Hydroxyzine 10mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Hydroxyzine hydrochloride
Available from:
DE Pharmaceuticals
ATC code:
N05BB01
INN (International Name):
Hydroxyzine hydrochloride
Dosage:
10mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04010200
Authorization number:
PL 20117/0317

Public Assessment Report

Decentralised Procedure

Hydroxyzine hydrochloride 10mg Film-coated

Tablets

Hydroxyzine hydrochloride 25mg Film-coated

Tablets

(Hydroxyzine hydrochloride)

Procedure No: UK/H/6891/001-002/DC

UK Licence Number: PL 20117/0317-0318

Morningside Healthcare Ltd

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

LAY SUMMARY

Hydroxyzine hydrochloride 10mg Film-coated Tablets

Hydroxyzine hydrochloride 25mg Film-coated Tablets

(hydroxyzine hydrochloride)

This is a summary of the Public Assessment Report (PAR) for Hydroxyzine hydrochloride 10mg Film-

coated Tablets (PL 20117/0317; UK/H/6891/001/DC) and Hydroxyzine hydrochloride 25mg Film-coated

Tablets (PL 20117/0318; UK/H/6891/002/DC). It explains how Hydroxyzine hydrochloride 10mg and

25mg Film-coated Tablets were assessed and their authorisation recommended, as well as their

conditions of use. It is not intended to provide practical advice on how to use these products.

The products will be collectively referred to as ‘Hydroxyzine Tablets’ throughout the remainder of this

PAR.

For practical information about using Hydroxyzine Tablets, patients should read the package leaflet or

contact their doctor or pharmacist.

What are Hydroxyzine Tablets and what are they used for?

Hydroxyzine Tablets are ‘generic medicines’. This means that Hydroxyzine Tablets are similar to

‘reference medicines’ already authorised in the European Union (EU) called Atarax 10mg and 25mg

Film-coated tablets (PL 16853/0094-0095; Alliance Pharmaceuticals, UK).

This medicine is used in adults and children to reduce itching caused by urticaria (nettle rash) and

dermatitis (eczema).

Hydroxyzine Tablets are also used to treat anxiety in adults.

How do Hydroxyzine Tablets work?

Hydroxyzine Tablets contain the active ingredient called hydroxyzine hydrochloride. This belongs to a

group of medicines called antihistamines (used to treat allergic reactions).

Histamine is a substance produced by the body as part of an allergic reaction. It causes an increase in

blood flow to the area of the allergy, and the release of other chemicals that add to the allergic

response. All this results in the symptoms of allergic reactions. Histamine is responsible for causing the

itching associated with a nettle-type rash and with allergic eczema.

Hydroxyzine hydrochloride blocks histamine receptors and so stops these actions of histamine.

Hydroxyzine hydrochloride enters the brain in significant quantities and causes drowsiness.

The antihistamine action and the fact that it causes drowsiness make hydroxyzine hydrochloride useful

for relieving itching associated with nettle rash and allergic eczema. It may be especially helpful for

itching that is worse at night. This is often the case in children, who notice itching less during the day

when they are active, but are bothered by it at night when they are still and have nothing else to focus

Hydroxyzine hydrochloride is also sometimes used in the short-term treatment of anxiety in adults. It

produces a calming effect in anxious, tense adults because it causes drowsiness and may suppress

activity in certain regions of the central nervous system.

How are Hydroxyzine Tablets used?

The pharmaceutical form of this medicine is a film-coated tablet and the route of administration is oral

(by mouth).

The patient should always take this medicine exactly as their doctor or pharmacist has told them to. The

patient should check with their doctor or pharmacist if they are not sure.

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

Hydroxyzine Tablets should be used at the lowest effective dose and the treatment period should be as

short as possible.

The recommended dose is:

In adults and children over 40 kg in weight, the maximum daily dose is 100 mg per day in all indications.

