CONFIDENTIAL

VENTOLIN EVOHALER

Salbutamol

QUALITATIVE AND QUANTITATIVE COMPOSITION

VENTOLIN EVOHALER is a pressurised metered-dose inhaler which delivers
100 micrograms salbutamol (as sulphate) per actuation, into the mouthpiece of a specially
designed actuator. The inhaler also contains the CFC-free propellant HFA 134a. Each
canister contains at least 200 actuations.

CLINICAL INFORMATION

Indications

Pharmaceutical form: Pressurised inhalation, suspension.

Salbutamol is a selective beta2 adrenoceptor agonist indicated for the treatment or

prevention of bronchospasm. It provides short acting (four hours) bronchodilation in
reversible airways obstruction due to asthma, chronic bronchitis and emphysema. For
patients with asthma salbutamol may be used to relieve symptoms when they occur and to
prevent them prior to a known trigger.

Bronchodilators should not be the only or main treatment in patients with persistent
asthma. In patients with persistent asthma unresponsive to VENTOLIN, treatment with
inhaled corticosteroids is recommended to achieve and maintain control. Failing to
respond to treatment with VENTOLIN may signal a need for urgent medical advice or
treatment.

Dosage and Administration

VENTOLIN has a duration of action of 4 to 6 hours in most patients.

Increasing use of beta2 agonists may be a sign of worsening asthma. Under these
conditions a reassessment of the patient's therapy plan may be required and concomitant
corticosteroid therapy should be considered.

As there may be adverse effects associated with excessive dosing, the dosage or
frequency of administration should only be increased on medical advice.

VENTOLIN is administered by the oral inhaled route only.

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In patients who find co-ordination of a pressurised metered-dose inhaler difficult a spacer

may be used with VENTOLIN Evohaler.

Babies and young children using the VENTOLIN Evohaler may benefit from the use of a
paediatric spacer device with a face mask (for example the BABYHALER™).
(Recommended statement “for example the BABYHALER™” is for use only in those
markets where the Babyhaler spacer device is available). (See Clinical Studies).

RELIEF OF ACUTE BRONCHOSPASM

• Adults

100 or 200 micrograms.

• Children

100 micrograms. The dose may be increased to 200 micrograms if required.

PREVENTION OF ALLERGEN OR EXERCISE-INDUCED BRONCHOSPASM

• Adults

200 micrograms before challenge or exertion.

• Children

100 micrograms before challenge or exertion. The dose may be increased to 200
micrograms if required.

CHRONIC THERAPY

• Adults

Up to 200 micrograms 4 times daily.

• Children

Up to 200 micrograms 4 times daily.

On demand use of VENTOLIN should not exceed four times daily. Reliance on such
supplementary use or a sudden increase in dose indicates deteriorating asthma (see
Warnings and Precautions).

Contraindications

VENTOLIN is contraindicated in patients with a history of hypersensitivity to any of its

components. Non-i.v. formulations of VENTOLIN must not be used to arrest
uncomplicated premature labour or threatened abortion.
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Warnings and Precautions

The management of asthma should normally follow a stepwise programme, and patient
response should be monitored clinically and by lung function tests.

Increasing use of short-acting bronchodilators, in particular beta2 agonists to relieve

symptoms indicates deterioration of asthma control. Under these conditions, the patient's
therapy plan should be reassessed.

Sudden and progressive deterioration in asthma control is potentially life-threatening and

consideration should be given to starting or increasing corticosteroid therapy. In patients
considered at risk, daily peak flow monitoring may be instituted.

VENTOLIN should be administered cautiously to patients with thyrotoxicosis.

Potentially serious hypokalaemia may result from beta2 agonist therapy mainly from
parenteral and nebulised administration.

Particular caution is advised in acute severe asthma as this effect may be potentiated by
concomitant treatment with xanthine derivatives, steroids, diuretics and by hypoxia. It is
recommended that serum potassium levels are monitored in such situations.

As with other inhalation therapy, paradoxical bronchospasm may occur, resulting in an

immediate increase in wheezing after dosing. This should be treated immediately with an
alternative presentation or a different fast-acting inhaled bronchodilator, if immediately
available. VENTOLIN Evohaler should be discontinued, and if necessary a different fast-
acting bronchodilator instituted for ongoing use.

