Glycopyrronium bromide 1mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Glycopyrronium bromide
Available from:
DE Pharmaceuticals
ATC code:
A03AB02
INN (International Name):
Glycopyrronium bromide
Dosage:
1mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF:
Authorization number:
; PL 30684/0125

Size: 160(L) x 225(W) mm

Front Size

Pharmacode

Size: 160(L) x 225(W) mm

Back Size

BBUK Code

Artwork Code

VERSION

DATE

REMARKS

V0.

V1.

19/12/2016

21-07-2017

28-07-2017

New leaflet prepared for NA submission as per New text from RA.

Text Replaced As Per RA Comments

Text Replaced As Per RA Comments

Colours used

Black

Keylines

Colours not for Printing

Product

MICRO LABS LIMITED

Bangalore, INDIA

Head QA

(Site)

Head QC

(Site)

Head Production/

Packing (Site)

Packaging

Development

Code No. :

Approved

by

Reason for Change

Glycopyrronium Bromide _Kinedexe_BBUK

Strength

1 mg & 2 mg

Component

Leaflet(Blister)

No. of Colours

Dimension

160(L)mm x 225(W) mm (Folding Size 80x20mm)

Artwork Code

Pharma Code

Font Type and Size

Arial Narrow, 9 pt

Technical Specification

Revision: 00

Date : 29-05-2018

Contract Giver/

PL holder

Regulatory

Affairs

Sign/

Date

200 mm

160 mm

160 mm

80 mm

20 mm

80 mm

80 mm

80 mm

225 mm

225 mm

350 mm

PACKAGE LEAFLET: INFORMATION FOR THE USER

GLYCOPYRRONIUM BROMIDE

1 MG & 2 MG TABLETS

Read all of this leaflet carefully before you start taking this medicine

because it contains important information for you.

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

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

This medicine has been prescribed for you only. Do not pass it on to

others. It may harm them, even if their signs of illness are the same as

yours.

If you get any side effects, talk to your doctor or pharmacist. This

includes any possible side effects not listed in this leaflet. See section

What is in this leaflet

What Glycopyrronium Bromide Tablets are and what they are used for

What you need to know before you take Glycopyrronium Bromide

Tablets

How to take Glycopyrronium Bromide Tablets

Possible side effects

How to store Glycopyrronium Bromide Tablets

Contents of the pack and other information

1.

WHAT GLYCOPYRRONIUM BROMIDE TABLETS ARE AND WHAT

THEY ARE USED FOR

Glycopyrronium bromide (the active substance in Glycopyrronium Bromide

Tablets) belongs to a group of medicines called anticholinergics or

antimuscaranics.

It is used together with other medicines to make the stomach contents less

acidic and to help treat peptic (stomach) ulcers in adults.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE

GLYCOPYRRONIUM BROMIDE TABLETS

DO NOT take Glycopyrronium Bromide Tablets and talk to your doctor

if:

you are allergic to glycopyrronium bromide or any of the ingredients of

this medicine (listed in section 6 at the end of the leaflet)

you suffer from:

glaucoma (increased pressure in the eye)

an enlarged prostate gland (prostatic hypertrophy)

obstruction of the stomach (pyloric stenosis) or bowel causing

vomiting, abdominal pain and swelling (paralytic ileus)

myasthenia gravis (leading to muscle weakness and fatigue).

Tell your doctor if you are not sure about any of the above.

Warnings and precautions

Talk to your doctor or pharmacist before taking Glycopyrronium Bromide

Tablets if you:

are over 60 years of age

are a child or this medicine has been prescribed for a child

have recently had a heart attack or are suffering from heart disease,

irregular heartbeat or high blood pressure

have a condition characterised by rapid heartbeat (including an

overactive thyroid gland, heart failure or conditions due to heart

surgery)

are about to receive inhalation anaesthesia (to put you to sleep before

an operation), as it may cause a change in your normal heart rhythm

have gastric reflux (a condition in which the liquid contents of the

stomach back up into the gullet)

have diarrhoea

have ulcerative colitis (a chronic inflammation of the large intestine

(colon) which can cause abdominal pain, diarrhoea, and bleeding

from the back passage)

have a high temperature (fever), as this medicine will prevent

sweating

Pharmacode

Pharmacode

have kidney disease; your dose may need to be decreased.

Children

This medicine is NOT recommended for use in children (see section 3).

Other medicines and Glycopyrronium Bromide Tablets

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

taken any other medicines, including medicines obtained without a

prescription. If they are taken with Glycopyrronium Bromide Tablets, their

effect or the effect of Glycopyrronium Bromide Tablets may be changed.

Use of Glycopyrronium Bromide along with one or more similar medicines

can increase side effects such as dry mouth, retention of urine and

constipation. The elderly may become confused.

Please tell the doctor if you are taking, or have recently taken:

medicines for depression such as tricyclic antidepressants (eg.

amitriptyline or imipramine) or monoamine oxidase inhibitor (MAOIs),

antidepressants (eg. phenelzine, tranylcypromine)

clozapine, used to treat schizophrenia

phenothiazines used to treat mental problems or nausea, vomiting or

vertigo (eg. chlorpromazine, fluphenazine, prochlorperazine,

trifluoperazine)

antihistamines, used to treat allergies (eg. promethazine)

nefopam, used to treat acute and chronic pain

pethidine, used to treat moderate to severe pain

domperidone or metoclopramide, used to treat nausea and vomiting

ketoconazole, used to treat fungal infections

amantadine, levodopa, used to treat Parkinson's disease

memantine, used to treat Alzheimer's disease

parasympathomimetics, medicines that affect chemicals in the body

which are involved in transmission of nerve impulses to a muscle (eg.

carbachol, neostigmine, physostigmine)

ritodrine, used to prevent complicated premature labour

corticosteroids, used to treat various conditions including asthma and

inflammatory disease (eg. prednisolone)

slow-dissolving digoxin tablets, disopyramide, used to treat heart

problems

glyceryl trinitrate tablets, used to treat angina, may not dissolve under

the tongue as well as usual due to the dry mouth which

Glycopyrronium Bromide causes.

If you are in doubt about any of these medicines, ask your doctor or

pharmacist.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are

planning to have a baby, ask your doctor or pharmacist for advice before

taking this medicine.