For treating itching in adults

The starting dose is 25mg at night, the patient’s doctor may increase the dose up to 25mg three or four

times daily.

Children and adolescents

For treating itching in children

In children up to 40 kg in weight, the maximum daily dose is 2 mg/kg/day.

Children aged 6 months to 6 years:

5mg to 15mg daily taken throughout the day, the doctor may change this depending on the child’s

weight.

Children over 6 years:

15mg to 25mg daily which the patient’s doctor may increase up to 50mg - 100mg daily, taken

throughout the day. The doctor may change this depending on the child’s weight.

For treating anxiety in adults

The dose is 50mg to 100mg daily, taken throughout the day.

For patients with liver disease

The patient’s doctor will reduce their dose by about one third if the patient has liver disease.

Hydroxyzine Tablets are not suitable for patients with severe liver disease or liver failure.

Please read section 3 of the package leaflet for detailed dosing recommendations, the route of

administration, and the duration of treatment.

For further information on how Hydroxyzine Tablets are used, refer to the package leaflet and

Summaries of Product Characteristics available on the Medicines and Healthcare products Regulatory

Agency (MHRA) website.

This medicine can only be obtained with a prescription.

What benefits of Hydroxyzine Tablets have been shown in studies?

Because Hydroxyzine Tablets are generic medicines, studies in healthy volunteers have been limited to

tests to determine that they are bioequivalent to the reference medicines Atarax 10mg and 25mg Film-

coated tablets (Alliance Pharmaceuticals, UK). Two medicines are considered to be bioequivalent when

they produce the same levels of the active substance in the body.

What are the possible side effects of Hydroxyzine Tablets?

Hydroxyzine Tablets are generic medicines and are bioequivalent to the reference medicines Atarax

10mg and 25mg Film-coated tablets (Alliance Pharmaceuticals, UK) so the benefits and possible side

effects are taken as being the same as for the reference medicines.

For the full list of restrictions, see the package leaflet.

For the full list of all side effects reported with Hydroxyzine Tablets, see section 4 of the package leaflet

available on the MHRA website.

Why was Hydroxyzine Tablets approved?

It was concluded that, in accordance with EU requirements, Hydroxyzine Tablets have been shown to

have comparable quality and to be bioequivalent to Atarax 10mg and 25mg Film-coated tablets

(Alliance Pharmaceuticals, UK). Therefore, the MHRA decided that, as for Atarax 10mg and 25mg Film-

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

coated tablets (Alliance Pharmaceuticals, UK), the benefits are greater than the risks and

recommended that they can be approved for use.

What measures are being taken to ensure the safe and effective use of Hydroxyzine Tablets?

A risk management plan (RMP) has been developed to ensure that Hydroxyzine Tablets are used as

safely as possible. Based on this plan, safety information has been included in the SmPCs and the

package leaflet for Hydroxyzine Tablets including the appropriate precautions to be followed by

healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore, new safety signals reported by

patients/healthcare professionals will be monitored/reviewed continuously.

Other information about Hydroxyzine Tablets

Malta and the UK agreed to grant Marketing Authorisations for Hydroxyzine Tablets on 08 November

2018. Marketing Authorisations were granted in the UK on 29 November 2018.

The full PAR for Hydroxyzine Tablets follows this summary.

This summary was last updated in January 2019.

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

TABLE OF CONTENTS

TABLE OF CONTENTS

INTRODUCTION

QUALITY ASPECTS

NON‐CLINICAL ASPECTS

CLINICAL ASPECTS

USER CONSULTATION

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

TABLE OF CONTENT OF THE PAR UPDATE FOR MRP AND DCP

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

I

INTRODUCTION

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

applications for Hydroxyzine Tablets (PL 20117/0317-318; UK/H/6891/001-002/DC), are approvable.

Hydroxyzine Tablets are Prescription-Only Medicines (POM) indicated:

to assist in the management of anxiety in adults.

for the management of pruritus associated with acute and chronic urticaria, including cholinergic

and physical types, and atopic and contact dermatitis in adults and children.

The applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference

Member State and Malta as Concerned Member State (CMS).

The applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, as generic

applications. The reference medicinal products are Atarax 10mg and 25mg Film-coated tablets which

were first authorised to the marketing authorisation holder (MAH), Pfizer Limited on 27 April 1987 (PL

00057/5003-5004R) and subsequently underwent a change of ownership procedure to the current MAH

Alliance Pharmaceuticals, UK on 01 November 2006 (Atarax 10mg Film-coated tablets; PL

16853/0094) and 30 January 2007 (Atarax 25mg Film-coated tablets; PL 16853/0095).

Hydroxyzine is a first generation antihistamine, a piperazine derivative, with antimuscarinic and

sedative properties.

Antihistamines act as competitive antagonists of histamine at H

histamine receptors, thus inhibiting H

receptor-mediated reactions, such as vasodilation, flare and itch reactions and sneezing.

First-generation H

antagonists easily cross the blood-brain barrier, consequently producing well-

documented sedative and anticholinergic effects.

First-generation antihistamines also have affinity for 5-HT receptors, alpha-adrenoreceptors, and

muscarinic receptors. They also reduce cyclic GMP concentrations, increase atrioventricular nodal

conduction, and inhibit activation of airway vagal afferent nerves.

Two bioequivalence studies (conducted under fasting conditions) were submitted to support these

applications. The applicant has stated that the bioequivalence studies were conducted in accordance

with Good Clinical Practice (GCP) guidelines.

The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for

this product type at all sites responsible for the manufacture, assembly and batch release of these

products.

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.

For manufacturing sites outside the community, the RMS has accepted copies of current GMP

Certificates or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’

issued by the inspection services of the competent authorities (or those countries with which the EEA

has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards

of GMP are in place at those non-Community sites.

The RMS and CMS considered that the applications could be approved at the end of procedure on 08

November 2018. After a subsequent national phase, licences were granted in the UK on 29 November

2018.

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

II

QUALITY ASPECTS

II.1

Introduction

Each film-coated tablet contains 10mg or 25mg of hydroxyzine hydrochloride as the active ingredient.

Other ingredients consist of the pharmaceutical excipients:

Tablet core:

Lactose monohydrate; microcrystalline cellulose; croscarmellose sodium; colloidal anhydrous silica and

magnesium stearate.

Film coating:

Opadry white Y-1-7000 which contains hypromellose 2910, titanium dioxide (E 171), and polyethylene

glycol 400 (E 1520).

Both strengths of the finished product are packaged in PVC/Aclar-Alu blisters in pack sizes of 7, 10, 14,

15, 20, 28, 30, 56, 60, 84, 90, 100, 112 and 120 tablets.

Not all pack sizes may be marketed.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations concerning

materials in contact with food.

II.2

Drug Substance

INN:

Hydroxyzine hydrochloride

Chemical name:

Ethanol, 2-[2-[4-[(4-chlorophenyl) phenylmethyl]- 1-piperazinyl] ethoxy]-,

dihydrochloride, (±)-.

(±)-2-[2-[4-(p-Chloro-α-phenylbenzyl)-1-piperazinyl] ethoxy] ethanol

dihydrochloride.

(RS)-2-[2-[4-[(4-chlorophenyl) phenylmethyl] piperazin-l-yl]ethoxy]ethanol

dihydrochloride.

Structure:

Molecular formula:

Molecular weight:

447.8

Appearance:

White or almost white, hygroscopic, crystalline powder.

Solubility:

Freely soluble in water and in ethanol (96 per cent), very slightly soluble in

acetone.

Hydroxyzine hydrochloride is the subject of a European Pharmacopeia monograph.

All aspects of the manufacture and control of the active substance, hydroxyzine hydrochloride, are

covered by the European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of

Suitability.

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

II.3.

