Public Assessment Report

Mutual Recognition Procedure

Arlevert 20mg/40mg Tablets

UK/H/984/01/MR
UK licence no: PL 11249/0001

HENNIG ARZNEIMITTEL GmbH & Co. KG

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LAY SUMMARY
The MHRA granted HENNIG ARZNEIMITTEL GmbH & Co. KG a Marketing
Authorisation (licence) for the medicinal product Arlevert 20mg/40mg Tablets on 20th May
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

Module 6

1 Introduction
2 Quality aspects
3 Non-clinical aspects
4 Clinical aspects
5 Overall conclusions

Page 14
Page 16
Page 19
Page 23
Page 27

Steps taken after initial procedure

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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 Flrsheim am Main, Germany

Reference Member
State (RMS)
CMS

UK

Procedure Number

UK/H/0984/001/MR

Timetable

Day 90 3rd April 2007

Austria, Belgium, Denmark, Ireland, Italy, Luxembourg, The

Netherlands, Poland, Slovenia, Sweden

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Module 2
Summary of Product Characteristics
1

NAME OF THE MEDICINAL PRODUCT

Arlevert 20 mg/40 mg tablets

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg cinnarizine and 40 mg dimenhydrinate.
For full list of excipients, see section 6.1.

PHARMACEUTICAL FORM
Tablet, round, biconvex white tablets embossed with A on one side.

4
4.1

CLINICAL PARTICULARS
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 Parkinsons 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

Body system:
Blood and
lymphatic system
disorders
Immune system
disorders

Common
>1/100,
<1/10

Uncommon
>1/1,000,
<1/100

Rare
>1/10,000,
<1/1,000

Very rare
<1/10,000

Leucopenia
Thrombopenia
Aplastic anaemia
Hypersensitivity
reactions
(eg cutaneous

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Frequency of ADR

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Common
>1/100,
<1/10

Uncommon
>1/1,000,
<1/100

Nervous system
disorders

Somnolence
Headache

Paraesthesia
Amnesia
Tinnitus
Tremor
Nervousness
Convulsions

Eye disorders
Gastrointestinal
disorders

Dry mouth
Abdominal pain

Dyspepsia
Nausea
Diarrhoea
Perspiration
Rash

Skin and
subcutaneous tissue
disorders
Renal and urinary
disorders

Rare
>1/10,000,
<1/1,000
reactions)

Very rare
<1/10,000

Visual disorders

Photosensitivity
Urinary hesitancy

In addition the following adverse reactions are associated with dimenhydrinate and cinnarizine:
Dimenhydrinate: paradoxical excitability (especially in children), worsening of an existing angleclosure 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
5.1

PHARMACOLOGICAL PROPERTIES
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 4th 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 (Cmax) 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 Ndesalkylation 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
6.1

PHARMACEUTICAL PARTICULARS
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

MARKETING AUTHORISATION HOLDER

HENNIG ARZNEIMITTEL GmbH & Co. KG
Liebigstrasse 1-2
D-65439 Flrsheim am Main/Germany

MARKETING AUTHORISATION NUMBER(S)

PL 11249/0001

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

May 2005

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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
Arlevert 20 mg/ 40mg tablets
Pack size of 20 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 20th 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.

UK/H/984/001/MR

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
Histamine (5HT1) antagonists (N07C A52)

Pharmacotherapeutic classification
(ATC code)
Pharmaceutical form and strength(s)
Reference numbers for the Mutual Recognition
Procedure
Reference Member State
Member States concerned

Marketing Authorisation Number(s)

Name and address of the
authorisation holder

Tablets, Cinnarizine 20mg/Dimenhydrinate

40mg
UK/H/984/001/MR
United Kingdom
Austria, Belgium, Denmark, Ireland, Italy,
Luxembourg, The Netherlands, Poland,
Slovenia, Sweden
PL 11249/0001
HENNIG ARZNEIMITTEL GmbH & Co. KG
Liebigstrasse 1-2, D-65439 Flrsheim am
Main, Germany

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III

SCIENTIFIC OVERVIEW AND DISCUSSION

III.1

QUALITY ASPECTS

S.
Drug substance (1)
INN/Ph Eur name:
Cinnarizine
Chemical name:

1-benzhydryl-4-cinnamyl-piperazine

Structural formula

Molecular formula:

C26H28N2

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-2oxo-purin-6-olate

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Structural formula:

Molecular formula:

C17H21NO,C7H7ClN4O2

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 25C.
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 receptoroperated channels) inhibiting the influx of extracellular Ca2+. Cinnarizine also has
antihistamine properties blocking histamine H1 receptors (Ki=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 H1 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 (Ki 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 (Ki = 0.2 M) 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
(LD50, mouse: 1600 mg/kg; rat: 5760 mg/kg) in rodents appears to be lower than those of
cinnarizine (LD50 mouse: >1000 mg/kg; rat: >2500 mg/kg) or dimenhydrinate (LD50 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

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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:
1. The individual pharmaceutical ingredients have been available for adults and children as
prescription and OTC medicines for many years
2. 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
3. The lack of published data indicate that safety concerns have not arisen
4. The paucity of published data indicates the lack of molecular structural concerns
5. The limited data available on the individual drug substances and the combination product
do not indicate the potential for genotoxicity
6. 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

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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.

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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
The pharmacokinetic study was an open, single-dose, randomised, three-period, and
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.

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Primary parameters of AUCo- or exp , Cmax, tmax were determined as well as the mean body
residence time to infinity (MRTo- or exp) and the elimination half-life (t1/2) for both
cinnarizine and dimenhydrinate.
Cinnarizine Pharmacokinetic Parameters (Mean s.e.m., n = 11)
Parameter
Units
Cinnarizine
Cmax
ng/ml
38.58 6.16
Tmax
h
2.05 0.42
AUCexp
ng/ml.h
225.22 49.70
MRTexp
h
7.89 1.39
T
h
4.94 1.00
Diphenhydramine Pharmacokinetic Parameters (Mean s.e.m., n = 12)
Parameter
Units
Dimenhydrinate
Cmax
ng/ml
40.91 3.45
Tmax
h
1.71 0.19
AUCexp
ng/ml.h
265.14 25.19
MRTexp
h
7.81 0.40
T
h
4.76 0.22

Arlevert 20mg/40mg Tablets

37.36 4.46
2.27 0.22
238.26 38.61
7.03 0.54
4.10 0.35
Arlevert 20mg/40mg Tablets

37.36 4.46
1.88 0.27
240.94 23.63
7.65 0.37
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 AUCexp 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.

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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
Central and/or
peripheral vertigo

Formulation used in the

clinical study
Arlevert tablets
Cinnarizine 50 mg tablets
Dimenhydrinate 100 mg
tablets
Placebo tablets

Control groups

Patient population

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

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

Menires disease

Arlevert tablets
Betahistine 12 mg tablets

Betahistine
12 mg

Outpatients with
Menires 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

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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.

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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.

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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.

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Module 6
STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY
Date
submitted

Application
type

Scope

Outcome

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