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Active ingredient group (AIG) number: 0108887007; AHFS: 12:12.08.12
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(Salbutamol Sulphate Solution)

1 mg salbutamol/mL

2 mg salbutamol/mL



-adrenergic agonist)

Teva Canada Limited

30 Novopharm Court

Toronto, Ontario

M1B 2K9


Submission Control No: 187916

Date of Revision:

December 21, 2017

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ......................................................... 3




............................................................................. 3



USE ...................................................................................... 3

CONTRAINDICATIONS ........................................................................................................... 3


PRECAUTIONS .......................................................................................... 4


REACTIONS ........................................................................................................... 7


INTERACTIONS ............................................................................................................ 9


ADMINISTRATION ...................................................................................... 10

OVERDOSAGE ........................................................................................................................ 12



PHARMACOLOGY ..................................................................... 13


STABILITY .................................................................................................. 14




PACKAGING ...................................................... 14

PART II: SCIENTIFIC INFORMATION ............................................................................... 15


INFORMATION ................................................................................. 15


TRIALS .................................................................................................................. 17


PHARMACOLOGY ............................................................................................. 19

TOXICOLOGY ......................................................................................................................... 20

REFERENCES .......................................................................................................................... 23

PART III: CONSUMER INFORMATION .............................................................................. 31





(Salbutamol Sulphate)



Route of


Dosage Form / Strength

Clinically Relevant Nonmedicinal


Oral Inhalation

Sterinebs/unit dose/2.5 or

5.0 mg salbutamol base/2.5

sodium chloride, sulphuric acid and




P.F. (salbutamol sulphate Solution) is indicated for:

the treatment of severe bronchospasm associated with exacerbations of chronic bronchitis

and bronchial asthma. It can be used by “wet” nebulization. When administered through a

nebulizer, it should be used with compressed air or oxygen.

Pediatrics (< 5 years of age):

Experience is insufficient for recommending the treatment of children under 5 years of age.


Patients who are hypersensitive to this drug or to any of the ingredients in the formulation

or component of the container and in patients with tachyarrythmias. (see DOSAGE


As a tocolytic in patients at risk of premature labour or threatened abortion.



Patients should always carry their salbutamol aerosol or dry powder to use immediately if an

episode of asthma is experienced. If therapy does not produce a significant improvement or if the

patient’s condition worsens, medical advice must be sought to determine a new plan of

treatment. In the case of acute or rapidly worsening dyspnea, a doctor should be consulted


The application of these inhalation systems in children depends on the ability of the individual

child to learn the proper use of the devices. During inhalation, children should be assisted or

supervised by an adult who knows the proper use of the devices.


P.F must only be used by inhalation, to be breathed in

through the mouth, and must not be injected or swallowed.

A small number of cases of acute angle closure glaucoma have been reported in patients treated

with a combination of nebulized salbutamol and ipratropium bromide. A combination of

nebulized salbutamol with nebulized anticholinergics should therefore be used cautiously.

Patients should receive adequate instruction in correct administration and be warned not to let the

solution or mist enter the eye.

Use of Anti-Inflammatory Agents

In accordance with the present practice for asthma treatment, concomitant anti-inflammatory

therapy (e.g. corticosteroid) should be part of the regimen if inhaled salbutamol needs to be used

on a regular daily basis (see DOSAGE AND ADMINISTRATION). It is essential that the

physician instruct the patient in the need for further evaluation if the patient's asthma becomes



In individual patients, any beta

-adrenergic agonist, including salbutamol, may have a clinically

significant cardiac effect. Care should be taken with patients suffering from cardiovascular

disorders, especially coronary insufficiency, cardiac arrhythmias and hypertension. Special care

and supervision are required in patients with idiopathic hypertrophic subvalvular aortic stenosis,

in whom an increase in the pressure gradient between the left ventricle and the aorta may occur,

causing increased strain on the left ventricle.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic

drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following

an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is


Endocrine and Metabolism

Metabolic Effects

In common with other beta-adrenergic agents, salbutamol can induce reversible metabolic

changes such as potentially serious hypokalemia, particularly following nebulized or especially

infused administration. Particular caution is advised in acute severe asthma since hypokalemia

may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics

and by hypoxia. Hypokalemia will increase the susceptibility of digitalis-treated patients to

cardiac arrhythmias. It is recommended that serum potassium levels be monitored in such


Care should be taken with patients with diabetes mellitus. Salbutamol can induce reversible

hyperglycemia during nebulized administration or especially during infusions of the drug. The

diabetic patient may be unable to compensate for this and the development of ketoacidosis has

been reported. Concurrent administration of corticosteroids can exaggerate this effect.