Medicinal Product

Pharmaceutical Development

The objective of the development programme was to formulate safe, efficacious, film-coated tablets

containing 10mg or 25mg hydroxyzine hydrochloride per tablet, that are generic versions of the

reference products, Atarax 10mg and 25mg Film-coated tablets (Alliance Pharmaceuticals, UK). A

satisfactory account of the pharmaceutical development has been provided.

Comparative in vitro dissolution profiles have been provided for the proposed and originator products.

All excipients comply with their respective European Pharmacopoeia (Ph.Eur) monograph with the

exception of the film coat Opadry white Y-1-7000, which is controlled to a suitable in-house

specification. Satisfactory Certificates of Analysis have been provided for all excipients. Suitable batch

analysis data have been provided for each excipient.

With the exception of lactose monohydrate none of the excipients used contain material of animal or

human origin. The supplier of lactose monohydrate has confirmed that it is sourced from healthy

animals under the same conditions as milk for human consumption.

This product does not contain or consist of genetically modified organisms (GMO).

Manufacture of the product

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 at

commercial scale and has shown satisfactory results.

Finished Product Specification

The finished product release and shelf life specifications proposed are acceptable. Test methods have

been described that have been adequately validated. Batch data have been provided which comply

with the release specification. Certificates of Analysis have been provided for all working standards

used.

Stability of the Product

Finished product stability studies were performed in accordance with current guidelines on batches of

the finished products in the packaging proposed for marketing. The data from these studies support a

shelf-life of 2 years. This medicinal product does not require any special storage conditions.

Suitable post approval stability commitments have been provided to continue stability testing on

batches of finished product.

II.4

Discussion on chemical, pharmaceutical and biological aspects

There are no objections to the approval of these applications from a pharmaceutical viewpoint.

III

NON-CLINICAL ASPECTS

III.1

Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of hydroxyzine hydrochloride

are well-known, no new non-clinical studies are required and none have been provided. An overview

based on the literature review is, thus, appropriate.

The applicant’s non-clinical expert report has been written by an appropriately qualified person and is

satisfactory, providing an appropriate review of the relevant non-clinical pharmacology,

pharmacokinetics and toxicology.

III.2

Pharmacology

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

III.3

Pharmacokinetics

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

III.4

Ecotoxicity/environmental risk assessment (ERA)

Since Hydroxyzine Tablets are intended for generic substitution, this will not lead to an increased

exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

III.5

Discussion on the non-clinical aspects

There are no objections to the approval of these applications from a non-clinical viewpoint.

IV

CLINICAL ASPECTS

IV.1

Introduction

The clinical pharmacology of hydroxyzine hydrochloride is well-known. With the exception of data from

the bioequivalence studies detailed below, no new pharmacodynamics or pharmacokinetic data are

provided or are required for these applications.

No new efficacy or safety studies have been performed and none are required for this type of

application. A comprehensive review of the published literature has been provided by the applicant,

citing the well-established clinical pharmacology, efficacy and safety of hydroxyzine hydrochloride.

Based on the data provided, Hydroxyzine Tablets can be considered bioequivalent to Atarax 10mg and

25mg Film-coated tablets (Alliance Pharmaceuticals, UK).

IV.2

Pharmacokinetics

In support of these applications, the applicant submitted the following bioequivalence studies:

STUDY 1

A randomised, open-label, balanced, two treatment, two period, two sequence, single dose, crossover

bioequivalence study of the applicant’s test product Hydroxyzine hydrochloride 10mg Film-coated

Tablets (Morningside Healthcare Ltd, UK) versus the reference product Atarax 10mg Film-coated

tablets (Alliance Pharmaceuticals, UK) in healthy, adult, subjects under fasting conditions.

Subjects were administered a single oral dose (1 x 10 mg tablet) of the test or reference product with

240mL of water under fasting conditions.