Glycopyrronium Bromide Tablets may be used in pregnancy only if

considered essential by the doctor.

You should NOT breast-feed if you are taking this medicine.

Driving and using machines

Glycopyrronium Bromide Tablets may cause your eyesight to become

blurred, which could interfere with your ability to drive or operate machinery

safely. If you are affected in this way, DO NOT drive or operate machinery

until such symptoms go away.

Glycopyrronium Bromide Tablets contain lactose

If you have been told by your doctor that you have an intolerance to some

sugars, contact your doctor before taking this medicinal product.

3. HOW TO TAKE GLYCOPYRRONIUM BROMIDE TABLETS

Follow your doctor's instructions exactly. You should check with your doctor

or pharmacist if you are not sure.

The recommended dose for adults is:

Glycopyrronium Bromide 1 mg Tablets:

One tablet three times daily (in the morning, early afternoon, and at

bedtime). Some patients may require two tablets at bedtime to control the

symptoms overnight.

When your symptoms are controlled, a dose of one tablet twice a day may

be sufficient.

Glycopyrronium Bromide 2 mg Tablets:

One tablet two or three times a day at equally spaced intervals.

The score line is not intended for breaking the tablet.

Children MUST NOT take Glycopyrronium Bromide Tablets.

If you take more Glycopyrronium Bromide Tablets than you should

Consult your doctor or pharmacist immediately or go to the emergency

department of the nearest hospital right away. Always take any leftover

medicine with you, as well as the container and label, so that the medical

staff know what you have taken.

If you forget to take Glycopyrronium Bromide Tablets

Do not worry. If you remember later on that day, take that day's dose as

usual. If you miss a whole day's dose, take the normal dose on the next

day. DO NOT take a double dose to make up for a forgotten dose. If you

are not sure, ask your doctor or pharmacist.

If you stop taking Glycopyrronium Bromide Tablets

Your doctor will tell you how long to take the treatment for. DO NOT stop

earlier than you are told, even if you feel better.

If you have any further questions on the use of this medicine, ask your

doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Glycopyrronium Bromide Tablets can cause side effects,

although not everybody gets them.

If you experience any of the side effects detailed below, and if these are

persistent or troublesome, consult your doctor:

dry mouth

difficulty in passing stools (constipation)

irregular heartbeat, slow heartbeats followed by rapid heartbeats

reduced secretions in the lungs

reduced sweating

difficulty in passing urine

enlarged pupils accompanied by visual disturbances

increased sensitivity towards light (photophobia)

confusion

nausea (feeling sick), vomiting (being sick)

eye disorder (glaucoma)

flushing and/or dryness of the skin

giddiness

confusion, especially in the elderly.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This

includes any possible side effects not listed in this leaflet. You can also

report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard.

By reporting side effects, you can help provide more information on the

safety of this medicine.

5. HOW TO STORE GLYCOPYRRONIUM BROMIDE TABLETS

Keep this medicine out of the sight and reach of children.

Do not use Glycopyrronium Bromide Tablets after the expiry date, which is

stated on the pack. The expiry date refers to the last day of that month.

After opening the container, Glycopyrronium Bromide Tablets can be used

for 3 months.

Do not throw away any medicines via wastewater or household waste. Ask

your pharmacist how to throw away medicines you no longer use. These

measures will help protect the environment.

6.

CONTENTS OF THE PACK AND OTHER INFORMATION

What Glycopyrronium Bromide Tablets contain

The active substance is glycopyrronium bromide.

Each 1 mg tablet contains 1 mg of glycopyrronium bromide.

Each 2 mg tablet contains 2 mg of glycopyrronium bromide.

The other ingredients are: calcium hydrogen phosphate dihydrate, lactose

anhydrous, povidone, sodium starch glycolate and magnesium stearate.

What Glycopyrronium Bromide Tablets look like and contents of the

pack

Glycopyrronium Bromide 1 mg Tablets are white to off-white round scored

uncoated tablets, engraved with GP and “1” on either side of the score line

and plain on the other.

Glycopyrronium Bromide 2 mg Tablets are white to off-white round scored

uncoated tablets, engraved with GP & “2” on either side of the score line

and plain on the other.

Tablets are supplied in pack sizes of 10, 14, 28, 30, 56, 60, 90 and 100

tablets. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Kinedexe UK Limited, Unit 15 Moorcroft, Harlington Road, Uxbridge, UB8

3HD, United Kingdom.

Distributed by:

Brown & Burk UK Ltd.

5 Marryat Close,Hounslow West,

Middlesex, TW4 5DQ, United Kingdom

This leaflet was last revised in 01/2016.

Pharmacode

Pharmacode

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Glycopyrronium Bromide 1mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1mg of Glycopyrronium Bromide

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Tablets

White to off white round scored uncoated tablet engraved with “GP” & “1” on either

side of score line and plain on the other.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

For use in adults as add-on therapy in the treatment of peptic ulcer.

4.2

Posology and method of administration

Posology

The dosage of Glycopyrronium Bromide 1 mg or 2 mg Tablets should be adjusted to

the needs of the individual patient to assure symptomatic control with a minimum of

adverse reactions. The presently recommended maximum daily dosage of

Glycopyrronium Bromide is 8 mg.

Glycopyrronium Bromide 1mg Tablets.

The recommended initial dosage of Glycopyrronium Bromide 1 mg Tablets for adults

is one tablet three times daily (in the morning, early afternoon, and at bedtime). Some

patients may require two tablets at bedtime to assure overnight control of symptoms.

For maintenance, a dosage of one tablet twice a day is frequently adequate.

Glycopyrronium Bromide 2mg Tablets.

The recommended dosage of Glycopyrronium Bromide 2 mg Tablets for adults is one

tablet two or three times daily at equally spaced intervals.

Paediatric population

Glycopyrronium Bromide Tablets are not recommended for use in children.

Method of administration

For oral administration

4.3

Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section

6.1.

In common with other antimuscarinics: angle-closure glaucoma; myasthenia gravis

(large doses of quaternary ammonium compounds have been shown to block end

plate nicotinic receptors); paralytic ileus; pyloric stenosis; prostatic enlargement.

