacea (Gesichtsröte, teilweise zusammen mit

Pusteln) bei plötzlicher Verschlechterung des Hautzustandes und wenn die Entzündung als störend

empfunden wird.

1 g Nidazea enthält 7,5 mg Metronidazol als Wirkstoff.

Metronidazol wirkt gegen einige Pilze und Organismen, die die Haut beeinflussen. Bei Patienten, die

an Rosacea leiden, kann Metronidazol das Befinden verbessern durch eine Wirkung gegen die

Entzündung, die bei Verschlechterung des Hautzustandes auftritt.

2.

WAS SOLLTEN SIE VOR DER ANWENDUNG VON NIDAZEA BEACHTEN?

Nidazea darf nicht angewendet werden,

wenn Sie überempfindlich (allergisch) gegen Metronidazol oder Propylenglykol oder einen der

in Abschnitt 6. genannten sonstigen Bestandteile dieses Arzneimittels sind.

Warnhinweise und Vorsichtsmaßnahmen

Bitte sprechen Sie mit Ihrem Arzt oder Apotheker bevor Sie Nidazea anwenden.

Lassen Sie das Gel nicht in Kontakt mit den Augen oder Schleimhäuten kommen. Falls es doch dazu

kommt, spülen Sie das Gel sorgfältig mit warmem Wasser aus den Augen.

Wenn es zu einer Hautreizung kommt, wenden Sie Nidazea weniger häufig an oder unterbrechen Sie

die Behandlung. Falls nötig, wenden Sie sich bitte an Ihren Arzt.

Vermeiden Sie starkes Sonnenlicht (Sonnenbaden) oder die Anwendung von UV-Bestrahlung

(Solarium, Höhensonne) während der Behandlung mit Nidazea. Metronidazol kann durch UV-Licht

inaktiviert werden.

Vermeiden Sie eine länger als vorgesehene und unnötige Anwendung von Nidazea. Sie sollten die

empfohlene Anwendungsdauer nicht überschreiten. Wenn nötig, kann die Behandlung auf ärztliche

Anweisung wiederholt werden. Bitte beachten Sie, dass zwischen den Behandlungen eine Pause von

sechs Wochen eingehalten werden muss.

Verwenden Sie Nidazea mit Vorsicht, falls bei Ihnen eine Bluterkrankung (Blutdyskrasie) vorliegt

oder in der Vergangenheit festgestellt wurde.

Kinder und Jugendliche

Es existieren keine ausreichenden klinischen Daten für die Wirksamkeit und Sicherheit der

Anwendung von Metrosa 7,5 mg/g Gel bei Kindern; daher sollte es nicht bei Kindern und

Jugendlichen angewendet werden.

Anwendung von Nidazea zusammen mit anderen Arzneimitteln

Informieren Sie Ihren Arzt oder Apotheker wenn Sie andere Arzneimittel einnehmen/anwenden,

kürzlich andere Arzneimittel eingenommen/angewendet haben oder beabsichtigen andere Arzneimittel

einzunehmen/anzuwenden.

Wechselwirkungen mit systemisch wirkenden Arzneimitteln sind unwahrscheinlich, da die Absorption

(die Fähigkeit durch die Haut in den Körper zu gelangen) bei äußerlich angewendetem Metronidazol

gering ist.

Dennoch traten nach gleichzeitiger Einnahme von Metronidazol und Alkohol bei einigen Patienten

Disulfiram-artige Reaktionen auf. Diese äußern sich als Übelkeit, Erbrechen, Hautrötung, Herzrasen

und Atemnot.

Die Anwendung von Nidazea kann Wechselwirkungen mit Arzneimitteln zur Blutverdünnung

(Antikoagulantien) verursachen (z.B. Warfarin oder Kumarin).

Bitte fragen Sie Ihren Arzt um Rat, wenn Sie Arzneimittel zur Blutverdünnung einnehmen, oder wenn

Sie an einer anderen Bluterkrankung leiden.

Anwendung von Nidazea zusammen mit Nahrungsmitteln, Getränken und Alkohol

Mit nur einer Ausnahme können Nahrungsmittel und Getränke gegessen bzw. getrunken werden:

Alkohol sollte während der Anwendung des Gels nicht getrunken werden. Mit sehr geringer

Wahrscheinlichkeit können Übelkeit und Erbrechen auftreten.

