Arlevert

Hauptinformation

  • Handelsname:
  • Arlevert 20 mg/40 mg Tabletten
  • Einheiten im Paket:
  • 20 Stück (Blister), Laufzeit: 36 Monate,50 Stück (Blister), Laufzeit: 36 Monate,100 Stück (Blister), Laufzeit: 36 Monate
  • Verschreibungstyp:
  • Arzneimittel zur wiederholten Abgabe gegen aerztliche Verschreibung
  • Verwenden für:
  • Menschen
  • Art der Medizin:
  • allopathic Droge

Dokumenten

Lokalisierung

  • Erhältlich in:
  • Arlevert 20 mg/40 mg Tabletten
    Österreich
  • Sprache:
  • Deutsch

Therapeutische Informationen

  • Therapiebereich:
  • Cinnarizin, Kombination
  • Produktbesonderheiten:
  • Abgabe durch eine (öffentliche) Apotheke

Weitere Informationen

Status

  • Quelle:
  • AGES
  • Zulassungsnummer:
  • 1-27198
  • Berechtigungsdatum:
  • 06-09-2007
  • Letzte Änderung:
  • 07-03-2018

Öffentlichen Beurteilungsberichts

Public Assessment Report

Mutual Recognition Procedure

Arlevert 20mg/40mg Tablets

AT/H/0500/001

Arlevert 20 mg/40 mg Tabletten

Former procedure number: UK/H/984/01/MR

UK licence no: PL 11249/0001

HENNIG ARZNEIMITTEL GmbH & Co. KG

PAR Arlevert Tablets

Former: UK/H/984/001/MR

LAY SUMMARY

The MHRA granted HENNIG ARZNEIMITTEL GmbH & Co. KG a Marketing

Authorisation (licence) for the medicinal product Arlevert 20mg/40mg Tablets on 20

2005. This is a prescription-only medicine (POM) indicated for the treatment of vertigo

symptoms of various origins.

Arlevert 20mg/40mg Tablets contain two active substances; cinnarizine and dimenhydrinate.

The two substances belong to different groups of medicines. Cinnarizine is a part of a group

called calcium antagonists. Dimenhydrinate belongs to a group called antihistamines. Both

substances work by reducing symptoms of vertigo (a feeling of dizziness or “spinning”) and

nausea (feeling sick). When these two substances are used together they are more effective

than when each one is used on their own.

No new or unexpected safety concerns arose from this application and it was therefore judged

that the benefits of taking Arlevert 20mg/40mg Tablets outweigh the risks; hence a

Marketing Authorisation has been granted.

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TABLE OF CONTENTS

Module 1: Information about initial procedure

Page 4

Module 2: Summary of Product Characteristics

Page 5

Module 3: Product Information Leaflet

Page 10

Module 4: Labelling

Page 12

Module 5: Scientific Discussion

Page 14

1 Introduction

Page 14

2 Quality aspects

Page 16

3 Non-clinical aspects

Page 19

4 Clinical aspects

Page 23

Module 6

5 Overall conclusions

Update

Page 27

Page 29

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Module 1

Product Name

Arlevert 20mg/40mg Tablets

Type of Application

New Combinations, Article 10b

Active Substance(s)

Cinnarizine

Dimenhydrinate

Form

Tablets

Strength

Cinnarizine 20mg/Dimenhydrinate 40mg

MA Holder

HENNIG ARZNEIMITTEL GmbH & Co. KG

Liebigstrasse 1-2, D-65439 Flörsheim am Main, Germany

Reference Member

State (RMS)

CMS

Austria,

Belgium,

Denmark,

Ireland,

Italy,

Luxembourg,

Netherlands, Poland, Slovenia, Sweden

Procedure Number

UK/H/0984/001/MR

Timetable

Day 90 – 3

April 2007

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Module 2

Summary of Product Characteristics

1

NAME OF THE MEDICINAL PRODUCT

Arlevert 20 mg/40 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg cinnarizine and 40 mg dimenhydrinate.

For full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Tablet, round, biconvex white tablets embossed with ‘A’ on one side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of vertigo symptoms of various origins.

4.2

Posology and method of administration

Adults: 1 tablet three times daily, to be taken unchewed with some liquid after meals.

Children and adolescents under the age of 18 years: Arlevert is not recommended in children and

adolescents under the age of 18 years because there are no data available on the use of Arlevert in this

age group.

Elderly: Dosage as for adults.

Renal impairment:

Arlevert should be used with caution in patients with mild to moderate renal impairment. Arlevert

should not be used by patients with a creatinine clearance of < 25mL/min (severe renal impairment).

Hepatic impairment:

No studies in patients with hepatic impairment are available. Arlevert should not be used by patients

with severe hepatic impairment.

In general, the duration of treatment should not exceed four weeks. The physician shall decide whether

longer treatment is required.

4.3

Contraindications

Diphenhydramine is completely excreted renally, and patients with severe renal impairment were

excluded from the clinical development programme. Arlevert should not be used by patients with a

creatinine clearance of

25 ml/min (severe renal impairment).

Since both active components of Arlevert are extensively metabolised by hepatic cytochrome P450

enzymes, the plasma concentrations of the unchanged drugs and their half-lives will increase in

patients with severe hepatic impairment. This has been shown for diphenhydramine in patients with

cirrhosis. Arlevert should therefore not be used by patients with severe hepatic impairment.

Arlevert is contra-indicated in patients with known

hypersensitivity to the active substances,

diphenhydramine or other antihistamines of similar structure or to any of the excipients.

Arlevert should not be used in patients with angle-closure glaucoma, convulsions, suspicion of raised

intracranial pressure, alcohol abuse or urine retention due to urethroprostatic disorders.

4.4

Special warnings and precautions for use

Arlevert does not reduce blood pressure significantly, however, it should be used with caution in

hypotensive patients.

Arlevert should be taken after meals to minimise any gastric irritation.

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Arlevert should be used with caution in patients with conditions that might be aggravated by

anticholinergic therapy, e.g. raised intra-ocular pressure, pyloro-duodenal obstruction, prostatic

hypertrophy, hypertension, hyperthyroidism or severe coronary heart disease.

Caution should be exercised when administering Arlevert to patients with Parkinson’s disease.

4.5

Interaction with other medicinal products and other forms of interaction

The anticholinergic and sedative effects of Arlevert may be potentiated by monoamine oxidase

inhibitors. Procarbazine may enhance the effect of Arlevert.

In common with other antihistamines, Arlevert may potentiate the sedative effects of CNS depressants

including alcohol, barbiturates, narcotic analgesics and tranquillisers. Patients should be advised to

avoid alcoholic drinks. Arlevert may also enhance the effects of antihypertensives, ephedrine and

anticholinergics such as atropine and tricyclic antidepressants.

Arlevert may mask ototoxic symptoms associated with amino glycosidic antibiotics and mask the

response of the skin to allergic skin tests.

The concomitant administration of medicines that prolong the QT interval of the ECG (such as Class Ia

and Class III anti-arrhythmics) should be avoided.

The information about potential pharmacokinetic interactions with cinnarizine and diphenhydramine

and other medicinal products is limited. Diphenhydramine inhibits CYP2D6 mediated metabolism and

caution is advised if Arlevert is combined with substrates of this enzyme, especially those with narrow

therapeutic range

4.6

Pregnancy and lactation

Pregnancy:

The safety of Arlevert in human pregnancy has not been established. Animal studies are insufficient

with respect to effects on pregnancy, embryonal/foetal development and postnatal development (see

Section 5.3). The teratogenic risk of the single actives dimenhydrinate/diphenhydramine and

cinnarizine is low. No teratogenic effects were observed in animal studies.

Dimenhydrinate may have an oxytocic effect and may shorten labour. Arlevert should not be used

during pregnancy.

Lactation:

Dimenhydrinate and cinnarizine are excreted in human breast milk. Arlevert should not be taken by

women who are breast feeding.