4.4

Special warnings and precautions for use

Glycopyrronium Bromide Tablets should be used with caution in the elderly.

They should also be used with caution in gastro-oesophageal reflux disease,

ulcerative colitis, acute myocardial infarction, hypertension, conditions characterised

by tachycardia (including hyperthyroidism, cardiac insufficiency, cardiac surgery)

because of the increase in heart rate produced by their administration, coronary artery

disease and cardiac arrhythmias.

Diarrhoea may be an early symptom of incomplete intestinal obstruction, especially

in patients with ileostomy or colostomy. In this instance treatment with this drug

would be inappropriate and possibly harmful.

As Glycopyrronium Bromide inhibits sweating, patients with increased temperature

should be observed closely. In the presence of a high environmental temperature, heat

prostration (fever and heat stroke due to decreased sweating) can occur with use of

Glycopyrronium Bromide tablets.

Because of prolongation of renal elimination, repeated or large doses of

Glycopyrronium Bromide should be avoided in patients with uraemia.

Large doses of quaternary anticholinergic compounds have been shown to block end

plate nicotinic receptors. This should be considered before using Glycopyrronium

Bromide in patients with myasthenia gravis.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicine.

Paediatric population

Not applicable

4.5

Interaction with other medicinal products and other forms of interaction

Many drugs have antimuscarinic effects; concomitant use of two or more of such

drugs can increase side-effects such as dry mouth, urine retention and constipation.

Concomitant use can also lead to confusion in the elderly.

Anticholinergic agents may delay absorption of other medication given

concomitantly.

Concurrent administration of anticholinergics and corticosteroids may result in

increased intraocular pressure.

Concurrent use of anticholinergic agents with slow-dissolving tablets of digoxin may

cause increased serum digoxin levels.

Increased antimuscarinic side-effects: amantadine; tricyclic antidepressants;

antihistamines; clozapine; disopyramide; MAOIs; nefopam; pethidine; phenothiazines

(increased antimuscarinic side effects of phenothiazines but reduced plasma

concentrations)

Possibly increased antimuscarinic side-effects: tricyclic (related) antidepressants

Domperidone/Metoclopramide: antagonism of effect on gastro-intestinal activity

Ketoconazole: reduced absorption of ketoconazole

Levodopa: absorption of levodopa possibly reduced

Memantine: effects possibly enhanced by memantine

Nitrates: possibly reduced effect of sublingual nitrates (failure to dissolve under the

tongue owing to dry mouth)

Parasympathomimetics: antagonism of effect

Ritodrine: tachycardia

Paediatric population

Not applicable

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of Glycopyrronium Bromide in

pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to

reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Glycopyrronium

Bromide Tablets during pregnancy.

Breastfeeding

It is unknown whether Glycopyrronium Bromide or its metabolites are excreted in

human milk.

A risk to the newborns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment with Glycopyrronium

Bromide Tablets.

Fertility

Reproduction studies in rats revealed no teratogenic effects from Glycopyrronium

Bromide; however, the potent anticholinergic action of this agent resulted in

diminished rates of conception and of survival at weaning, in a dose-related manner.

Other studies in dogs suggest that this may be due to diminished seminal secretion

which is evident at high doses of Glycopyrronium Bromide.

No data are available in humans.

4.7

Effects on ability to drive and use machines

Glycopyrronium Bromide tablets may produce drowsiness or blurred vision. In this

event, the patient should be warned not to engage in activities requiring mental

alertness such as operating a motor vehicle or other machinery, or performing

hazardous work while taking this drug.

4.8

Undesirable effects

Glycopyrronium Bromide may produce the following effects which are extensions of

its fundamental pharmacological actions: dry mouth, difficulty in micturition,

inhibition of sweating. Side-effects of antimuscarinics include constipation, transient

bradycardia (followed by tachycardia, palpitation and arrhythmias), reduced bronchial

secretions, urinary urgency and retention, dilatation of the pupils with loss of

accommodation, photophobia, flushing, and dryness of the skin.

Side-effects that occur occasionally include confusion (particularly in the elderly),

nausea, vomiting, and giddiness; very rarely, angle-closure glaucoma may occur.

Paediatric population

Not applicable

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse reactions

via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose

Since Glycopyrronium Bromide is a quaternary ammonium agent, symptoms of

overdosage are peripheral rather than central in nature. Theoretically, with

overdosage, a curare-like action may occur, i.e., neuro-muscular blockade leading to

muscular weakness and possible paralysis.

The symptoms of overdosage of Glycopyrronium Bromide are peripheral in nature

rather than central. Treatment is symptomatic and supportive.

To guard against further absorption of the drug–use gastric lavage, cathartics

and/or enemas.

To combat peripheral anticholinergic effects (residual mydriasis, dry mouth,

etc.) – utilize a quaternary ammonium anticholinesterase, such as neostigmine

methylsulfate in increments of 0.25mg in adults. The dose may be repeated

every 5 – 10 minutes until anticholinergic over-activity is reversed or up to a

maximum of 2.5mg. Proportionately smaller doses should be used in children.

To combat hypotension – use pressor amines (norepinephrine, metaraminol)

i.v.; and supportive care.

To combat respiratory depression – administer oxygen; utilize a respiratory

stimulant such as Doxapram hydrochloride i.v.; artificial respiration.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Synthetic anticholinergics, quaternary ammonium

compounds;

ATC code: A03AB02

Mechanism of action

Glycopyrronium Bromide is a quaternary ammonium antimuscarinic agent and like

other anticholinergic agents, it inhibits the action of acetylcholine on structures

innervated by postganglionic cholinergic nerves and on smooth muscles that respond

to acetylcholine but lack cholinergic innervation. These peripheral cholinergic

receptors are present in the autonomic effector cells of smooth muscle, cardiac

muscle, the sinoatrial node, the atrioventricular node, exocrine glands and to a limited

degree in the autonomic ganglia. Thus it diminishes the volume and free acidity of

gastric secretions and controls excessive pharyngeal, tracheal and bronchial

secretions. Glycopyrronium Bromide antagonizes muscarinic symptoms (e.g.

bronchorrhea, bronchospasm, bradycardia and intestinal hypermotility) induced by

cholinergic drugs such as the anticholinesterases.

