Sie sind auf Seite 1von 7

Public Assessment Report

Scientific discussion

Dimenhydrinat Galenica

50 mg sublingual tablets

DK/H/2310/001/DC

2 October 2015

This module reflects the scientific discussion for the approval of Dimenhydrinat Galenica. The
procedure was finalised on 10 December 2014. For information on changes after this date please
refer to the module Update.
I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing
authorisation for Dimenhydrinat Galenica 50 mg sublingual tablets, from Galenica SA.

The product is indicated for prevention and treatment of motion sickness.


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

Dimenhydrinate, a monoethanolamine derivative, is a sedating antihistamine with antimuscarinic and


significant sedative effects. It is mainly an antiemetic in the prevention and treatment of motion sickness.
The usual dose of dimenhydrinate by mouth is 50 to 100 mg, given 3 or 4 times daily. For the prevention
of motion sickness, the first dose should be given at least 30 minutes before travelling.

Chemically, dimenhydrinate is a salt of two active substances: diphenhydramine and 8-


chlorotheophylline, a chlorinated derivative of the theophylline. Theophylline is closely related to
caffeine and theobromine, mild central nervous system stimulants. It was thought that by combining the
antiemetic effects of diphenhydramine with a stimulant, the marked drowsiness induced by
diphenhydramine could be moderated somewhat by 8-chlorotheophylline. The sedation caused by
diphenhydramine, however, is substantially stronger than the stimulation caused by 8-
chlorotheophylline, so the overall effect is still mostly sedating.

This decentralised procedure concerns a well established use application. For this kind of application,
the applicant should justify the eligibility of the drug substance to be of well-established use. Under the
European regulatory framework, a bibliographic application is admissible if the applicant can
demonstrate that the active substance of the medicinal product was in well-established medicinal use
within the EU for at least 10 years, with recognised efficacy and an acceptable level of safety. In that
event, the pre-clinical and clinical-trial data normally required for an application may be replaced by
appropriate scientific literature.

The marketing authorisation is granted based on article 10a of Directive 2001/83/EC.

II. QUALITY ASPECTS

II.1 Introduction

Each sublingual tablet contains 50 mg of dimenhydrinate (consists of not less than 26.5 mg and not more
than 27.75 mg diphenhydramine and not less than 22.0 mg and not more than 23.25 mg 8-
chlorotheophylline).

The tablets are white, round, biconvex, sublingual tablets, 9.0 mm 0.1 mm in diameter and 4.5 0.2
mm in thickness.

The tablets are packed in a cardboard box containing the appropriate number of PA/Alu/PVC-
Aluminium foil (Alu-Alu) blisters containing 4, 10 or 20 sublingual tablets or white opaque HDPE
bottles with child resistant screw cap (PP) and mounted desiccant of white low-density polyethylene
capsule, containing 2 gr silica gel (amorphous silicon dioxide), containing 30 sublingual tablets.
However, not all pack sizes may be marketed.

The tablets contain: Methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L100);
Microcrystalline cellulose; Mannitol; Sodium starch glycolate - type A; Vanilla flavor; Saccharin;
Silica colloidal anhydrous; Magnesium stearate; Levomenthol and Talc.

2/7
The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place
for this product type at all sites responsible for the manufacturing of the active substance as well as for
the manufacturing and assembly of this product prior to granting its national authorisation.

II.2 Drug Substance

The active substance is described in the European Pharmacopoeia. It is a white crystalline powder,
slightly soluble in water, freely soluble in ethanol and chloroform and sparingly soluble in ethyl ether.

Dimenhydrinate is a combination of two active substances; diphenhydramine and 8-hlorotheophylline.

INN: Dimenhydrinate

Chemical name(s): 2-benzhydryloxyethyldimethylamine compound with 8-chloro-1,3-dimethylpurine-


2,6(3H,1H)-dione (1:1) or
1H-Purine-2,6-dione, 8-chloro-3,7-dihydro-1,3-dimethyl-, compound with 2-(diphenylmethoxy)-
N,Ndimethylethanamine (1:1) or
8-Chlorotheophylline, compound with 2-(diphenylmethoxy)-N,N-dimethylethylamine (1:1)

Molecular mass: 469.96

Molecular formula:

The documentation on the active substance is submitted as a CEP.

No stability studies have been performed and therefore no retest period has been accepted.

Additional documentation on the applicants testing of the drug substance has been presented.

II.3 Medicinal Product

The pharmaceutical development work is described in detail, including satisfactory compatibility studies
for the active substance in combination with excipients. The formulation is chosen in order to obtain
fast disintegration and dissolution in the oral cavity. The choice of dissolution method and specification
limits have been discussed in detail and has been accepted.

The manufacturing process has been described and justified by validation.

The drug product specification covers appropriate parameters for this dosage form. Batch analysis
results show that the finished product meets the specification proposed.

Validation of the analytical methods has been presented.


The conditions used in the stability studies are according to the ICH stability guideline.

3/7
Shelf-life/storage conditions for both the blister and the HDPE bottle: 2 years, This medicinal product
does not require any special storage conditions.

III. NON-CLINICAL ASPECTS

III.1 Introduction

The application for a marketing authorisation for Dimenhydrinat Galenica 50 mg sublingual tablets is
according to Article 10a in Directive 2001/83/EC.

This application is a literature based application, and the MAH has not performed any non-clinical
studies in support of the application.