Lactic acidosis has been reported very rarely in association with high therapeutic doses of

intravenous and nebulized short-acting beta-agonist therapy, mainly in patients being treated for

an acute asthma exacerbation (see ADVERSE REACTION section). Increase in lactate levels

may lead to dyspnea and compensatory hyperventilation, which could be misinterpreted as a sign

of asthma treatment failure and lead to inappropriate intensification of short-acting beta-agonist

treatment. It is therefore recommended that patients are monitored for the development of

elevated serum lactate and consequent metabolic acidosis in this setting.

Care should be taken with patients with hyperthyroidism.


Immediate hypersensitivity reactions may occur after administration of salbutamol sulphate, as

demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, hypotension,

anaphylaxis, and oropharyngeal edema.

Care should be taken with patients who are unusually responsive to sympathomimetic amines.


Care should be taken with patients with convulsive disorders.


As with other inhaled medications, paradoxical bronchospasm may occur characterized by an

immediate increase in wheezing after dosing. This should be treated immediately with an

alternative presentation or a different fast-acting inhaled bronchodilator to relieve acute

asthmatic symptoms. Salbutamol should be discontinued immediately, the patient assessed and if

necessary, alternative therapy instituted (see ADVERSE REACTIONS).The cause of either the

refractory state or death is unknown. However, it is suspected in the fatal episodes that cardiac

arrest occurred following the unexpected development of a severe acute asthmatic crisis and

subsequent hypoxia. Several cases have been reported in which intermittent positive pressure

ventilation in acute asthma attacks was related to lethal episodes of hypoxia and pneumothorax.

This method of drug administration may be ineffective in patients with severe obstruction and

greatly increased airway resistance, and it may induce severe hypercapnia and hypoxia. During

intermittent ventilation therapy, the monitoring of arterial blood gases is highly desirable. It is

advisable that in the event of either hypoxia and pneumothorax or paradoxical bronchospasm the

use of the preparation should be discontinued immediately and alternate therapy instituted, since

in the reported cases the patients did not respond to other forms of therapy until the drug was


Special Populations

Pregnant Women:

Salbutamol has been in widespread use for many years in humans without

apparent ill consequence. However, there are no adequate and well-controlled studies in pregnant

women and there is little published evidence of its safety in the early stages of human pregnancy.

Administration of any drug to pregnant women should only be considered if the anticipated

benefits to the expectant woman are greater than any possible risks to the foetus (see

TOXICOLOGY, Teratogenicity Studies).

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

salbutamol. Some of the mothers were taking multiple medications during their pregnancies.

Because no consistent pattern of defects can be discerned, and baseline rate for congenital

anomalies is 2-3%, a relationship with salbutamol use cannot be established.

Labour and Delivery:

Although there have been no reports concerning the use of inhaled

salbutamol during labour and delivery, intravenously administered salbutamol given at high

doses may inhibit uterine contractions. While this effect is extremely unlikely as a consequence

of using inhaled formulations, it should be kept in mind. Oral salbutamol has been shown to

delay preterm labour in some reports but there are no well-controlled studies which demonstrate

that it will stop preterm labour or prevent labour at term. When given to pregnant patients for

relief of bronchospasm, cautious use of Salbutamol Sulphate Respirator Solution is required to

avoid interference with uterine contractility.

Nursing Women:

Since salbutamol is probably excreted in breast milk and because of its

observed tumorigenicity in animal studies, a decision should be made whether to discontinue

nursing or to discontinue the drug, taking into account the benefit of the drug to the mother. It is

not known whether salbutamol in breast milk has a harmful effect on the neonate.





P.F should be used under the supervision of an adult

who understands the proper use of the nebulizer (and TEVA-SALBUTAMOL STERINEBS

applicable) and only as presented by the doctor.