The highly polar quaternary ammonium group of Glycopyrronium Bromide limits its

passage across lipid membranes, such as the blood-brain barrier, in contrast to

atropine sulphate and scopolamine hydrobromide, which are non-polar tertiary

amines which penetrate lipid barriers easily.

Pharmacodynamic effects

In common with other cholinergics, Glycopyrronium Bromide has gastrointestinal,

genitourinary, cardiovascular, respiratory, and ophthalmic effects. Some

antimuscarinic agents such as atropine cross the blood brain barrier to cause CNS

effects such as drowsiness. In contrast, Glycopyrronium Bromide does not, so

drowsiness is not a common adverse event. Specific known effects of

Glycopyrronium Bromide include xerostomia, diminished gastrointestinal motility,

decreased perspiration, increased body temperature, urinary retention, pupil dilation,

loss of focusing accommodation, and increased heart rate. These expected effects of

antimuscarinic drugs make them useful in treating certain conditions such as gastric

ulcers, excess perspiration, overactive bladder, and pupil dilation during

ophthalmologic examination. Treatment of drooling, is also a potential therapeutic

use for the xerostomic effect of Glycopyrronium Bromide.

Clinical efficacy and safety

Glycopyrronium Bromide, like other anticholinergic (antimuscarinic) agents, inhibits

the action of acetylcholine on structures innervated by postganglionic cholinergic

nerves and on smooth muscles that respond to acetylcholine but lack cholinergic

innervation. These peripheral cholinergic receptors are present in the autonomic

effector cells of smooth muscle, cardiac muscle, the sino-atrial node, the

atrioventricular node, exocrine glands, and, to a limited degree, in the autonomic

ganglia. Thus, it diminishes the volume and free acidity of gastric secretions and

controls excessive pharyngeal, tracheal, and bronchial secretions. Glycopyrronium

Bromide antagonizes muscarinic symptoms (e.g., bronchorrhoea, bronchospasm,

bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as the

anticholinesterases. The highly polar quaternary ammonium group of

Glycopyrronium Bromide limits its passage across lipid membranes, such as the

blood-brain barrier, in contrast to atropine sulphate and scopolamine hydrobromide,

which are non-polar tertiary amines which penetrate lipid barriers easily.

The incidence of expected adverse events is dose-related. Therefore, dose is to be

titrated to achieve an optimal balance of effectiveness with minimal anticholinergic

associated adverse events.

5.2

Pharmacokinetic properties

Absorption

Glycopyrronium Bromide is poorly absorbed from the gastrointestinal tract; about 10

to 25% is absorbed after an oral dose. Oral Glycopyrronium Bromide has low oral

bioavailability, a median of 3.3% is found in plasma.

Oral Glycopyrronium Bromide (2 mg) produces low plasma concentrations (C

- 440 pg/mL) lasting up to 12 hours.

Food effect data indicate that the mean C

under fed high fat meal conditions is

about 74% lower than the C

observed under fasting conditions.

Distribution

Glycopyrronium Bromide penetrates the blood-brain barrier poorly. Glycopyrronium

Bromide crosses the placenta to a limited extent; and is not known whether it is

distributed into milk.

Biotransformation

In adult patients who underwent surgery for cholelithiasis and were given a single IV

dose of tritiated Glycopyrronium Bromide, approximately 85% of total radioactivity

was excreted in urine and < 5% was present in T-tube drainage of bile. In both urine

and bile, > 80% of the radioactivity corresponded to unchanged drug. These data

suggest a small proportion of IV Glycopyrronium Bromide is excreted as one or more

metabolites.

Elimination

Glycopyrronium Bromide is excreted largely unchanged in the urine. Approximately

65-80% of an IV Glycopyrronium Bromide dose was eliminated unchanged in urine

in adults. In two studies, after IV administration to paediatric patients ages 1-14 years,

mean clearance values ranged from 1.01- 1.41 L/kg/hr (range 0.32 – 2.22 L/kg/hr). In

adults, IV clearance values were 0.54 ± 0.14 L/kg/hr.

5.3

Preclinical safety data

Acute toxicity of Glycopyrronium Bromide was studied in mice and rats. Following

intraperitoneal administration, the LD

was estimated to be 107 mg/kg in mice and

196 mg/kg in rats. Following oral dosing, the LD

was estimated to be 1150 mg/kg in

rats. Chronic oral administration doses of 4, 16, and 64 mg/kg for up to 27 weeks in

dogs produced mydriasis, cycloplegia, xerostomia, emesis, occasional lacrimation,

injection of sclera and rhinorrhoea. There were no changes in organ weight and

histopathology showed no drug-related changes.

Although reproduction studies in rats and rabbits revealed no teratogenic effects from

Glycopyrronium Bromide, safety in human pregnancy and lactation has not been

established. Diminished rates of conception and of survival at weaning were observed

in rats, in a dose-related manner. Studies in dogs suggest that this may be due to

diminished seminal secretion which is evident at high doses of Glycopyrronium

Bromide. The significance of this for man is not clear.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Calcium hydrogen phosphate dihydrate

Lactose anhydrous

Povidone

Sodium starch glycolate

Magnesium stearate

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years

After first opening: 3 months

6.4

Special precautions for storage

None

6.5

Nature and contents of container

Tablets are packed in a white HDPE bottle with a child resistant closure containing

10, 14, 28, 30, 56, 60, 90 and 100 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No Special requirements for disposal.

7

MARKETING AUTHORISATION HOLDER

Kinedexe UK Ltd

Unit 15 Moorcroft

Harlington Road

Uxbridge

UB8 3HD, UK

8

MARKETING AUTHORISATION NUMBER(S)

PL 44710/0017

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

20/04/2016

10

DATE OF REVISION OF THE TEXT

26/04/2018

1

Public Assessment Report

UKPAR

Glycopyrronium Bromide 1mg Tablets

Glycopyrronium Bromide 2mg Tablets

(Glycopyrronium bromide)

UK Licence Numbers: PL 44710/0017-0018

Kinedexe UK Ltd

PAR Glycopyrronium Bromide 1mg & 2mg Tablets

PL 44710/0017-0018

2

LAY SUMMARY

Glycopyrronium Bromide 1mg and 2mg Tablets

(Glycopyrronium bromide, tablet, 1mg and 2mg)

This is a summary of the Public Assessment Report (PAR) for Glycopyrronium Bromide 1mg Tablets

(PL 44710/0017) and Glycopyrronium Bromide 2mg Tablets (PL 44710/0018). It explains how

Glycopyrronium Bromide 1mg and 2mg 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

Glycopyrronium Bromide 1mg and 2mg Tablets.