Schwangerschaft und Stillzeit

Nidazea darf in der Schwangerschaft nur nach strenger Nutzen-Risiko-Bewertung durch Ihren Arzt

verordnet werden.

In der Stillzeit sollten Sie entweder das Stillen oder die Anwendung von Nidazea unterbrechen. Fragen

Sie hierzu Ihren Arzt.

Verkehrstüchtigkeit und Fähigkeit zum Bedienen von Maschinen

Sie können während der Anwendung von Nidazea Fahrzeuge steuern und Maschinen bedienen, da

keine Einschränkung der Verkehrstüchtigkeit bekannt ist.

Nidazea enthält Propylenglycol

Propylenglycol kann Hautreizungen auslösen. Beenden Sie die Anwendung von Nidazea in diesem

Fall und suchen Sie Ihren Arzt auf.

3.

WIE IST NIDAZEA ANZUWENDEN?

Nidazea Gel ist zur Anwendung auf der Haut bestimmt.

Falls vom Arzt nicht anders verordnet, tragen Sie einen 2 – 3 cm langen Strang des Gels auf die

betroffenen Hautbereiche auf und reiben das Gel sanft in die Haut ein. Wenden Sie das Gel zweimal

täglich über einen Zeitraum bis zu 4 Wochen an.

Wenden Sie Nidazea immer genau nach der Anweisung des Arztes an. Bitte fragen Sie bei Ihrem Arzt

oder Apotheker nach, wenn Sie sich nicht ganz sicher sind.

Metronidazol sollte zweimal täglich, morgens und abends, in einer dünnen Schicht auf die betroffenen

Hautstellen aufgetragen werden. Die zu behandelnden Hautstellen sollten vor dem Auftragen mit

einem milden Reinigungsmittel gewaschen werden. Die Patienten können nach der Anwendung von

Metronidazol nicht komedogen und nicht adstringierende Kosmetika verwenden.

Für ältere Patienten muss die Dosierung nicht angepasst werden. Die empfohlene Behandlungsdauer

sollte nicht überschritten werden.

Anwendung bei Kindern und Jugendlichen

Metrosa wird nicht für die Anwendung bei Kindern empfohlen, da keine Daten zur Sicherheit und

Wirksamkeit vorliegen.

Wenn Sie eine größere Menge von Nidazea angewendet haben, als Sie sollten

Falls Sie zuviel Gel aufgetragen haben, wischen Sie den Überschuss einfach mit einem Papiertuch

bzw. warmem Wasser ab. Das Gel ist nur zur Anwendung auf der Haut bestimmt. Wenn Sie oder

jemand anders versehentlich etwas Gel verschlucken, informieren Sie sofort den Arzt oder suchen die

nächste Ambulanz auf.

Wenn Sie die Anwendung von Nidazea vergessen haben

Wenn Sie die Anwendung von Nidazea vergessen haben, wenden Sie das Gel unverzüglich an. Wenn

die nächste reguläre Anwendung in zwei bis drei Stunden erfolgen würde, lassen Sie die vergessene

Anwendung aus.

Wenn Sie die Anwendung von Nidazea abbrechen

Wenn Sie die Anwendung von Nidazea abbrechen, sprechen Sie Ihren Arzt oder Apotheker an.

Wenn Sie weitere Fragen zur Anwendung des Arzneimittels haben, fragen Sie Ihren Arzt oder

Apotheker.

4.

WELCHE NEBENWIRKUNGEN SIND MÖGLICH?

Wie alle Arzneimittel kann Nidazea Nebenwirkungen haben, die aber nicht bei jedem auftreten

müssen.

Bei der Bewertung von Nebenwirkungen werden folgende Häufigkeitsangaben zugrunde gelegt:

Sehr häufig:

mehr als 1 von 10 Behandelten

Häufig:

weniger als 1 von 10, aber mehr als 1 von 100 Behandelten

Gelegentlich:

weniger als 1 von 100, aber mehr als 1 von 1000 Behandelten

Selten:

weniger als 1 von 1000, aber mehr als 1 von 10 000 Behandelten

Sehr selten:

weniger als 1 von 10 000 Behandelten, einschließlich Einzelfälle

Bedeutsame Nebenwirkungen oder Zeichen, auf die Sie achten sollten, und Maßnahmen, wenn

Sie betroffen sind:

Falls eine der nachstehend aufgelisteten Nebenwirkung bei Ihnen auftritt, setzen Sie die Behandlung

mit Nidazea ab und informieren Sie schnellstmöglich Ihren Arzt.