In the event of a previously effective dose of inhaled VENTOLIN failing to give relief for
at least three hours, the patient should be advised to seek medical advice in order that any
necessary additional steps may be taken.

The patient’s inhaler technique should be checked to make sure that aerosol actuation is
synchronised with inspiration of breath for optimum delivery of the drug to the lungs.

Interactions

VENTOLIN and non-selective beta-blocking drugs, such as propranolol, should not

usually be prescribed together.

VENTOLIN is not contraindicated in patients under treatment with monoamine oxidase

inhibitors (MAOIs).
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Pregnancy and Lactation

Fertility

There is no information on the effects of salbutamol on human fertility. There were no

adverse effects on fertility in animals (see Non-Clinical Information).

Pregnancy

Administration of drugs during pregnancy should only be considered if the expected

benefit to the mother is greater than any possible risk to the foetus.

During worldwide marketing experience, rare cases of various congenital anomalies,

including cleft palate and limb defects have been reported in the offspring of patients
being treated with VENTOLIN. Some of the mothers were taking multiple medications
during their pregnancies. As no consistent pattern of defects can be discerned, and
baseline rate for congenital anomalies is 2 to 3%, a relationship with salbutamol use
cannot be established.

Lactation

As salbutamol is probably secreted in breast milk, its use in nursing mothers is not
recommended unless the expected benefits outweigh any potential risk. It is not known
whether salbutamol in breast milk has a harmful effect on the neonate.

Effects on Ability to Drive and Use Machines

None reported.

Adverse Reactions

Adverse events are listed below by system organ class and frequency. Frequencies are
defined as: very common (1/10), common (1/100 to 1/10), uncommon (1/1000 to
1/100), rare (1/10,000 to 1/1000) and very rare (1/10,000) including isolated reports.
Very common and common events were generally determined from clinical trial data.
Rare and very rare events were generally determined from spontaneous data.

Immune system disorders

Very rare: Hypersensitivity reactions including angioedema, urticaria,

bronchospasm, hypotension and collapse

Metabolism and nutrition disorders

Rare: Hypokalaemia

Potentially serious hypokalaemia may result from beta2 agonist therapy.

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Nervous system disorders

Common: Tremor, headache

Very rare: Hyperactivity

Cardiac disorders

Common: Tachycardia

Uncommon: Palpitations

Very rare: Cardiac arrhythmias including atrial fibrillation, supraventricular

tachycardia and extrasystoles

Vascular disorders

Rare: Peripheral vasodilatation

Respiratory, thoracic and mediastinal disorders

Very rare: Paradoxical bronchospasm

Gastrointestinal disorders

Uncommon: Mouth and throat irritation

Musculoskeletal and connective tissue disorders

Uncommon: Muscle cramps

Overdose

The most common signs and symptoms of overdose with VENTOLIN are transient beta
agonist pharmacologically mediated events (see Warnings and Precautions and Adverse
Reactions).

Hypokalaemia may occur following overdosage with VENTOLIN. Serum potassium

levels should be monitored.

Lactic acidosis has been reported in association with high therapeutic doses as well as
overdoses of short-acting beta-agonist therapy, therefore monitoring for elevated serum
lactate and consequent metabolic acidosis (particularly if there is persistence or
worsening of tachypnea despite resolution of other signs of bronchospasm such as
wheezing) may be indicated in the setting of overdose.
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PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Salbutamol is a selective beta2-adrenoceptor agonist. At therapeutic doses it acts on the

beta2-adrenoceptors of bronchial muscle providing short acting (4 to 6 hour)
bronchodilation with a fast onset (within 5 minutes) in reversible airways obstruction.

Pharmacokinetics
Absorption

After administration by the inhaled route, between 10 and 20% of the dose reaches the
lower airways. The remainder is retained in the delivery system or is deposited in the
oropharynx from where it is swallowed. The fraction deposited in the airways is
absorbed into the pulmonary tissues and circulation but is not metabolised by the lung.

Distribution

Salbutamol is bound to plasma proteins to the extent of 10%.

Metabolism

On reaching the systemic circulation, salbutamol becomes accessible to hepatic

metabolism and is excreted, primarily in the urine, as unchanged drug and as the phenolic
sulphate.

The swallowed portion of an inhaled dose is absorbed from the gastrointestinal tract and
undergoes considerable first-pass metabolism to the phenolic sulphate. Both unchanged
drug and conjugate are excreted primarily in the urine.