4.7

Effects on ability to drive and use machines

Arlevert may cause drowsiness, especially at the start of treatment. Patients affected in this way should

not drive or operate machinery.

4.8

Undesirable effects

The most frequently occurring ADRs are somnolence (including drowsiness, tiredness, fatigue, daze)

occurring in about 8% of patients and dry mouth occurring in about 5% of patients in clinical trials.

These reactions are usually mild and disappear within a few days even if treatment is continued. The

frequency of ADRs associated with Arlevert in clinical trials and following spontaneous reports are

included in the next table:

Frequency of ADR

Common

>1/100,

<1/10

Uncommon

>1/1,000,

<1/100

Rare

>1/10,000,

<1/1,000

Very rare

<1/10,000

Body system:

Blood and

lymphatic system

disorders

Leucopenia

Thrombopenia

Aplastic anaemia

Immune system

disorders

Hypersensitivity

reactions

(eg cutaneous

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Frequency of ADR

Common

>1/100,

<1/10

Uncommon

>1/1,000,

<1/100

Rare

>1/10,000,

<1/1,000

Very rare

<1/10,000

reactions)

Nervous system

disorders

Somnolence

Headache

Paraesthesia

Amnesia

Tinnitus

Tremor

Nervousness

Convulsions

Eye disorders

Visual disorders

Gastrointestinal

disorders

Dry mouth

Abdominal pain

Dyspepsia

Nausea

Diarrhoea

Skin and

subcutaneous tissue

disorders

Perspiration

Rash

Photosensitivity

Renal and urinary

disorders

Urinary hesitancy

In addition the following adverse reactions are associated with dimenhydrinate and cinnarizine:

Dimenhydrinate: paradoxical excitability (especially in children), worsening of an existing angle-

closure glaucoma, reversible agranulocytosis.

Cinnarizine: constipation, weight gain, tightness of the chest, cholestatic jaundice, extrapyramidal

symptoms, lupus-like skin reactions, lichen planus.

4.9

Overdose

Symptoms of overdosage with Arlevert include drowsiness, dizziness and ataxia with anticholinergic

effects such as dry mouth, flushing of the face, dilated pupils, tachycardia, pyrexia, headache and

urinary retention. Convulsions, hallucinations, excitement, respiratory depression, hypertension,

tremor and coma may occur, particularly in cases of massive overdosage.

Management of overdose: General supportive measures should be used to treat respiratory

insufficiency or circulatory failure. Gastric lavage with isotonic sodium chloride solution is

recommended. Body temperature should be closely monitored, since pyrexia may occur as a

consequence of antihistamine intoxication, especially in children.

Cramp-like symptoms may be controlled by careful application of a short-acting barbiturate. In cases

of marked central-anticholinergic effects, physostigmine (after physostigmine test) should be

administered slowly intravenously (or, if necessary, intramuscularly) : 0.03 mg/kg body weight (adults

max. 2 mg, children max. 0.5 mg).

Dimenhydrinate is dialyzable, however treatment of overdosage by this measure is considered as

unsatisfactory. Sufficient elimination can be achieved by means of haemoperfusion using activated

charcoal. No data are available concerning the dialysability of cinnarizine.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: cinnarizine combination; ATC code: N07CA52.

Dimenhydrinate, the chlorotheophylline salt of diphenhydramine, acts as antihistamine with

anticholinergic (antimuscarinic) properties, exerting parasympatholytic and centrally-depressant

effects. The substance exhibits anti-emetic and antivertiginous effects through influencing the

chemoreceptor trigger zone in the region of the 4

ventricle. Dimenhydrinate thus acts predominantly

on the central vestibular system.

Due to its calcium antagonistic properties, cinnarizine acts mainly as a vestibular sedative through

inhibition of the calcium influx into the vestibular sensory cells. Cinnarizine thus acts predominantly

on the peripheral vestibular system.

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Both cinnarizine and dimenhydrinate are known to be effective in the treatment of vertigo. The

combination product is more effective than the individual compounds in the population studied.

The product has not been evaluated in motion sickness.

5.2

Pharmacokinetic properties

Absorption and distribution:

Dimenhydrinate rapidly releases its diphenhydramine moiety after oral administration.

Diphenhydramine and cinnarizine are rapidly absorbed from the gastro-intestinal tract. Maximum

plasma concentrations (C

) of cinnarizine and diphenhydramine are reached in humans within 2 - 4

hours. The plasma elimination half-lives of both substances range from 4 to 5 hours, when given either

alone or as the combination product.

Metabolism:

Cinnarizine and diphenhydramine are extensively metabolised in the liver. The metabolism of

cinnarizine involves ring hydroxylation reactions that are in part catalysed by CYP2D6 and N-

desalkylation reactions of low CYP-enzyme specificity. The main pathway in the diphenhydramine

metabolism is the sequential N-demethylation of the tertiary amine. Studies in human liver microsomes

in vitro indicate the involvement of various CYP-enzymes, including CYP2D6.

Elimination:

Cinnarizine is mainly eliminated via the faeces (40-60%) and to a lower extent also in urine, mainly in

the form of metabolites conjugated with glucuronic acid. The major route of elimination of

diphenhydramine is in the urine, mainly in the form of metabolites, with the deaminated compound,

diphenylmethoxy acetic acid, being the predominant metabolite (40-60%).

5.3

Preclinical safety data

Preclinical data revealed no specific hazard for humans based on repeated dose toxicity studies with the

combination of cinnarizine and dimenhydrinate, fertility studies with cinnarizine or dimenhydrinate, and

embryo/foetal development studies with dimenhydrinate. Doses were well in excess of the maximum

human dose. Studies in dogs, rabbits and rats gave no evidence for teratogenic effects of cinnarizine. In

one study in rats, cinnarizine decreased litter size, increased the number of resorbed foetuses and

decreased the birth weight of pups.

The genotoxic and carcinogenic potential of the cinnarizine/dimenhydrinate combination has not fully

been evaluated.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

cellulose, microcrystalline,

maize starch,

talc,

hypromellose,

silica, colloidal anhydrous,

magnesium stearate,

croscarmellose sodium

6.2

Incompatibilities

Not applicable

6.3

Shelf life

3 years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

Carton containing 20, 50, or 100 tablets.

Tablets are packed in PVC/PVDC/Aluminium blisters containing 20 or 25 tablets, as appropriate.

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6.6

Special precautions for disposal

No special requirements

7

MARKETING AUTHORISATION HOLDER

HENNIG ARZNEIMITTEL GmbH & Co. KG

Liebigstrasse 1-2

D-65439 Flörsheim am Main/Germany

8

MARKETING AUTHORISATION NUMBER(S)

PL 11249/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

May 2005

10

DATE OF REVISION OF THE TEXT

31/10/2007

11

DOSIMETRY (IF APPLICABLE)

12

INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF

APPLICABLE)

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Module 3

Patient Information Leaflet

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Module 4

Labelling

Pack size of 20 tablets

Arlevert 20 mg/ 40mg tablets

Pack size of 50 tablets

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Pack size of 100 tablets

Blister foil

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Module 5

Scientific discussion during initial procedure

I

INTRODUCTION

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

application for Arlevert 20mg/40mg Tablets in the treatment of vertigo of various origins

could be approved. A national marketing authorisation was granted on 20

May 2005.

This application was made under EC article 10.b (Fixed Combination) of the Directive

2001/83/EC as amended. Arlevert 20mg/40mg Tablets, containing the fixed combination of

cinnarizine Ph Eur and dimenhydrinate Ph Eur (20 mg/40 mg), was first registered in

Germany in 1977 and the product has been available on prescription in Germany since 1982.

The drug substance cinnarizine is a piperazine derivative and a selective calcium antagonist.

It has weak antihistamine and sedative activity, and is used for symptomatic treatment of

motion sickness, nausea, vertigo and other vestibular disorders. The usual dose for vertigo

and vestibular disorders is 30 mg three times daily by mouth.