Erkrankungen der Haut und des Unterhautzellgewebes

Häufig: Trockene Haut, Erytheme (Hautrötung und Entzündung), Juckreiz, Hautausschlag

(Entzündung mit Hautrötung), Missempfindungen der Haut (Brennen, schmerzhafte Haut/Stechen),

Hautreizung, Verschlimmerung einer Rosacea (chronisch entzündliche Hauterkrankung der Wangen,

Nase, Kinn, Stirn und Augenlider).

Unbekannt: Kontaktdermatitis (Hautreaktion, die durch Kontakt mit Allergen entsteht)

Allgemeine Erkrankungen

Gelegentlich: Schmerzen.

Erkrankungen des Nervensystems

Gelegentlich: Hypoästhesie (eingeschränktes Schmerzempfinden und Erregbarkeit der Haut),

Parästhesie (Missempfindung), Dysgeusie (metallischer Geschmack).

Erkrankungen des Magen-Darmtraktes

Gelegentlich: Übelkeit.

Meldung von Nebenwirkungen

Wenn Sie Nebenwirkungen bemerken, wenden Sie sich an Ihren Arzt oder Apotheker. Dies gilt auch

für Nebenwirkungen, die nicht in dieser Gebrauchsinformation angegeben sind. Sie können

Nebenwirkungen auch direkt dem Bundesinstitut für Arzneimittel und Medizinprodukte, Abt.

Pharmakovigilanz, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Website: www.bfarm.de anzeigen.

Indem Sie Nebenwirkungen melden, können Sie dazu beitragen, dass mehr Informationen über die

Sicherheit dieses Arzneimittels zur Verfügung gestellt werden.

5.

WIE IST NIDAZEA AUFZUBEWAHREN?

Nicht im Kühlschrank lagern oder einfrieren.

Die Haltbarkeit nach Anbruch beträgt 3 Monate.

Bewahren Sie dieses Arzneimittel für Kinder unzugänglich auf.

Sie dürfen dieses Arzneimittel nach dem auf dem Umkarton und der Tube angegebenen Verfalldatum

nicht mehr verwenden. Das Verfallsdatum bezieht sich auf den letzten Tag des angegebenen Monats.

6.

INHALT DER PACKUNG UND WEITERE INFORMATIONEN

Was Nidazea enthält

Der Wirkstoff ist Metronidazol

1 g Gel enthält 7,5 mg Metronidazol

Die sonstigen Bestandteile sind Phenoxyethanol (Ph. Eur.), Propylenglycol, Hypromellose (E 464)

und gereinigtes Wasser.

Wie Nidazea aussieht und Inhalt der Packung

Nidazea ist erhältlich in Aluminium-Tuben mit 25 g, 30 g, 40 g oder 50 g Gel. Eventuell werden nicht

gleichzeitig alle Packungsgrößen erhältlich sein.

Pharmazeutischer Unternehmer und Hersteller

Dr. August Wolff GmbH & Co. KG Arzneimittel

Sudbrackstraße 56,

33611 Bielefeld,

Deutschland

Telefon: +49 (0)521 8808-05;

Fax: +49 (0)521 8808-334

E-Mail: info@wolff-arzneimittel.de

Dieses Arzneimittel ist in den Mitgliedsstaaten des Europäischen Wirtschaftsraumes (EWR)

unter den folgenden Bezeichnungen zugelassen:

Deutschland:

MetroGalen 7,5 mg/g Gel

Estland:

Metrosa 7,5 mg/g geel

Lettland:

Metrosa 7,5 mg/g gels

Litauen:

Metrosa 7,5 mg/g gelis

Ungarn:

Metrosa 7,5 mg/g gél

Belgien, Österreich :

Nidazea 7,5 mg/g Gel

Niederlande:

Metrosa 7,5 mg/g, gel

Vereinigtes Königreich

Metrosa 0.75 % Gel

Diese Packungsbeilage wurde zuletzt überarbeitet im Jänner 2015.

22-6-2018

Metronidazole intravenous infusion 500 mg/100 mL bag

Metronidazole intravenous infusion 500 mg/100 mL bag

Shortage and althernative supply of Metronidazole intravenous infusion 500 mg/100 mL bag

Therapeutic Goods Administration - Australia