Elimination

Salbutamol administered intravenously has a half-life of four to six hours and is cleared
partly renally and partly by metabolism to the inactive 4'-O-sulphate (phenolic sulphate)
which is also excreted primarily in the urine. The faeces are a minor route of excretion.
The majority of a dose of salbutamol given intravenously, orally or by inhalation is
excreted within 72 hours.

Clinical Studies
Special Patient Populations

Children < 4 years of age

Paediatric clinical studies conducted at the recommended dose (SB020001, SB030001,

SB030002), in patients < 4 years with bronchospasm associated with reversible
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obstructive airways disease, show that the Evohaler has a safety profile comparable to
that in children ≥ 4 years, adolescents and adults.

Non-Clinical Information

In common with other potent selective beta2 receptor agonists, salbutamol has been
shown to be teratogenic in mice when given subcutaneously. In a reproductive study,
9.3% of foetuses were found to have cleft palate, at 2.5 mg/kg, four times the maximum
human oral dose. In rats, treatment at the levels of 0.5, 2.32, 10.75 and 50mg/kg/day
orally throughout pregnancy resulted in no significant foetal abnormalities. The only
toxic effect was an increase in neonatal mortality at the highest dose level as the result of
lack of maternal care. A reproductive study in rabbits revealed cranial malformations in
37% of foetuses at 50mg/kg/day, 78 times the maximum human oral dose.

In an oral fertility and general reproductive performance study in rats at doses of 2 and 50
mg/kg/day, with the exception of a reduction in number of weanlings surviving to day 21
post partum at 50 mg/kg/day, there were no adverse effects on fertility, embryofetal
development, litter size, birth weight or growth rate.

HFA 134a has been shown to be non-toxic at very high vapour concentrations, far in
excess of those likely to be experienced by patients, in a wide range of animal species
exposed daily for periods of two years.

PHARMACEUTICAL INFORMATION

List of Excipients

1,1,1,2-tetrafluoroethane (also known as HFA 134a or norflurane).

Shelf Life

The expiry date is indicated on the packaging.

Storage

The storage conditions are detailed on the packaging

Replace the mouthpiece cover firmly and snap it into position.

Protect from frost and direct sunlight.

As with most inhaled medications in aerosol canisters, the therapeutic effect of this
medication may decrease when the canister is cold.

Pressurised container. Do not expose to temperatures higher than 50°C. The canister
should not be broken, punctured or burnt, even when apparently empty.
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Nature and Contents of Container

VENTOLIN Evohaler comprises a suspension of salbutamol sulphate in the propellant

HFA 134a. The suspension is contained in an aluminium alloy can, sealed with a
metering valve. Each canister is fitted with a plastic actuator incorporating an atomising
nozzle and fitted with a dustcap. VENTOLIN Evohaler delivers 100 micrograms of
salbutamol (as sulphate) per actuation.

Each canister contains at least 200 actuations.

Incompatibilities

None reported.

Use and Handling

Testing your inhaler

Before using for the first time, remove the mouthpiece cover by gently squeezing the
sides of the cover, shake the inhaler well, and release two puffs into the air to make sure
that it works. If it has not been used for 5 days or more, shake it well and release 2 puffs
into the air to make sure that it works.

Using your inhaler

1. Remove the mouthpiece cover by gently squeezing the sides of the cover.

2. Check inside and outside of the inhaler including the mouthpiece for the presence
of loose objects.

3. Shake the inhaler well to ensure that any loose objects are removed and that the
contents of the inhaler are evenly mixed.

4. Hold the inhaler upright between fingers and thumb with your thumb on the base,
below the mouthpiece.

5. Breathe out as far as is comfortable and then place the mouthpiece in your mouth
between your teeth and close your lips around it but do not bite it.

6. Just after starting to breathe in through your mouth press down on the top of the
inhaler to release VENTOLIN while still breathing in steadily and deeply.

7. While holding your breath, take the inhaler from your mouth and take your finger
from the top of the inhaler. Continue holding your breath for as long as is
comfortable.

8. If you are to take further puffs keep the inhaler upright and wait about half a
minute before repeating steps three to seven.
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9. Replace the mouthpiece cover by firmly pushing and snapping the cap into
position.