The drug substance dimenhydrinate is an ethanolamine derivative and is a sedating

antihistamine with antimuscarinic and significant sedative effects. It is used mainly as an

antiemetic in the prevention and treatment of motion sickness, nausea, vertigo and other

vestibular disorders. The usual dose for vertigo and vestibular disorders is 50 to 100 mg,

given two or three times daily by mouth.

No new preclinical studies were submitted and none were required. In view of the extensive

toxicology data available on both the known active substances the pre-clinical section of the

application was based on published bibliography and was found to be satisfactory. No new

toxicological problems for this product were found.

Clinical studies on Arlevert 20mg/40mg Tablets were carried out in accordance with Good

Clinical Practice (GCP). The clinical programme showed that Arlevert 20mg/40mg Tablets

provide satisfactory clinical benefits.

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.

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II.

ABOUT THE PRODUCT

Name of the product in the Reference Member

State

Arlevert 20mg/40mg Tablets

Name(s) of the active substance(s) (INN)

Cinnarizine 20mg

Dimenhydrinate 40mg

Pharmacotherapeutic classification

(ATC code)

Histamine (5HT1) antagonists (N07C A52)

Pharmaceutical form and strength(s)

Tablets, Cinnarizine 20mg/Dimenhydrinate

40mg

Reference numbers for the Mutual Recognition

Procedure

UK/H/984/001/MR

Reference Member State

United Kingdom

Member States concerned

Austria, Belgium, Denmark, Ireland, Italy,

Luxembourg, The Netherlands, Poland,

Slovenia, Sweden

Marketing Authorisation Number(s)

PL 11249/0001

Name and address of the

authorisation holder

HENNIG ARZNEIMITTEL GmbH & Co. KG

Liebigstrasse 1-2, D-65439 Flörsheim am

Main, Germany

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III.1

QUALITY ASPECTS

S.

Drug substance (1)

INN/Ph Eur name:

Cinnarizine

Chemical name:

1-benzhydryl-4-cinnamyl-piperazine

Structural formula

Molecular formula:

Molecular weight:

368.5

General Properties

Characters:

White or almost white powder.

Solubility:

Practically insoluble in water, freely soluble in methylene chloride, soluble in

acetone, slightly soluble in alcohol and methanol.

Cinnarizine is the subject of a European Pharmacopoeia monograph.

A Certificate of Suitability has been provided covering the manufacture and control of the

drug substance cinnarizine. The drug substance specification complies with the Ph Eur

monograph.

The Certificate of Suitability specifies a re-test date for the drug substance of 6 years when

stored in container-closure comprising of double polyethylene bags inside a cardboard box.

S.

Drug substance (2)

INN/Ph Eur name:

Dimenhydrinate

Chemical name:

2-benzhydryloxyethyl-dimethyl-ammonium; 8-chloro-1,3-dimethyl-2-

oxo-purin-6-olate

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Structural formula:

Molecular formula:

NO,C

Molecular weight:

470.0

General Properties

Characters:

White, crystalline powder or colourless crystals

Solubility:

Slightly soluble in water, freely soluble in alcohol and sparingly soluble in

ether.

Synthesis of the drug substance from the designated starting materials has been adequately

described, and appropriate in-process controls and intermediate specifications are applied.

Satisfactory specification tests are in place for all starting materials and reagents, and these

are supported by relevant certificates of analysis.

An appropriate drug substance specification based on the European Pharmacopoeia has been

provided. Analytical methods have been appropriately validated and are satisfactory for

ensuring compliance with the relevant specifications. Satisfactory certificates of analysis

have been provided for working standards used by the active substance manufacturer and

finished product manufacturer during validation studies. Batch analysis data are provided

and comply with the proposed specification.

Active dimenhydrinate is stored in appropriate packaging. The specifications and typical

analytical test reports are provided and are satisfactory.

Appropriate stability data have been generated supporting a shelf life of 60 months when

stored at 25˚C.

P.

Medicinal Product

Other Ingredients

Other ingredients consist of pharmaceutical excipients cellulose microcrystalline, maize

starch, talc, hypermellose, colloidal anhydrous silica, magnesium stearate and croscarmellose

sodium.

All excipients comply with their respective European Pharmacopoeial monographs.

Satisfactory certificates of analysis have been provided for all ingredients showing

compliance with their respective monograph/specifications.

None of the excipients used contain material of animal or human origin.

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Pharmaceutical development

The objective of the development programme was to establish a beneficial risk/benefit for

Arlevert 20mg/40mg Tablets compared to co-administered cinnarizine 20 mg and

dimenhydrinate 40 mg. To this end HENNIG ARZNEIMITTEL GmbH & Co. KG has

conducted clinical safety and efficacy as well as pharmacokinetic studies comparing Arlevert

20mg/40mg Tablets versus co-administered cinnarizine 20 mg and dimenhydrinate 40 mg

tablets.

The rationale for the type of pharmaceutical form developed and formulation variables

evaluated during development was stated and is satisfactory.

The rationale and function of each excipient added is discussed. Levels of each ingredient

are typical for a product of this nature and have been optimised on the basis of results from

development studies.

In vitro dissolution profiles have been generated for the proposed product with satisfactory

results. Impurity studies have also been undertaken. Two new impurities were identified and

are both controlled satisfactorily.

Manufacturing Process

Satisfactory batch formulae have been provided for the manufacture of the product, along

with an appropriate account of the manufacturing process. The manufacturing process has

been validated and has shown satisfactory results at commercial-scale.

Finished Product Specification

The finished product specification proposed is acceptable. Test methods have been described

and have been adequately validated. Batch data have been provided and comply with the

release specification. Certificates of analysis have been provided for any working standards

used.

Container-Closure System

All strengths of the tablet are packaged in polyvinylchloride/polyvinylidene aluminium/

blister strips in pack sizes of 20, 50 and 100 tablets.

Satisfactory specifications and certificates of analysis have been provided for all packaging

components. All primary packaging complies with the relevant regulations regarding

materials for use in contact with food.

Stability of the product

Stability studies were performed on ten production-scale batches of the finished product, in

accordance with current guidelines and in the packaging proposed for marketing. All results

from stability studies were within specified limits. These data support a shelf-life of

36 months with no storage conditions.

SPC, PIL, Labels

The SPC, PIL and labels are pharmaceutically acceptable. A package leaflet has been

submitted to the MHRA along with results of consultations with target patient groups ("user

testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results

indicate that the package leaflet is well-structured and organised, easy to understand and

written in a comprehensive manner. The test shows that the patients/users are able to act upon

the information that it contains.

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Conclusion

The grant of this marketing authorisation is recommended.

III.2

PRE-CLINICAL ASPECTS

INTRODUCTION

Arlevert 20mg/40mg Tablets are indicated for treatment of vertigo symptoms of various

origins. Each Arlevert 20mg/40mg Tablet contains 20 mg cinnarizine in combination with

40 mg dimenhydrinate for oral administration. The proposed therapeutic dose is one Arlevert

20mg/40mg Tablet three times daily i.e. equivalent to 60 mg cinnarizine and 120 mg

dimenhydrinate per day (l mg cinnarizine/kg/day and 2 mg dimenhydrinate/kg/day for a

60 kg person). This application is based on published bibliography and a number of

preclinical bridging toxicity studies with the formulation intended for marketing. After initial

assessment by the Pharmaceutical Assessor, an Expert Comment on the toxicity and safety of

benzhydrol was provided. The rationale for combining cinnarizine and dimenhydrinate is that

synergism at low doses of the two actives, which act at the peripheral and central vestibular

system, respectively, will lower the incidence of side-effects and increase therapeutic

efficacy.

PHARMACODYNAMICS

Cinnarizine is a selective calcium antagonist (blocks L-, T- and N-type voltage- and receptor-

operated channels) inhibiting the influx of extracellular Ca

. Cinnarizine also has

antihistamine properties blocking histamine H

receptors (K

=60nM).