The pharmacodynamic, pharmacokinetic, and toxicological properties of dimenhydrinate, the active


ingredient in Dimenhydrinat Galenica 50 mg sublingual tablets, are well-established and similar
preparations have been marketed worldwide for over half a century. Therefore, dimenhydrinate can be
regarded as an active ingredient with well-established medicinal use, with recognized efficacy and an
acceptable level of safety.

It can be summarized for substances with well-established medicinal use(s):


No new non-clinical safety experiments are necessary, if the available literature contains sufficient
information on pharmacodynamic, pharmacokinetic and toxicology
This is supported if sufficient clinical experience is available in humans.

The non-clinical experience has shown dimenhydrinate to:


1. be pharmacologically effective prevention and treatment of non-febrile nausea and vomiting
associated with motion sickness
2. possess a favorable pharmacokinetic profile for the given indication.
3. have an extensive and favourable safety/toxicological profile.

All non-clinical data appearing in the application are based solely on bibliographical research. The cited
articles refer to reviews and/or non-clinical studies performed in vitro or in vivo in animal species.

III.2 Ecotoxicity/environmental risk assessment (ERA)

Since Dimenhydrinat Galenica is intended to substitute identical products, this will not lead to an
increased exposure to the environment. An environmental risk assessment is therefore not deemed
necessary.

IV. CLINICAL ASPECTS

IV.1 Pharmacokinetics

A bioavailability study has been performed to establish that the product has clinical effect, and as a
means of bridging to studies reported in the literature.

The study was performed as an open-label, randomized, two-way crossover, single-dose study
conducted under fasting conditions, to compare the pharmacokinetics of 50 mg dimenhydrinate
administered sublingually with approximately the same amount of dimenhydrinate administered orally

4/7
as a syrup containing 49.5 mg dimenhydrianate pr. 15 ml. In keeping with the proposed posology, the
sublingual tablet was administered without concomitant water whereas syrup intake was followed by
240 ml water.

Pharmacokinetics were measured for plasma diphenhydramine using the standard bioequivalence
parameters for single dose studies.

The study results showed that the sublingual tablets and syrup were bioequivalent for both AUC0-t and
AUC0- based on standard 90% CI limits of 80.00-125.00%. Cmax for the sublingual tablets was
marginally outside the 90% CI limits (78.16-88.80%) but as the plasma levels were greater than 30
ng/ml and lie within the therapeutic range of 30-100 ng/ml for dimenhydrinate, the results are considered
acceptable. Median Tmax was established at 2.83 hrs (range 1.50-3.50) compared with 1.75 hrs (range
1.50-3.50) for the syrup preparation. Both products showed similar t values, 10.76 hours and 10.54
hours for test and syrup products respectively. These values are within the known literature values for
diphenhydramine of 9 hours for adults (range: 7 to 12 hours); Elderly: 13.5 hours (range: 9 to 18 hours).

The data are supportive of the fact that dimenhydrinate (as measured via diphenhydramine plasma
levels) is absorbed systemically from the test tablets without the need for concomitant water, and
therapeutic plasma concentrations of the active moiety are achieved.

IV.2 Clinical efficacy

Bibliographical evidence is presented to support that dimenhydrinate can be used for prophylaxis and
treatment of motion sickness. As the bioavailability study demonstrates that the sublingual tablets
subject of the application show therapeutic plasma concentrations within the ranges reported in the
literature for various orally administered dimenhydrinate formulations, bridging to the literature is
acceptable.

IV.3 Clinical safety

The bioavailability study also allows bridging to the literature to support the safety of the product.
Exposure and potential adverse events are satisfactorily addressed for the proposed indication and
posology. No local tolerance issues were reported with the sublingual tablet during the performance of
the bioavailability study. Any potential issues in this regard following use in actual clinical practice, will
be followed via routine pharmacovigilance in line with agreements in the Risk Management Plan.

IV.4 Risk Management Plan

The MAH has submitted a risk management plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Dimenhydrinat Galenica.

The agreed summary table of safety concerns is as follows with no additional pharmacovigilance or risk
minimisation measures:

5/7
Table 1. Summary table of safety concerns as approved in RMP

V. USER CONSULTATION

The package leaflet has been evaluated via a user consultation study in accordance with the requirements
of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing
the PIL was English.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND


RECOMMENDATION

Dimenhydrinat Galenica 50 mg sublingual tablets has a proven chemical-pharmaceutical quality and


it has been demonstrate that the active substance of the medicinal product was in well-established
medicinal use within the EU for at least 10 years, with recognised efficacy and an acceptable level of
safety.

6/7
The MAH has provided written confirmation that systems and services are in place to ensure compliance
with their pharmacovigilance obligations. A Risk Management Plan has been presented summarising
the safety concerns.

Agreement between Member States was reached during a written procedure. There was no discussion
in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that well-
established use has been demonstrated for Dimenhydrinat Galenica, and have therefore granted a
marketing authorisation. The decentralised procedure was finalised on 10 December 2014.
Dimenhydrinat Galenica was authorised in Denmark on 29 June 2015.

According to the List of Union reference dates and frequency of submission of periodic safety update
reports (PSURs), the next DLP is 10-02-2025, after which the PSUR cycle is 13 years.

The date for the first renewal will be: 10 December 2019.

The following post-approval commitments have been made during the procedure:

Batch analyses of further 2 batches of active substance will be submitted.


Batch analyses of the first three batches of the finished product will be submitted as soon as
they have been manufactured and released for the market.
Update of relevant parts of the dossier to reflect the new ASM, including sections 3.2.S, 3.2.P.2
and 3.2. P.3 will be submitted.

7/7