The products will collectively be referred to as Glycopyrronium Bromide Tablets throughout the

remainder of this public assessment report.

For practical information about using Glycopyrronium Bromide Tablets, patients should read the

package leaflet or contact their doctor or pharmacist.

What are Glycopyrronium Bromide Tablets

and what are they used for?

Glycopyrronium Bromide Tablets are a medicine with ‘well established use’. This means that the

medicinal use of the active substance, glycopyrronium bromide, is well established in the European

Union for at least ten years, with recognised efficacy and an acceptable level of safety.

Glycopyrronium Bromide Tablets are used with other medicines to make the stomach contents less

acidic and to help treat peptic (stomach) ulcers in adults

.

How do Glycopyrronium Bromide Tablets work?

Glycopyrronium bromide (the active substance in Glycopyrronium Bromide Tablets) belongs to a group

of medicines called anticholinergics or antimuscarinics. It makes the stomach contents less acidic.

How are Glycopyrronium Bromide Tablets used?

The pharmaceutical form of this medicine is a tablet and the route of administration is oral (by mouth).

The patient should follow their doctor’s instructions exactly. The patient should check with their doctor

or pharmacist if they are not sure.

The recommended dose for adults is:

Glycopyrronium Bromide 1 mg Tablets:

One tablet

three times

daily (in the morning, early afternoon, and at bedtime). Some patients may

require two tablets at bedtime to control the symptoms overnight.

When the patient’s symptoms are controlled, a dose of one tablet twice a day may be sufficient.

The score line is

not

intended for breaking the tablet.

Glycopyrronium Bromide 2 mg Tablets:

One tablet

two or three times

a day at equally spaced intervals.

The score line is

not

intended for breaking the tablet.

Children must not

take this medicine

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

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route of administration and the duration of treatment.

Glycopyrronium Bromide Tablets can only be obtained with a prescription.

What benefits of Glycopyrronium Bromide Tablets

have been shown in studies?

As glycopyrronium bromide is a well-known substance, and its use in the treatment of peptic ulcers in

adults is well established, the applicant presented data from the scientific literature. The literature

provided confirmed the efficacy and safety of the use of glycopyrronium bromide for the treatment of

peptic ulcers in adults.

What are the possible side effects of Glycopyrronium Bromide Tablets?

Like all medicines, Glycopyrronium Bromide Tablets can cause side effects, although not everybody

gets them.

For the full list of all side effects reported with this medicine, see section 4 of the package leaflet or the

Summaries of Product Characteristics (SmPCs) available on the MHRA website.

Why were Glycopyrronium Bromide Tablets approved?

The MHRA decided that the benefits of Glycopyrronium Bromide Tablets are greater than their risks

and recommended that they be approved for use.

What measures are being taken to ensure the safe and effective use of Glycopyrronium Bromide

Tablets?

A Risk Management Plan has been developed to ensure that Glycopyrronium Bromide Tablets are used

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

Product Characteristics and the package leaflet for Glycopyrronium Bromide 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 Glycopyrronium Bromide Tablets

Marketing Authorisations for Glycopyrronium Bromide Tablets were granted on 20 April 2016.

The full PAR for Glycopyrronium Bromide Tablets follows this summary.

For more information about treatment with Glycopyrronium Bromide Tablets, read the package leaflet,

or contact your doctor, dentist or pharmacist.

This summary was last updated in May 2016.

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TABLE OF CONTENTS

Introduction

Page 5

Quality aspects

Page 6

Non-clinical aspects

Page 8

Clinical aspects

Page 8

User consultation

Page 16

Overall conclusion, benefit/risk assessment and

recommendation

Page 17

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I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products

Regulatory Agency (MHRA) granted Kinedexe UK Ltd Marketing Authorisations for the medicinal

products Glycopyrronium Bromide 1mg Tablets (PL 44710/0017) and Glycopyrronium Bromide 2mg

Tablets (PL 44710/0018) on 20 April 2016. The products are prescription only medicines (POM)

indicated for use in adults as add-on therapy in the treatment of peptic ulcer.

These applications were submitted under Article 10a of Directive 2001/83/EC, as amended, claiming to

be applications for products containing an active substance of well-established use.

Glycopyrronium bromide is a quaternary ammonium antimuscarinic agent and like other anticholinergic

agents, it inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic

nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These

peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac

muscle, the sinoatrial node, the atrioventricular node, exocrine glands and to a limited degree in the

autonomic ganglia. Thus it diminishes the volume and free acidity of gastric secretions and controls

excessive pharyngeal, tracheal and bronchial secretions. Glycopyrronium bromide antagonises

muscarinic symptoms (e.g. bronchorrhea, bronchospasm, bradycardia and intestinal hypermotility)

induced by cholinergic drugs such as the anticholinesterases.

The highly polar quaternary ammonium group of glycopyrronium bromide limits its passage across lipid

membranes, such as the blood-brain barrier, in contrast to atropine sulphate and scopolamine

hydrobromide, which are non-polar tertiary amines which penetrate lipid barriers easily.

Bibliographic data on glycopyrronium bromide have been submitted to support these applications. No

new non-clinical or clinical studies were conducted for these applications, which is acceptable given that

these are bibliographic applications for products containing an active ingredient of well-established use.

The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in

place for this product type at all sites responsible for the manufacture and assembly of these products.

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II

QUALITY ASPECTS

II.1

Introduction

Each tablet contains 1mg or 2mg of glycopyrronium bromide. Other ingredients consist of the following

pharmaceutical excipients

calcium hydrogen phosphate dihydrate, anhydrous lactose, povidone, sodium

starch glycolate and magnesium stearate.

Both strengths (1mg and 2mg tablets) of the finished product are packed into white high-density

polyethylene (HDPE bottles) with a child resistant closure containing 10, 14, 28, 30, 56, 60, 90 and 100

tablets. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have

been provided for all packaging components.