Dimenhydrinate is the 8chloro-theophylline salt of diphenhydramine. The drug substance

diphenhydramine is an ethanolamine class antihistamine that acts predominantly as a

competitive (reversible) inhibitor of histamine H

receptors with additional sedative,

anticholinergic and local anaesthetic activity.

The rationale for using Arlevert 20mg/40mg Tablets in treatment of vertigo is that vertigo, in

the majority of cases, originates from both central and peripheral vestibular regions. The

labyrinth-depressive effect of cinnarizine and central effect of dimenhydrinate on vestibular

nuclei can be used in combination for treatment of vertigo of various origins.

Considering the wealth of clinical data and absence of suitable animal models correlating

with vertigo in man, the absence of preclinical data with the proposed combination seems

justified.

In vitro, cinnarizine and its major metabolite 4-hydroxy-cinnarizine (C-2) inhibit binding of

specific ligands to D2-receptors (K

13nM and 4nM, respectively). Given the plasma

cinnarizine and C-2 concentrations observed after repeat oral administration of cinnarizine

(7 mg/kg daily for 10-15 consecutive days) to rats, inhibition of D2-receptors and

consequential parkinsonian symptoms are possible at therapeutic doses. Use of cinnarizine in

patients with manifest Parkinson's disease should be considered with caution. The

antimuscarinic activity of dimenhydrinate (25-50 mg, 3 times daily) can apparently be used

in treatment of Parkinson's disease. The combination of cinnarizine with dimenhydrinate may

counteract the occurrence of cinnarizine-induced parkinsonism. A precautionary warning of

use of Arlevert 20mg/40mg Tablets in patients with Parkinson's disease is included under

section 4.4 of the SmPC.

Side-effects associated with clinical use of Arlevert 20mg/40mg Tablets are discussed in

Module

2.6.2.4

In view of the extensive clinical data on potential side-effects of Arlevert

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20mg/40mg Tablets, absence of preclinical data is acceptable. Symptoms of overdosage are

also adequately discussed in Module 2.6.2.4.

Cinnarizine, in contrast to other calcium antagonists, has no significant effects on blood

pressure but regular monitoring of blood pressure is recommended when cinnarizine is used

in combination with hyper/hypotensive medicines.

No preclinical safety pharmacology studies with the formulation proposed for marketing are

provided.

Cinnarizine was shown to inhibit the in vitro binding of other calcium antagonists such as

diltiazem (K

= 0.2 µM) by allosteric modulation.

Side-effects associated with the anticholinergic activity of diphenhydramine (e.g. narrow

angle glaucoma and urinary retention) may increase, when used concomitantly with tricyclic

antidepressants, parasympatholytics and MAOIs.

PHARMACOKINETICS

No preclinical pharmacokinetic (PK) data on cinnarizine or Arlevert 20mg/40mg Tablets in

animals are provided. In monkeys benzhydrol apparently accounts for 1-2% of the dose

excreted in urine, but it has been suggested that benzhydrol may arise from decomposition of

diphenylmethoxyacetic acid or its glucuronide which is acid labile. Evidence of benzhydrol

being a metabolite in man is discussed below. Pharmacokinetics of single oral dose of

individual actives and Arlevert 20mg/40mg Tablets in humans are presented. Absence of

preclinical PK studies with Arlevert 20mg/40mg Tablets is considered acceptable as such

data will be superseded with clinical PK data.

TOXICOLOGY

Acute and chronic toxicity

The acute oral toxicity of combination of 20 mg cinnarizine with 40 mg dimenhydrinate

, mouse: 1600 mg/kg; rat: 5760 mg/kg) in rodents appears to be lower than those of

cinnarizine (LD

mouse: >1000 mg/kg; rat: >2500 mg/kg) or dimenhydrinate (LD

mouse:

203 mg/kg; rat: 1320 mg/kg).

In a study by Heisler (1986), rats fed with combination of cinnarizine and dimenhydrinate

(ca 250, 333 and 416 mg/kg/day) for up to 9 months, slight increase in body weight gain was

seen at mid- (females only) and high-doses (males only). The increase in weights of liver

(high-dose males) and adrenal gland (high-dose females) were apparently not accompanied

with histopathological changes and were not considered dose related.

Reproductive toxicity

Oral doses of cinnarizine had no effects on fertility of male and female rats. In rats,

cinnarizine (320 mg/kg/day, GD6-15) decreased litter size, increased number of resorbed

fetuses and decreased birth weight of pups.

Oral doses of dimenhydrinate administered to rats (75 mg/kg/day from 3 days pre-mating to

end of gestation period) or rabbits (50 and 100 mg/kg/day, GD8-16) were not potentially

teratogenic. Clinically, however, the incidence of cleft palate and clefts with other defects

was higher in children whose mothers had taken diphenhydramine (active ingredient of

dimenhydrinate) in the first trimester of pregnancy. The review by Leathem, however,

concluded that teratogenic risk of dimenhydrinate and diphenhydramine is low and that

dimenhydrinate may have a relaxing or a stimulating effect on the uterus depending on the

PAR Arlevert Tablets

Former: UK/H/984/001/MR

stage of pregnancy at which it is given (for example at term dimenhydrinate may have an

oxytocic effect and may shorten labour).

Diphenhydramine crosses the placenta and also enters human milk. In the absence of

peripost-natal studies with Arlevert 20mg/40mg Tablets this medicine should not be taken by

women who are breast-feeding.

Mutagenicity and carcinogenicity

An Ames test performed in 1985 by Safepharm Laboratories (UK) with the combination of

cinnarizine and dimenhydrinate (1:2 ratio) was negative at concentrations up to 0.5 mg/plate.

During assessment of the National application the MHRA asked for justification for absence

of a full genotoxicity package.

The applicant provided additional data from an in vitro chromosome aberration test in

hamster V79 cells with cinnarizine. The conclusions of this GLP compliant study are that

cinnarizine is non-clastogenic in the assay both with and without S9 mix. Dimenhydrinate

was not included in the study.

The applicant also refers to a paper published as part of the National Toxicology Program

(NTP) in the USA, in which dimenhydrinate was tested for its ability to induce mutations in a

number of Salmonella strains. A positive result was recorded in one strain (TA 1535),

although when the experiment was repeated by a separate team the results were negative.

Equivocal results were recorded in a second strain (TA 100) and negative results in three

others (TA 1537, TA 97 and TA 98).

In the applicant's own bacterial mutagenicity tests the combination product produced

negative results in five Salmonella strains (including TA 1535 and TA 100). It is noteworthy

that the top concentrations of dimenhydrinate used in the NTP study were greater (at least

three fold) than those used in the applicant's study, although even at the doses used in the

applicant's study some equivocal results were seen in the NTP study.

The applicant concluded that the absence of a full genotoxicity package is justified for the

following reasons:

The individual pharmaceutical ingredients have been available for adults and children as

prescription and OTC medicines for many years

Arlevert 20mg/40mg Tablets has been available in Germany for 20 years and in various

other countries for 5 to 10 years without serious adverse effects being reported

The lack of published data indicate that safety concerns have not arisen

The paucity of published data indicates the lack of molecular structural concerns

The limited data available on the individual drug substances and the combination product

do not indicate the potential for genotoxicity

No new impurities were formed during stability studies with the combination product.

While some additional data have been provided, including in vivo genotoxicity testing

(micronucleus assay in bone marrow) of the combination product, a full genotoxicity package

is still lacking. The strongest justification for this is the extent of clinical experience, both

PAR Arlevert Tablets

Former: UK/H/984/001/MR

with the individual actives (across Europe) and with the combination (particularly in

Germany).

Cinnarizine has been licensed in the UK as Stugeron since 1973, and as Stugeron Forte since

1977. Dimenhydrinate has been licensed in the UK as Dramamine/Gravol since 1972; and the

proposed combination product has been available in Germany for over 20 years.