IMPORTANT

Do not rush Stages 5, 6 and 7. It is important that you start to breathe in as slowly as
possible just before operating your Inhaler.

Practise in front of a mirror for the first few times. If you see 'mist' coming from the top
of the inhaler or the sides of your mouth you should start again from stage two.

If your doctor has given you different instructions for using your inhaler, please follow
them carefully. Tell your doctor if you have any difficulties.

CLEANING

Your inhaler should be cleaned at least once a week.

1. Remove the metal canister from the plastic casing of the inhaler and remove the
mouthpiece cover.

2. Rinse the actuator thoroughly under warm running water.

3. Dry the actuator THOROUGHLY inside and out.

4. Replace the metal canister and mouthpiece cover.

DO NOT PUT THE METAL CANISTER INTO WATER.

Not all presentations are available in every country.

Version number: GDS28/IPI10

Date of issue: 15 Dec 2020

Trade marks are owned by or licensed to the GSK group of companies.

[GSK logo]
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LABELLING TEXT

PARTICULARS TO APPEAR ON THE CARTON LABEL

NAME OF THE MEDICINAL PRODUCT

Ventolin Evohaler 100 micrograms

salbutamol (as sulfate)

STATEMENT OF ACTIVE SUBSTANCE(S)

This aerosol contains 100 micrograms salbutamol (as sulfate) per actuation

EXCIPIENTS WARNING(S), IF NECESSARY

Contains propellant HFA 134a

PHARMACEUTICAL FORM AND CONTENTS

Pressurised inhalation, suspension

200 metered actuation

METHOD AND ROUTE(S) OF ADMINISTRATION

Inhale through your mouth into your lungs

Pressurised metered-dose inhaler. Do not puncture, break or burn even when apparently
empty

To be used as directed by your physician

OTHER SPECIAL WARNING(S), IF NECESSARY

Shake the inhaler well before use

Keep out of the sight and reach of children

PRE-PRINT INFORMATION

BATCH
EXP
MANFD
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STORAGE CONDITIONS

Store below 30°C.

Protect from frost and direct sunlight.

MANUFACTURING SITE ADDRESS (PACKAGING SITE ADDRESS IF

DIFFERENT)

Manufactured by:
GlaxoWellcome Production*
Evreux, France

*Member of GSK group of companies

TRADE MARK STATEMENTS

Trade marks are owned by or licensed to the GSK group of companies.

COPYRIGHT STATEMENTS

© 2020 GSK group of companies or its licensor

LOGO(S)

GSK

QR CODE TEXT
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PARTUCULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

As advised by the Legal Global Trade Marks department for inner packaging components (such as blisters,
injection devices, inhalers, sachets etc) we should aim to include the trade mark and copyright statements,
if there are space constraints we should adopt the shortened term. There are good reasons to include trade
mark and copyright statements on these components, for example, if the outer carton contains a number of
sachets which might be dispersed between different patients who then receive the sachet without the outer
packaging. In such circumstances the trade mark and copyright statements should appear on each sachet
where possible.

NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF

ADMINISTRATION

Ventolin Evohaler 100 micrograms

salbutamol (as sulfate)

METHOD OF ADMINISTRATION

Shake the inhaler well before use

Inhale through your mouth into your lungs
To be used as directed by your physician

PRE-PRINT INFORMATION (WHERE POSSIBLE)

BATCH
EXP

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

200 metered actuation

OTHER

Store below 30°C. Protect from frost and direct sunlight.

Pressurised metered-dose inhaler. Do not puncture, break or burn even when apparently
empty
Keep out of the sight and reach of children

TRADE MARK STATEMENTS (IF REQUIRED)

Trade marks are owned by or licensed to the GSK group of companies.

COPYRIGHT STATEMENTS (IF REQUIRED)

© 2020 GSK group of companies or its licensor

LOGO(S)
GSK
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DETAILS FOR LEAFLET

MANUFACTURING SITE ADDRESS (PACKAGING SITE ADDRESS IF

DIFFERENT)

Manufactured by:
GlaxoWellcome Production*,
Evreux, France

*Member of GSK group of companies

TRADEMARK STATEMENTS

Trade marks are owned by or licensed to the GSK group of companies.

COPYRIGHT STATEMENTS

© 2020 GSK group of companies or its licensor

LOGO(S)

GSK

QR CODE TEXT