II.2.

Drug Substance

INN:

Glycopyrronium bromide

Chemical name:

(3RS)-3-[(2SR)-(2-Cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-

dimethylpyrrolidinium bromide.

Structure:

Molecular formula:

BrNO

Molecular weight:

398.3 g/mol

Description:

White or almost white, crystalline powder.

Solubility

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

methylene chloride.

Glycopyrronium bromide is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, glycopyrronium bromide, are covered

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

Suitability.

Appropriate stability data have been generated supporting a suitable retest period when stored in the

proposed packaging.

II.3.

Medicinal Product

Pharmaceutical Development

The objective of the development programme was to formulate safe, efficacious, tablets containing 1mg

or 2mg glycopyrronium bromide per tablet.

A satisfactory account of the pharmaceutical development has been provided.

All excipients comply with their respective European Pharmacopoeia monographs. Satisfactory

Certificates of Analysis have been provided for all excipients. Suitable batch analysis data have been

provided for each excipient.

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

human origin. The supplier of anhydrous lactose has confirmed that the milk used in the production of

anhydrous lactose is sourced from healthy animals under the same conditions as milk for human

consumption.

No genetically modified organisms (GMO) have been used in the preparation of these products.

Manufacture of the product

A satisfactory batch formula has 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 batch size and shown satisfactory results.

Finished Product Specifications

The finished product specifications proposed are acceptable. Test methods have been described that have

been adequately validated. Batch data have been provided that comply with the release specifications.

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

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

shelf-life of 2 years for the unopened bottle with no special storage conditions. The in-use shelf life is 3

months after first opening.

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.

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III

NON-CLINICAL ASPECTS

III.1

Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of glycopyrronium bromide 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.

III.3

Pharmacokinetics

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

III.4

Toxicology

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

III.5

Ecotoxicity/environmental risk assessment (ERA)

The introduction of the generic products, Glycopyrronium Bromide 1mg and 2mg Tablets, onto the

market is unlikely to result in an increase in the combined sales of glycopyrronium bromide-containing

products, which in turn is unlikely to lead to an increased exposure of the environment to

glycopyrronium bromide. An environmental risk assessment is therefore not deemed necessary.

III.6

Discussion on the non-clinical aspects

No new non-clinical studies were conducted, which is acceptable given that these are bibliographic

applications for a product containing an active ingredient of well-established use.

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

IV

CLINICAL ASPECTS

IV.1

Introduction

No new clinical pharmacology data, efficacy data or safety data have been submitted 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

glycopyrronium bromide.

The applicant’s clinical overview has been written by an appropriately qualified person and is

considered acceptable.

IV.2

Pharmacokinetics

Overview

Glycopyrronium bromide is 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium

bromide. Glycopyrrolate exists in four distinct stereo isometric forms due to the presence of two chiral

centres in the glycopyrrolate molecule. One of the two enantiomeric pairs of diastereomers of

glycopyrrolate is (R,R)-glycopyrrolate and (S,S)-glycopyrrolate, and the other enantiomeric pair is

(R,S)-glycopyrrolate and (S,R)-glycopyrrolate.

Glycopyrrolate occurs as a white, odourless crystalline powder. It is soluble in water and alcohol and

practically insoluble in chloroform and ether. It is completely ionised at physiological pH values.

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Absorption

Oral glycopyrrolate has low oral bioavailability; a median of 3.3% is found in plasma. Oral

glycopyrrolate produces low plasma concentrations (C

190-440 pg/mL) lasting up to 12 hours.

In an open study with eight healthy male volunteers, after a single IV bolus of glycopyrrolate (5µg/kg)

the C

was 198 ± 137 (ng/mL) and AUC was 5.16 ± 0.97 (ng.h/mL).

The pharmacokinetics of glycopyrrolate after a single intramuscular dose demonstrate a very rapid

absorption rate with C

of 6.3 (1.5) ng/mL and T

10 (3.8) minutes. The respective AUC value from

0 to 8 hours was 5.61 (1.27) ng.h/mL.

The food effect data indicate the mean C

under fed (high fat meal) conditions is about 74% lower

than the C

observed under fasting conditions. Similarly the mean AUC of treatment given under fed

conditions was 3 to 4 times lower than those observed for the treatment given under fasted conditions.

These data indicate that a high fat meal reduces the oral bioavailability of glycopyrrolate.

Distribution

In an open study with eight healthy male volunteers, after a single IV bolus of glycopyrrolate (5µg/kg)

the volume of distribution at steady state was 0.37 ± 0.26 L/kg. After IV injection of 0.006mg/kg, the

mean distribution phase half-life was 2.22 ± 1.26 minutes.

Metabolism

It is reported that only 20% of bioavailable drug is metabolised and 80% is excreted unchanged in urine

and bile in man.

In a study, the metabolism of scopolamine and glycopyrrolate was studied in 11 healthy subjects having

undergone Caesarean section. Glycopyrrolate concentrations increased only slightly between 1 and 3

hours after the drug injection. Thus, it was suggested that β-glucuronide or sulphate conjugation plays

only a minor part in the metabolism of glycopyrrolate.

In adult patients who underwent surgery for cholelithiasis and were given a single IV dose of titrated

glycopyrrolate, approximately 85% of total radioactivity was excreted in urine and <5% was present in

T-tube drainage of bile. In both urine and bile >80% of the radioactivity corresponded to unchanged

drug. These data suggest that a small proportion of IV glycopyrrolate is excreted as one or more

metabolites.

Excretion

In a study glycopyrrolate was labelled in one methyl group with tritium and its fate was studied in six

patients with T-tube drainage by determining serum levels as well as the biliary and urinary excretion of

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radioactivity after i.v. injection. More than 90 % of the radioactivity had disappeared from serum in 5

min and after 30 min almost no radioactivity could be found.

The highest radioactivity in bile was found in samples taken 30 or 60 minutes after the injection.

However, measurable radioactivity was found in most cases after 48 hours (h). The first urine samples

(0-3 h) showed the greatest radioactivity, and in 48 h, 85% of the total radioactivity was excreted into

the urine. Paper chromatography showed that in both, in bile and in urine, over 80 % of the radioactivity

corresponded to unchanged glycopyrrolate. The excretion of appreciable amounts of glycopyrrolate into

the bile suggests that the spasmolysis achieved with glycopyrrolate could be based partly on a local

action on the bile ducts.