The note for guidance on fixed combination medicinal products states that "safety studies in

animals should be performed with the active substances of the fixed combination in the

proportion present in the product. Such studies will not be required where all the substances

have been extensively and safely used in humans in identical or very similar combinations for

a long period and the safety of such combinations is well documented".

Since the proposed product has been available in Germany for over 20 years it may be

considered that further preclinical studies including genotoxicity and carcinogenicity studies

are not required.

Drug substance and drug product

Sources of cinnarizine and dimenhydrinate are of Ph Eur specification. Drugs substance

specification limits for potential related substance/impurities of cinnarizine and

dimenhydrinate comply with current Ph Eur requirements and are of no safety concern.

An Expert Comment on potential toxicity and safety of benzhydrol was provided. It stated

that benzhydrol and benzophenone are potential metabolites of dimenhydrinate in both

animals and humans and as such they may be considered qualified. The applicant was asked

to provide evidence that benzhydrol and benzophenone are metabolites formed in humans to

justify their finished product limits.

Evidence for the presence of benzhydrol and benzophenone as metabolites of dimenhydrinate

in man is indirect and as yet to be fully confirmed.

The applicant reports that benzhydrol has been identified as a metabolite in in vitro studies

and refers to published data that show low levels of benzhydrol isolated from the urine of

Rhesus Monkeys treated with diphenhydramine. It is possible, however, that the benzhydrol

arose during the acidic extractions used during sample preparation. The applicant reports that

further evidence for the formation of benzhydrol and benzophenone comes from studies

reported by Pfeifer et al, in Rhesus Monkeys and other animal models.

The applicant was not able to provide the evidence requested but reduced the proposed

release and shelf-life specification limits for benzhydrol and benzophenone in line with the

relevant guideline (ICH Q3B).

All excipients of the proposed formulation are routinely used in pharmaceutical formulations

and are not of safety concern at the proposed levels and dose regimen.

Summary of Product Characteristics and Patient Information Leaflet

These are satisfactory.

CONCLUSIONS

A Marketing Authorisation may be granted.

PAR Arlevert Tablets

Former: UK/H/984/001/MR

III.3

CLINICAL ASPECTS

INDICATIONS

Treatment of vertigo symptoms of various origins.

DOSE AND DOSE SCHEDULE

Adults: 1 tablet three times daily, to be taken unchewed with some liquid after meals.

Children and adolescents under the age of 18 years: Not recommended.

Elderly: Dosage as for adults.

Renal impairment:

Arlevert 20mg/40mg Tablets should be used with caution in patients with mild to moderate

renal impairment. Arlevert 20mg/40mg Tablets should not be used by patients with a

creatinine clearance of < 25mL/min (severe renal impairment).

Hepatic impairment:

No studies in patients with hepatic impairment are available. Arlevert 20mg/40mg Tablets

should not be used by patients with severe hepatic impairment.

In general, the duration of treatment should not exceed four weeks. The physician shall

decide whether longer treatment is required.

The dose and dose schedule is satisfactory.

TOXICOLOGY

See preclinical section above.

CLINICAL PHARMACOLOGY

No new clinical pharmacology data on either the individual actives or the combination have

been generated.

PHARMACODYNAMICS

See preclinical section above.

PHARMACOKINETICS

pharmacokinetic

study

open,

single-dose,

randomised,

three-period,

crossover study to compare the rate and extent of absorption in healthy male volunteers. A

dose of 20 mg of cinnarizine and 40 mg of dimenhydrinate was administered separately or

simultaneously.

The following tablets were used in the pharmacokinetic studies:

Arlevert 20mg/40mg Tablets, HENNIG ARZNEIMITTEL

Cinnarizine 20 mg tablets, HENNIG ARZNEIMITTEL

Dimenhydrinate 40 mg tablets, HENNIG ARZNEIMITTEL

The study comprised three periods of single-dose administration, separated by a washout

period of 1 week. Blood samples were collected pre-dose and up to 12 hours post-dose after

administration of either Arlevert 20mg/40mg Tablets or cinnarizine. Blood samples were

collected pre-dose and up to 14 hours post-dose after administration of dimenhydrinate.

PAR Arlevert Tablets

Former: UK/H/984/001/MR

Primary parameters of AUC

o-∞

max,

were determined as well as the mean body

residence

time

infinity

(MRT

o-∞

elimination

half-life

both

cinnarizine and dimenhydrinate.

Cinnarizine Pharmacokinetic Parameters (Mean ± s.e.m., n = 11)

Parameter

Units

Cinnarizine

Arlevert 20mg/40mg Tablets

ng/ml

38.58 ± 6.16

37.36 ± 4.46

2.05 ± 0.42

2.27 ± 0.22

ng/ml.h

225.22 ± 49.70

238.26 ± 38.61

7.89 ± 1.39

7.03 ± 0.54

4.94 ± 1.00

4.10 ± 0.35

Diphenhydramine Pharmacokinetic Parameters (Mean ± s.e.m., n = 12)

Parameter

Units

Dimenhydrinate

Arlevert 20mg/40mg Tablets

ng/ml

40.91 ± 3.45

37.36 ± 4.46

1.71 ± 0.19

1.88 ± 0.27

ng/ml.h

265.14 ± 25.19

240.94± 23.63

7.81± 0.40

7.65 ± 0.37

4.76 ± 0.22

4.52 ± 0.20

The paired t-test revealed no significant difference for the pharmacokinetic parameters

between actives administered alone or as Arlevert 20mg/40mg Tablets.

The Westlake 95% confidence intervals for the AUC

of dimenhydrinate are reported as

±25.14% (power 70.17%). The figure is outside the ±20% range, therefore the 90%

confidence intervals (as per ICH guideline) were calculated and a figure of ±21.43% was

obtained.

For cinnarizine, the study could not exclude that a difference in bioavailability exists between

cinnarizine administered alone and as Arlevert 20mg/40mg Tablets. Even the 90%

confidence intervals were ±30.51% (power 30.23%).

The applicant concludes that the study results were close to showing bioequivalence for

dimenhydrinate administered alone and as Arlevert 20mg/40mg Tablets. A difference in

bioavailability between cinnarizine administered alone and as Arlevert 20mg/40mg Tablets

cannot be excluded. This might be due to the large interindividual variability or less than

optimal dissolution of the cinnarizine reference product.

PAR Arlevert Tablets

Former: UK/H/984/001/MR

EFFICACY

Clinical Studies

This assessment considers the evidence of efficacy for Arlevert 20mg/40mg Tablets, a fixed

combination of cinnarizine 20mg and dimenhydrinate 40mg.

The objectives of the clinical studies were to demonstrate the efficacy of Arlevert

20mg/40mg Tablets in the therapy of vertigo of various origins; to establish its possible

superiority over the single substances at the same or higher doses, as well as over betahistine

and placebo; and to establish whether Arlevert 20mg/40mg Tablets was associated with a

better safety profile. A summary of these studies is presented below.