Blood samples were collected for plasma levels before dosing and up to and including 96 hours after

each administration. The washout period between the treatment phases was 5 days. The

pharmacokinetic results are presented below:

Table: Summary of pharmacokinetic data for hydroxyzine (geometric means, ratios and 90%

confidence intervals):

Study conclusion

The 90% confidence intervals of the test/reference ratio for AUC and C

values for hydroxyzine lie

within the acceptable limits of 80.00% to 125.00%, in line with the guideline on the investigation of

bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the

applicant’s test product, Hydroxyzine hydrochloride 10mg Film-coated Tablets (Morningside Healthcare

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

Ltd, UK) is bioequivalent to the reference product Atarax 10mg Film-coated tablets (Alliance

Pharmaceuticals, UK).

STUDY 2

A randomised, open-label, balanced, two treatment, two period, two sequence, single dose, crossover

bioequivalence study of the applicant’s test product Hydroxyzine hydrochloride 25mg Film-coated

Tablets (Morningside Healthcare Ltd, UK) versus the reference product Atarax 25mg Film-coated

tablets (Alliance Pharmaceuticals, UK) in healthy, adult, subjects under fasting conditions.

Subjects were administered a single oral dose (1 x 25 mg tablet) of the test or reference product with

240mL of water under fasting conditions.

Blood samples were collected for plasma levels before dosing and up to and including 96 hours after

each administration. The washout period between the treatment phases was 5 days. The

pharmacokinetic results are presented below:

Table: Summary of pharmacokinetic data for hydroxyzine (geometric means, ratios and 90%

confidence intervals):

Study conclusion

The 90% confidence intervals of the test/reference ratio for AUC and C

values for hydroxyzine lie

within the acceptable limits of 80.00% to 125.00%, in line with the guideline on the investigation of

bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the

applicant’s test product, Hydroxyzine hydrochloride 25mg Film-coated Tablets (Morningside Healthcare

Ltd, UK) is bioequivalent to the reference product Atarax 25mg Film-coated tablets (Alliance

Pharmaceuticals, UK).

IV.3

Pharmacodynamics

No new pharmacodynamic data were submitted and none were required for applications of this type.

IV.4

Clinical efficacy

No new efficacy data were submitted, and none were required for applications of this type.

IV.5

Clinical safety

No new safety data were submitted and none are required.

IV.6

Risk Management Plan (RMP) and Pharmacovigilance System

The MAH has submitted a risk management plan, in accordance with the requirements of Directive

2001/83/EC as amended.

There are no differences from the reference product in terms of proposed uses, maximum pack size /

strength or pharmaceutical form / formulation that would have any implications for safety.

In line with other products containing this active, the applicant proposes only routine pharmacovigilance

and routine risk minimisation measures for all safety concerns (labelling in the SmPC and the PIL).

This is agreed.

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent

updates of the RMP.

An updated RMP should be submitted:

At the request of the RMS;

Whenever the risk management system is modified, especially as the result of new information

being received that may lead to a significant change to the benefit/risk profile or as the result of

an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the

same time, but via different procedures.

IV.7

Discussion on the clinical aspects

The grant of marketing authorisations is recommended for these applications from a clinical viewpoint.

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.

The results show that the package leaflet meets the criteria for readability as set out in the guideline on

the readability of the label and package leaflet of medicinal products for human use.

VI

Overall conclusion, benefit/risk assessment and recommendation

The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been

identified. Extensive clinical experience with hydroxyzine hydrochloride is considered to have

demonstrated the therapeutic value of the compound. The products are bioequivalent to the marketed

reference products and their risks and benefits are considered similar. The benefit-risk is, therefore,

considered to be positive.

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and

Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are

available on the MHRA website.

The approved labelling for this medicine is presented below:

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

PAR Hydroxyzine hydrochloride 10mg and 25mg Film-coated Tablets

UK/H/6891/001-002/DC

Annex 1

Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II

variations, PSURs, commitments)

Scope

Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

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