In a study investigating the pharmacokinetics of glycopyrrolate in 11 uraemic patients undergoing

cadaveric renal transplantation and in seven ASA I control patients undergoing general surgery,

glycopyrrolate 4 μg/kg was given intravenously (i.v.) before induction of anaesthesia. Volume of

distribution (V

) in the elimination phase was similar in both groups, the elimination half-life (t

) was

longer (P < 0.05), AUC larger (P < 0.01) and plasma clearance (CL) smaller (P < 0.01) in the uraemic

patients. In 3 h, mean 0.7% (range 0-3) and 50% (21-82) of glycopyrrolate was excreted in the urine in

the uraemic and healthy patients, respectively (P < 0.001). The 24 h renal excretion was 7% (0-25) in

uraemic and 65% (30-99) in control patients (P < 0.001). The authors concluded that the elimination of

glycopyrrolate was severely impaired in uraemic patients.

Special populations

Elderly

The basic pharmacokinetic properties of glycopyrrolate were evaluated in a study through radio receptor

assay (RRA) in elderly patients (59-79 years). The patients in Group I were premedicated with

glycopyrrolate 4 mg orally and those in Group 2 with glycopyrrolate 8μg/kg i.m., group 3 the patients

received a combination anaesthesia (thiopentone 3-5 mg/kg, vecuronium 0.1 mg/kg, N

O + O

, fentanyl

3 μg/kg and neostigmine as an anticurarizing agent in incremental doses up to 1.25 mg) and

glycopyrrolate 6 μg/kg was injected i.v. just before the induction of anaesthesia. Based on the plasma

levels after a single i.v. injection, 6 pg/kg (n = 6), the distribution phase t

(2.22±1.26 SD min) and the

elimination phase t

(0.83±0.29 h) of glycopyrrolate were short due to the low distribution volume

during the elimination phase (0.64±0.29 L/kg) and the respectively high total plasma clearance value

(0.54±0.14 L/kg/h). An intramuscular injection, 8 pg/kg (n = 6) was followed by a fast and predictable

systemic drug absorption and clinical effects (heart rate increase, dry mouth). In this group, the time to

maximum plasma concentration (T

) was 27.48±6.12 min and the C

was 3.47±1.48 pg/L. After oral

drug intake of 4 mg (n = 6), an apparently low and variable gastrointestinal absorption was found (T

300.0±197.2 min, C

= 0.76±0.35 pg/L), thus indicating that the oral route of drug administration is of

no value as a routine premedication. However, the oral glycopyrrolate produced significant

antisialogogue effect.

The applicant’s formulation (Glycopyrronium Bromide 1mg and 2mg Tablets) is indicated for add-on

therapy in the treatment of peptic ulcer and not as premedication. Many studies which also included

elderly patients, have shown that oral glycopyrrolate is effective in the treatment of peptic ulcer. Also in

the above study, oral glycopyrrolate produced significant antisialogogue effect. Hence, it can be said that

oral glycopyrrolate can be prescribed in elderly patients for the treatment of peptic ulcer.

Children

In a study in six children operated on twice over a period of several weeks and receiving a single p.o. (50

μg/kg) and i.v. (5 μg/kg) dose of glycopyrrolate, plasma levels were determined with a radio receptor

assay and resulted in the pharmacokinetic parameters displayed in Table 2:

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Overall conclusions on pharmacokinetics

The pharmacokinetics of glycopyrronium bromide are well known and adequately presented in the

applicant’s dossier. No new pharmacokinetic data were submitted and none were required for an

application of this type.

Bioequivalence

No bioequivalence study has been conducted to support these bibliographic applications. This is

appropriate for a well-established use application.

IV.3

Pharmacodynamics

Introduction

Glycopyrrolate inhibits parasympathetic transmission by selective blockade of acetylcholine at

muscarinic receptors. It has little effect on cholinergic stimulation at nicotinic receptors at physiological

doses, on structures innervated by postganglionic cholinergic neurones and on smooth muscles which

respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are

present in autonomic effector cells of smooth muscle, cardiac muscle, the sino-atrial node, the

atrioventricular node, exocrine glands and the autonomic ganglia. By this mechanism, glycopyrrolate

reduces the volume and acidity of gastric secretions and controls excessive pharyngeal, tracheal and

bronchial secretions.

Primary pharmacodynamics and mechanism of action

Glycopyrrolate inhibits the action of acetylcholine on peripheral acetylcholine (muscarinic M3)

receptors on smooth muscle, cardiac muscle, the sino-atrial and atrioventricular nodes, exocrine glands

and, to a lesser degree, autonomic ganglia. Thus it diminishes the volume and free acidity of gastric

secretion.

Secondary Pharmacodynamics

Glycopyrrolate also, by dint of its inherent pharmacology, exerts a physiological antisialogogue effect. It

is also useful in reverting the bradycardic effects of many anaesthetic drugs, as well as possessing a

significant antispasmodic effect.

Pharmacodynamic interactions

Glycopyrrolate increased serum levels of digoxin and haloperidol. Glycopyrrolate, alone or in

combination with aluminium hydroxide, clearly retards ethambutol absorption. Glycopyrrolate may

increase the bioavailability of atenolol.

Overall conclusions on pharmacodynamics

The pharmacodynamics of glycopyrronium bromide are well known and adequately presented in the

applicant’s clinical overview.

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

IV.4

Clinical efficacy

No new efficacy data were submitted and none were required for an application of this type. The clinical

efficacy of glycopyrronium bromide is well-established. Efficacy is adequately reviewed in the clinical

overview.

The applicant has provided an extensive assessment of the up to date published literature on the efficacy

of glycopyrronium bromide in the treatment of peptic ulcers by way of reduction in gastric acid secretion

secondary to anticholinergic effects. The majority of the literature is fifty years in the public domain and

few recent studies have been carried out to repeat the efficacy demonstrated in these original clinical

trials. No new efficacy data have been presented.

One study demonstrated a positive therapeutic response in 92% (n=46 of 50) patients with varying

gastroenterological complaints who were prescribed glycopyrronium bromide at doses between 3-8mg.