Study

Purpose of the

study

Formulation used in the

clinical study

Control groups

Patient population

I

Central and/or

peripheral vertigo

Arlevert tablets

Cinnarizine 50 mg tablets

Dimenhydrinate 100 mg

tablets

Placebo tablets

Cinnarizine

50 mg

Dimenhydrinate

100 mg

Placebo

Outpatients with

central and / or

peripheral vertigo

II

Vertigo due to

vertebrobasilar

insufficiency

Arlevert tablets

Betahistine 12 mg tablets

Placebo tablets

Betahistine

12 mg

Placebo

Outpatients with

symptomatic

vertebrobasilar

insufficiency

III

Acute vertigo of

peripheral origin

Arlevert tablets

Cinnarizine 20 mg tablets

Dimenhydrinate 40 mg

tablets

Cinnarizine

20 mg

Dimenhydrinate

40 mg

Inpatients with acute

vertigo of peripheral

origin

IV

Central and/or

peripheral vertigo

Arlevert tablets

Cinnarizine 20 mg tablets

Dimenhydrinate 40 mg

tablets

Cinnarizine

20 mg

Dimenhydrinate

40 mg

Outpatients with

central and / or

peripheral vertigo

V

Central and/or

peripheral vertigo

Arlevert tablets

Cinnarizine 50 mg tablets

Dimenhydrinate 100 mg

tablets

Cinnarizine

50 mg

Dimenhydrinate

100 mg

Outpatients with

central and / or

peripheral vertigo

VI

Otogenic

(peripheral) vertigo

Arlevert tablets

Betahistine 12 mg tablets

Betahistine

12 mg

Outpatients with

otogenic

(peripheral) vertigo

VII

Acute vestibular

disorders

Arlevert tablets

Betahistine 12 mg tablets

Betahistine

12 mg

Outpatients with

vertigo as a

consequence of

acute vestibular

disorders

VIII

Menière’s disease

Arlevert tablets

Betahistine 12 mg tablets

Betahistine

12 mg

Outpatients with

Menière’s disease

All eight clinical studies (Studies I-VIII) were conducted in patients and employed

randomised, double-blind, parallel-group designs and were carried out in accordance with the

guidelines of Good Clinical Practice (GCP). Possible bias was avoided by means of

double-blind design and randomisation. In addition to these studies, two crossover studies

were performed in healthy volunteers and the results of several open-label studies are

available. The investigational drug Arlevert 20mg/40mg Tablets and the reference products

were manufactured in accordance with the guidelines of Good Manufacturing Practice

(GMP).

The treatment period of the patients usually extended to 4 weeks, including a follow-up

examination after 1 week and a final examination after 4 weeks of therapy. No long-term

studies were carried out, since the combination preparation Arlevert 20mg/40mg Tablets has

PAR Arlevert Tablets

Former: UK/H/984/001/MR

been marketed in Germany for more than 20 years and a large amount of data on post

marketing experience concerning the efficacy and safety of the drug is available.

The patient's subjective evaluation of reduction of the vertigo symptoms, quantified by the

decrease of the variable “Mean Vertigo Score” (MVS), was used as the primary efficacy

criterion in all studies. In each case, it represents six vertigo symptoms (dysstasia and

walking unsteadiness, staggering, rotary sensation, tendency to fall, lift sensation, and

swaying resp. blackout), and the intensity of vertigo in consequence of six different

triggering factors (change of position, bowing, getting-up, walking resp. driving by car/train,

head movement, and eye movement). These 12 criteria were rated and quantified by the

patient using either a visual analogue scale (VAS) or a verbal rating scale (VRS). The results

of this evaluation were combined in the Mean Vertigo Score. Thus, the Mean Vertigo Score

is a method of measuring vertigo based on an assessment of symptoms and their intensity.

Studies I, III, IV and V are considered to be pivotal to this application. This is because the

active controls in these studies allow a risk:benefit assessment of the combination product

against its individual components, as required by the CPMP Note for guidance on fixed

combination medicinal products. Note that Studies I and V compare with higher doses of

each component therapy. Satisfactory certificates of analysis have been provided for the test

and reference batches used in the clinical studies.

The results from Studies I, III, IV and V are presented below.

Clinical relevance is further supported by the result that between 60 and 80% of the patients

treated with the combination reported either no or only mild symptoms of vertigo after the

end of treatment. To further corroborate the clinical relevance of Arlevert 20mg/40mg

Tablets, responder rates have been calculated. A responder is defined as any patient with a

change from baseline of at least 50 percent. There is a distinct and statistically high

significant difference between Arlevert 20mg/40mg Tablets and placebo. Not only has

Arlevert 20mg/40mg Tablets been demonstrated to be more effective than placebo, but it has

also been demonstrated to be more effective than both active treatments. This demonstrates

the clinical benefit of treatment with Arlevert 20mg/40mg Tablets.

In conclusion, the clinical relevance of the therapeutic success achieved with Arlevert

20mg/40mg Tablets has been demonstrated by a large effect size in comparison to placebo

and at least medium effect sizes in comparison to the single components.

SAFETY

In the clinical programme described above there were no serious and/or unexpected adverse

events.

CLINICAL OVERVIEW

The clinical overview was written by an appropriately qualified Doctor and is a suitable

summary of the clinical aspects of the dossier.

PAR Arlevert Tablets

Former: UK/H/984/001/MR

SUMMARY OF PRODUCT CHARACTERISTICS (SPC)

This SPC is medically satisfactory.

PATIENT INFORMATION LEAFLET (PIL)

The PIL is medically satisfactory and consistent with the information in the SPC.

LABELLING

The labels are medically satisfactory.

APPLICATION FORM (MAA)

The MAA form is medically satisfactory.

MEDICAL CONCLUSION

The grant of a marketing authorisation is recommended.

IV

OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

QUALITY

The important quality characteristics of Arlevert 20mg/40mg Tablets are 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.

PRECLINICAL

The preclinical sections of this application are based on published bibliographic data and no

new preclinical pharmacodynamic studies with the formulation intended for marketing have

been provided.

Absence of preclinical pharmacokinetics studies with Arlevert 20mg/40mg Tablets is

considered acceptable, as such data will be superseded with clinical pharmacokinetics data.

This is satisfactory.

The presented bibliographic data on acute and chronic toxicology, reproductive toxicology

and genotoxicity and carcinogenicity for both actives has been supplemented with bridging

studies with the combination preparation intended for marketing.

EFFICACY

Arlevert 20mg/40mg Tablets was consistently superior to its components on the primary

endpoints of each pivotal study, both at doses similar to those used in the combination

product and at higher doses. Evidence of efficacy therefore appears to have been robustly

demonstrated.

In the clinical programme there were no serious and/or unexpected adverse events. The most

frequent events were tiredness, dryness of mouth and headache. These adverse events did not

occur more frequently with the combination. No new or unexpected safety concerns arise

from this application.

The SPC, PIL and labelling are satisfactory.

PAR Arlevert Tablets

Former: UK/H/984/001/MR

RISK BENEFIT ASSESSMENT

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

have been identified. Extensive clinical experience with cinnarizine and dimenhydrinate is

considered to have demonstrated the therapeutic value of the compound. The risk-benefit is,

therefore, considered to be positive.

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5 | A-1200 Wien | www.basg.at | www.ages.at

Public Assessment Report

Update

Arlevert 20 mg/40 mg Tabletten

Cinnarizin/

Dimenhydrinat

This module reflects the procedural steps and scientific information after the

finalisation of the initial procedure.

PAR Scientific discussion

30/30

Scope

Procedure number

Product

Information

affected

Date of start of the

procedure

Date of

end of

procedure

Approval/

approval

Assessment

report

attached

Renewal

UK/H/0984/001/R/001

24.02.2010

20.10.201

approval

Repeat Use Procedure

UK/H/0984/001/E/001

19.12.2011

22.03.201

approval

Transfer of RMS

UK/H/0984/001

AT/H/0500/001

16.04.201

approval

Renewal

AT/H/0500/001/R/002

09.09.2016

16.02.201

approval

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

Gebrauchsinformation: Information für Anwender

Arlevert 20 mg/40 mg Tabletten

Wirkstoffe: Cinnarizin/Dimenhydrinat

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

Einnahme

dieses

Arzneimittels

beginnen,

denn

sie

enthält

wichtige

Informationen.

Heben

Packungsbeilage

auf.

Vielleicht

möchten

diese

später

nochmals lesen.

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

oder das medizinische Fachpersonal.

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,

Apotheker

oder

medizinische

Fachpersonal.

Dies

gilt

auch

für

Nebenwirkungen,

nicht

dieser

Packungsbeilage

angegeben

sind.

Siehe Abschnitt 4.

Was in dieser Packungsbeilage steht

Was ist Arlevert und wofür wird es angewendet?

Was sollten Sie vor der Einnahme von Arlevert beachten?