The drug was shown to have marked antisecretory and antispasmodic effects and was effective in acute

and chronic duodenal ulcers.

One study looked at 39 ambulant patients with uncomplicated peptic ulceration who received

glycopyrrolate at doses between 4-8mg daily. All patients became asymptomatic on glycopyrrolate and

the ulcer healed in 31 of the 39 patients. A reduction in gastric acidity was observed in 12 of 15 patients

studied. Due to the excellent acid inhibition, coupled with minimal suppression of motility,

glycopyrrolate was considered by the authors to be a useful anticholinergic agent.

In a placebo controlled study, patients were enrolled to receive either glycopyrrolate or placebo

following resolution of the acute phase of chronic duodenal ulcer and were followed up for 18 months.

After this period, the incidence of recurrence of duodenal ulceration was 15% in the glycopyrrolate

group and 71% in the placebo group, leading the authors to the conclusion that the use of glycopyrrolate

in long term ulcer therapy can minimise the recurrence of episodes.

Similarly, in a comparative double-blind efficacy trial in 120 patients with peptic ulcers comparing

glycopyrrolate, propantheline bromide and placebo, glycopyrrolate was found to be more effective than

propantheline, and both drugs superior to placebo. Symptomatic relief was seen in the glycopyrrolate

group after an average 3.5 days, compared to 7.5 days in the propantheline group.

In another study, glycopyrrolate was compared to atropine in the treatment of active or recurrent peptic

ulceration as well as other gastrointestinal disorders, in a randomised double-blind trial. Of 16 patients,

thirteen in the glycopyrrolate, atropine or both groups responded favourably, with glycopyrrolate

producing fewer side effects.

In a single-blind, controlled trial, glycopyrrolate was compared to 1-hyoscyamine in the long term

therapy of duodenal ulcer. In this study 106 male patients with duodenal ulcer were enrolled with 91

completing the study. They were randomised to receive, either, glycopyrrolate, 1-hyoscyamine or

placebo for one year. After this period, 79% of patients in the glycopyrrolate group experienced fewer

and less severe symptoms and used fewer antacids and had radiologically improved parameters. In this

study, this compared to 65% improvement in the 1-hyoscyamine group and 72% in the placebo group;

this is unlikely to represent clinical significance.

In various non-controlled studies, glycopyrrolate was administered either alone or as combination with

other drugs such as phenobarbital for a variety of gastrointestinal disorders. In these studies, good effects

were observed with glycopyrrolate use as evidenced by complete remission of symptoms, acceleration of

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ulcer healing times or reduction in pain symptoms. The authors conclude that glycopyrronium bromide

given in maximum tolerated doses might be an effective addition to present inpatient therapy of chronic

gastric ulceration. In one of the studies, satisfactory results were observed in 94.9% of patients with

significant side effects in only 2.6%.

Overall conclusions on clinical efficacy

The clinical efficacy of glycopyrronium bromide is well established and an adequate review of the

clinical literature has been presented by the applicant to confirm the efficacy of the drug in treating

peptic ulceration due to muscarinic drive.

IV.5

Clinical safety

No new safety data were submitted and none were required for these bibliographic applications. Safety

is adequately reviewed in the clinical overview. The safety profile of glycopyrronium bromide is well-

known.

The applicant has provided an extensive assessment of the published literature on the safety of

glycopyrronium bromide in the treatment of peptic ulcers by way of reduction in gastric acid secretion

secondary to anticholinergic effects. The majority of the literature is fifty years in the public domain and

few recent studies have been carried out to further investigate the safety aspects demonstrated in these

original clinical trials. No new safety data have been presented.

Glycopyrrolate has been found to be generally well tolerated and safety aspects have been documented

in a number of trials and a list of undesirable effects has been included.

In various trials to evaluate the safety of glycopyrrolate at doses ranging between 1mg and 5mg, the

commonest adverse events recorded were dry mouth, dry eyes, hoarseness and occasional blurring of

vision. These effects were dose dependent and reduced upon dose reduction. There were no

discontinuations due to adverse events, no serious adverse events and no deaths in the studies presented.

Due to the pharmacology of glycopyrrolate, blurred vision, intestinal obstruction or decreased sweating

may occur. In patients with fever or in the presence of high ambient temperatures or intense exercise,

anticholinergics may produce heat prostration. As an anticholinergic drug, glycopyrrolate should be used

with caution in patients with conditions that are exacerbated by such drugs, including autonomic

neuropathy, renal disease, ulcerative colitis, hyperthyroidism and cardiac disease.

Glycopyrrolate is contraindicated in patients with glaucoma, gastrointestinal obstruction, paralytic ileus,

ulcerative colitis, obstructive uropathy and myasthenia gravis.

The effects of IV glycopyrrolate on maternal and fetal heart rate, heart rate variability and maternal

electromechanical intervals and blood pressure were investigated in 20 patients in labour. Fetal heart rate

parameters remained constant but maternal heart rate increased with decreases in electromechanical

interval associated with tachycardia. Uterine activity increased in all cases. From this is may be

concluded that glycopyrronium bromide is not recommended during pregnancy.

It is unknown whether glycopyrrolate or its metabolites are excreted in human milk, hence use during

lactation is not advised.

Overall conclusions on clinical safety

The safety of glycopyrronium bromide is well known and adequately presented through the review of

the available literature. No new safety issues are identified.

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IV.6

Risk Management Plan (RMP) and Pharmacovigilance system

The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), 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

Glycopyrronium Bromide Tablets.

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are

listed below:

Summary table of safety concerns as approved in the RMP:

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Summary table of risk minimisation measures as approved in the RMP:

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IV.7

Discussion on the clinical aspects

The clinical overview has been written by an appropriately qualified physician and is a suitable

summary of the clinical aspects of the dossier.

The bibliographic data submitted for these applications does support the claim of well-established use

for the sought indication of use in adults as add-on therapy in the treatment of peptic ulcer.

The grant of marketing authorisations is recommended for these applications.

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, as amended. The language used for

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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 glycopyrronium bromide is considered to have

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

positive.

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

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

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

available on the MHRA website.

The approved labelling for Glycopyrronium Bromide Tablets is presented below:

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