Wie ist Arlevert einzunehmen?

Welche Nebenwirkungen sind möglich?

5.

Wie ist Arlevert aufzubewahren?

Inhalt der Packung und weitere Informationen

1. Was ist Arlevert und wofür wird es angewendet?

Arlevert

enthält

zwei

Wirkstoffe

Cinnarizin

Dimenhydrinat.

beiden

Substanzen gehören zu verschiedenen Wirkstoffgruppen. Cinnarizin gehört zur

Gruppe der so genannten Calciumantagonisten und Dimenhydrinat zur Gruppe der

so genannten Antihistaminika.

Beide Substanzen bewirken eine Reduzierung von Schwindelsymptomen (z. B.

Drehgefühl) und Übelkeit. Die Anwendung der beiden Wirkstoffe als Kombination ist

wirksamer als wenn jede der Einzelsubstanzen für sich alleine eingesetzt wird.

Arlevert

wird

Erwachsenen

angewendet

Behandlung

unterschiedlicher

Schwindelformen. Schwindel kann eine Reihe verschiedener Ursachen haben. Die

Einnahme

Arlevert

kann

dabei

unterstützen,

täglichen

Arbeiten

nachzugehen, die beim Vorhandensein von Schwindelbeschwerden Schwierigkeiten

bereiten.

2. Was sollten Sie vor der Einnahme von Arlevert beachten?

Arlevert darf nicht eingenommen werden,

wenn Sie jünger als 18 Jahre sind

wenn Sie allergisch gegen Cinnarizin, Dimenhydrinat bzw. Diphenhydramin oder

einen der in Abschnitt 6. genannten sonstigen Bestandteile dieses Arzneimittels sind

wenn

allergisch

sind

gegen

andere

Antihistaminika

Astemizol,

Chlorpheniramin und Terfenadin, die als Mittel gegen Allergien eingesetzt werden).

Sie sollten dieses Arzneimittel nicht einnehmen, außer auf Anweisung Ihres Arztes.

wenn Sie unter einem Engwinkelglaukom (eine spezielle Augenerkrankung) leiden

wenn Sie unter Epilepsie leiden

wenn Sie einen erhöhten Druck im Gehirn haben (z. B. aufgrund eines Tumors)

wenn Sie einen übermäßigen Alkoholkonsum haben

wenn Sie Prostatabeschwerden mit Schwierigkeiten beim Wasserlassen haben

wenn Sie unter Leber- oder Nierenversagen leiden.

Warnhinweise und Vorsichtsmaßnahmen

Bitte sprechen Sie mit Ihrem Arzt, Apotheker oder dem medizinischen Fachpersonal,

bevor Sie Arlevert einnehmen, wenn Sie an einer der folgenden Erkrankungen leiden:

niedriger oder hoher Blutdruck

erhöhter Augeninnendruck

Darmverschluss

vergrößerte Prostata

Überfunktion der Schilddrüse

schwere Herzerkrankung

Parkinson’sche Krankheit.

Die Einnahme von Arlevert kann zur Verschlechterung dieser Erkrankungen führen.

Arlevert kann trotzdem für Sie geeignet sein, Ihr Arzt muss jedoch gegebenenfalls

diese Umstände berücksichtigen.

Einnahme von Arlevert zusammen mit anderen Arzneimitteln

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

kürzlich angewendet haben oder beabsichtigen, andere Arzneimittel anzuwenden.

Arlevert kann mit anderen, gleichzeitig angewendeten Arzneimitteln wechselwirken.

Arlevert kann Sie müde oder schläfrig machen bei gleichzeitiger Einnahme folgender

Arzneimittel:

Barbiturate (Schlafmittel)

Zentralwirkende Analgetika (starke Schmerzmittel wie z. B. Morphium)

Tranquilizer (Arzneimittel zur Behandlung von Angst- und Spannungszuständen)

Monoaminooxidase-Hemmer

(zur

Behandlung

Depressionen

Angst-

zuständen eingesetzt).

Arlevert kann die Wirkungen der folgenden Arzneimittel verstärken:

trizyklische Antidepressiva (zur Behandlung von Depressionen und Angstzuständen

eingesetzt)

Atropin

(Arzneimittel

Muskelentspannung,

Augenuntersuchungen

verwendet)

Ephedrin

(kann

Behandlung

Husten

verstopfter

Nase

eingesetzt

werden)

Procarbazin

(Arzneimittel,

Behandlung

einiger

Arten

Krebserkrankungen eingesetzt wird)

Arzneimittel zur Blutdrucksenkung.

Aminoglykoside (bestimmte Antibiotika) können das Innenohr schädigen. Wenn Sie

Arlevert einnehmen, kann es sein, dass Sie diese Schädigung nicht bemerken.

Sie dürfen Arlevert nicht zusammen mit Arzneimitteln einnehmen, die zur Korrektur von

Herzrhythmusstörungen eingesetzt werden (Antiarrthymika). Arlevert kann auch die

Art, wie Ihre Haut auf Allergietests reagiert, verändern.

Einnahme von Arlevert zusammen mit Nahrungsmitteln, Getränken und Alkohol

Arlevert

kann

Verdauungsbeschwerden

verursachen,

durch

Einnahme

Tabletten nach den Mahlzeiten vermindert werden können. Trinken Sie während der

Einnahme von Arlevert keinen Alkohol, da Sie dies müde oder schläfrig machen kann.

Schwangerschaft, Stillzeit und Fortpflanzungsfähigkeit

Wenn Sie schwanger sind oder stillen,

oder wenn Sie vermuten, schwanger zu sein,

oder

beabsichtigen,

schwanger

werden,

fragen

Einnahme

dieses

Arzneimittels Ihren Arzt oder Apotheker um Rat.

Verkehrstüchtigkeit und Fähigkeit zum Bedienen von Maschinen

!

Achtung: Dieses Arzneimittel kann die Reaktionsfähigkeit und

Verkehrstüchtigkeit beeinträchtigen.

Arlevert kann bei Ihnen ein Gefühl der Schläfrigkeit hervorrufen. Falls dies der Fall ist,

dürfen Sie kein Fahrzeug lenken oder Maschinen bedienen.

3. Wie ist Arlevert einzunehmen?

Nehmen Sie dieses Arzneimittel immer genau nach der Absprache mit Ihrem Arzt oder

Apotheker ein. Fragen Sie bei Ihrem Arzt oder Apotheker nach, wenn Sie sich nicht

sicher sind.

Die empfohlene Dosis beträgt: 3-mal täglich 1 Tablette mit etwas Flüssigkeit nach

den Mahlzeiten. Schlucken Sie die Tablette als Ganzes, ohne zu kauen.

Normalerweise werden Sie Arlevert bis zu 4 Wochen lang einnehmen. Ihr Arzt wird

Ihnen sagen, ob Sie Arlevert über diesen Zeitraum hinaus einnehmen müssen.

Wenn Sie eine größere Menge von Arlevert eingenommen haben, als Sie sollten

Wenn Sie versehentlich zu viele Tabletten eingenommen haben, oder wenn Arlevert

von einem Kind eingenommen wurde, sollten Sie dringend ärztlichen Rat einholen.

Wenn Sie zu viel Arlevert einnehmen, kann es zu starker Müdigkeit, Schwindel und

Zittern kommen. Ihre Pupillen könnten sich erweitern und Sie könnten nicht in der Lage

sein, Wasser zu lassen. Es können Mundtrockenheit, Gesichtsrötung, beschleunigter

Herzschlag, Fieber, Schwitzen und Kopfschmerzen auftreten.

Wenn

eine

sehr

große

Menge

Arlevert

eingenommen

haben,

kann

dies

Krämpfen,

Halluzinationen,

hohem

Blutdruck,

einem

Gefühl

Schwankens,

Erregungserscheinungen und Schwierigkeiten beim Atmen führen. Es könnte zum

Koma kommen.

Wenn Sie die Einnahme von Arlevert vergessen haben

Wenn Sie die Einnahme einer Arlevert Tablette vergessen haben, lassen Sie diese

Tablette einfach aus. Nehmen Sie die folgende Tablette zum nächsten Zeitpunkt ein,

an dem Sie diese normalerweise einnehmen würden. Nehmen Sie nicht die doppelte

Menge ein, wenn Sie die vorherige Einnahme vergessen haben.

Wenn Sie die Einnahme von Arlevert abbrechen

Beenden Sie nicht die Einnahme von Arlevert ohne vorherige Anweisung Ihres Arztes.

werden

wahrscheinlich

wieder

Schwindelbeschwerden

„Drehgefühl“)

bekommen, falls Sie mit der Behandlung zu früh aufhören.

Wenn Sie weitere Fragen zur Einnahme dieses Arzneimittels haben, wenden Sie sich

an Ihren Arzt, Apotheker oder das medizinische Fachpersonal.

4. Welche Nebenwirkungen sind möglich?

Wie alle Arzneimittel kann auch dieses Arzneimittel Nebenwirkungen haben, die aber

nicht bei jedem auftreten müssen.

Häufige Nebenwirkungen (kann bis zu 1 von 10 Behandelten betreffen):

Schläfrigkeit, Mundtrockenheit, Kopfschmerzen, Magenschmerzen. Diese haben in der

Regel eine milde Ausprägung und verschwinden innerhalb weniger Tage, auch wenn

Sie weiterhin Arlevert einnehmen.

Gelegentliche Nebenwirkungen (kann bis zu 1 von 100 Behandelten betreffen):

Schwitzen, Hautrötungen, Verdauungsbeschwerden, Übelkeit, Durchfall, Nervosität,

Krämpfe, Vergesslichkeit, Tinnitus (Ohrgeräusche), Missempfindungen (Kribbeln in den

Händen oder Füßen), Zittern.

Seltene Nebenwirkungen (kann bis zu 1 von 1.000 Behandelten betreffen)):

Sehstörungen,

allergische

Reaktionen

Hautreaktionen),

Lichtempfindlichkeit,

Schwierigkeiten beim Wasserlassen.

Sehr seltene Nebenwirkungen (kann bis zu 1 von 10.000 Behandelten betreffen): die

Zahl der weißen Blutkörperchen und der Blutplättchen kann erniedrigt sein und es kann

zu einer starken Abnahme der roten Blutkörperchen kommen, was zu Schwächegefühl,

Hauteinblutungen oder einer Zunahme von Infektionen führen kann. Im Falle von

Infektionen mit Fieber und ernsthafter Verschlechterung Ihres Gesundheitszustandes

suchen Sie bitte Ihren Arzt auf und informieren Sie ihn über die Einnahme Ihres

Arzneimittels.

Weitere mögliche Nebenwirkungen (Häufigkeit auf Grundlage der verfügbaren Daten

nicht abschätzbar), die bei dieser Gruppe von Arzneimitteln auftreten können:

Gewichtszunahme, Verstopfung, Engegefühl in der Brust, Gelbsucht (Gelbverfärbung

Haut

oder

Augenweiß,

verursacht

durch

Leber-

oder

Blutprobleme),

Verschlechterung

eines

Engwinkelglaukoms

(Augenerkrankung

erhöhtem

Augeninnendruck),

unwillkürliche

Bewegungen,

ungewöhnliche

Erregungserscheinungen

Ruhelosigkeit

(besonders

Kindern),

schwere

Hautreaktionen.

Meldung von Nebenwirkungen

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

oder

das medizinische Fachpersonal. Dies gilt auch für Nebenwirkungen, die nicht in dieser

Packungsbeilage angegeben sind. Sie können Nebenwirkungen auch direkt dem

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5

1200 WIEN

ÖSTERREICH

Fax: + 43 (0) 50 555 36207

Website: http://www.basg.gv.at/

anzeigen. Indem Sie Nebenwirkungen melden, können Sie dazu beitragen, dass mehr

Informationen über die Sicherheit dieses Arzneimittels zur Verfügung gestellt werden.

5. Wie ist Arlevert aufzubewahren?

Bewahren Sie dieses Arzneimittel für Kinder unzugänglich auf.

dürfen

dieses

Arzneimittel

nach

Durchdrückpackung

Faltschachtel

nach

"Verwendbar

bis"

angegebenen

Verfalldatum

nicht

mehr

verwenden. Das Verfalldatum bezieht sich auf den letzten Tag des angegebenen

Monats.

Für dieses Arzneimittel sind keine besonderen Lagerungsbedingungen erforderlich.

Entsorgen Sie Arzneimittel nicht im Abwasser. Fragen Sie Ihren Apotheker, wie das

Arzneimittel zu entsorgen ist, wenn Sie es nicht mehr verwenden. Sie tragen damit

zum Schutz der Umwelt bei.

6. Inhalt der Packung und weitere Informationen

Was Arlevert enthält

Die Wirkstoffe sind: Cinnarizin (20 mg) und Dimenhydrinat (40 mg).

Die sonstigen Bestandteile sind: mikrokristalline Cellulose; Maisstärke; Talkum;

Hypromellose; hochdisperses, wasserfreies Siliciumdioxid; Magnesiumstearat und

Croscarmellose-Natrium.

Wie Arlevert aussieht und Inhalt der Packung

Arlevert

sind runde,

beidseitig

gewölbte,

weiße

bis blassgelbe

Tabletten

Prägung „A“ auf einer Seite und einem Durchmesser von 8 mm. Sie sind in Packungen

mit 20, 50 und 100 Tabletten erhältlich. Die Tabletten sind in PVC/PVDC/Aluminium-

Blistern mit jeweils 20 oder 25 Tabletten verpackt. Es werden möglicherweise nicht alle

Packungsgrößen in den Verkehr gebracht.

Pharmazeutischer Unternehmer und Hersteller

HENNIG ARZNEIMITTEL GmbH & Co. KG

Liebigstraße 1-2

65439 Flörsheim am Main

Deutschland

Z.Nr.: 1-27198

Dieses

Arzneimittel

ist

in

den

Mitgliedsstaaten

des

Europäischen

Wirtschaftsraumes (EWR) unter folgenden Bezeichnungen zugelassen:

Österreich:

Arlevert 20 mg/40 mg Tabletten

Belgien, Luxemburg:

Arlevertan 20 mg/40 mg tabletten/comprimés/Tabletten

Bulgarien:

Arlevert 20 mg/40 mg таблетки

Griechenland, Zypern:

Arlevert 20 mg/40 mg δισκία

Tschechische Republik:

Arlevert 20 mg/40 mg tablety

Dänemark, Schweden:

Arlevert 20 mg/40 mg tabletter

Estland:

Arlevert

Finnland:

Arlevert 20 mg/40 mg tabletit

Deutschland:

Arlevert 20 mg/40 mg Tabletten;

Cinnarizin Dimenhydrinat Hennig 20 mg/40 mg Tabletten;

Ungarn:

Arlevert 20 mg/40 mg tabletta

Italien:

Arlevertan 20 mg/40 mg compresse

Irland, Vereinigtes Königreich:

Arlevert 20 mg/40 mg tablets

Lettland:

Arlevert 20 mg/40 mg tabletes

Litauen:

Arlevert 20 mg/40 mg tabletės

Polen:

Arlevert 20 mg + 40 mg tabletki

Portugal:

Arlevert 20 mg + 40 mg comprmidos

Rumänien:

Arlevert 20 mg/40 mg comprimate

Slowakei:

Arlevert 20 mg/40 mg tablety

Slowenien:

Arlevert 20 mg/40 mg tablete

Spanien:

Arlevertan 20 mg/40 mg comprimidos

Niederlande:

Arlevert 20 mg/40 mg tabletten

Diese Packungsbeilage wurde zuletzt überarbeitet im 02/2017.