Rarely, in children, hyperactivity occurs and occasionally, sleep disturbances, hallucination or

atypical psychosis have been reported.

Pediatrics (< 5 years of age):

Experience is insufficient for recommending the treatment of

children under 5 years of age.

Monitoring and Laboratory Tests

The management of asthma should normally follow a stepwise program and patient response

should be monitored clinically and by lung function tests.

Monitoring Control of Asthma

Failure to respond for at least three hours to a previously effective dose of salbutamol indicates a

deterioration of the condition and the physician should be contacted promptly. Patients should be

warned not to exceed the recommended dose

as there may be adverse effects associated with

excessive dosing.

The increasing use of fast acting, short duration inhaled beta

-adrenergic agonists to control

symptoms indicates deterioration of asthma control and the patient’s therapy plan should be

reassessed. In worsening asthma it is inadequate to increase beta

-agonist use only, especially

over an extended period of time. In the case of acute or rapidly worsening dyspnea, a doctor

should be consulted immediately. Sudden or progressive deterioration in asthma control is

potentially life threatening; the treatment plan must be re-evaluated, and consideration be given

to corticosteroid therapy (see DOSAGE AND ADMINISTRATION).


As with other beta

-agonists, special caution should be observed when using

salbutamol in elderly patients who have concomitant cardiovascular disease that could be

adversely affected by this class of drug.


Because clinical trials are conducted under very specific conditions the adverse reaction

rates observed in the clinical trials may not reflect the rates observed in practice and

should not be compared to the rates in the clinical trials of another drug. Adverse drug

reaction information from clinical trials is useful for identifying drug-related adverse

events and for approximating rates

Adverse Drug Reaction Overview

Adverse events are listed below; frequencies are defined as: very common (≥1/10), common (≥1/100

and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000) and very rare

(<1/10,000) including isolated reports. Very common and common events were generally determined

from clinical trial data. Rare, very rare and unknown events were generally determined from

spontaneous data.

As with other bronchodilator inhalation therapy, the potential for paradoxical bronchospasm

should be kept in mind. If it occurs, the preparation should be discontinued immediately and

alternative therapy instituted.

Potentially serious hypokalemia may result from beta

-agonist therapy, primarily from parenteral

and nebulized routes of administration (see WARNINGS and PRECAUTIONS, Endocrine and


Peripheral vasodilation and a compensatory small increase in heart rate may occur in some

patients. Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and

extrasystoles) have been reported, usually in susceptible patients.

The most frequent adverse reactions associated with salbutamol inhalation aerosol, dry powder

or respirator solution formulations are nervousness and tremor. In some patients inhaled

salbutamol may cause a fine tremor of skeletal muscle, particularly in the hands. This effect is

common to all beta

-adrenergic-agonists. Adaptation occurs during the first few days of dosing

and the tremor usually disappears as treatment continues.

Headache, palpitations, transient muscle cramps, insomnia, nausea, weakness and dizziness have

been reported as untoward effects following salbutamol administration.

Rarely reported adverse effects include drowsiness, flushing, restlessness, irritability, chest

discomfort, difficulty in micturition, hypertension, angina, vomiting, vertigo, central nervous

system stimulation, hyperactivity in children, unusual taste and drying or irritation of the


Immediate hypersensitivity reactions including angioedema, urticaria, bronchospasm,

hypotension, rash, oropharyngeal oedema, anaphylaxis and collapse have been reported very


Rarely, in children, hyperactivity occurs and occasionally, sleep disturbances, hallucination or

atypical psychosis have been reported.

Lactic acidosis has been reported very rarely in patients receiving intravenous and nebulized

salbutamol therapy for the treatment of acute asthma exacerbation.


Drug-Drug Interactions

Table 1 Established or Potential Drug-Drug Interactions

Drug Type



Clinical comment

Monoamine oxidase

inhibitors or tricyclic


May potentiate

action of

salbutamol on



Salbutamol should be administered with

extreme caution to patients being treated with

monoamine oxidase inhibitors or tricyclic


Other inhaled


bronchodilators or


May lead to




Other inhaled sympathomimetic

bronchodilators or epinephrine should not be

used concomitantly with salbutamol. If

additional adrenergic drugs are to be

administered by any route to the patient

using inhaled salbutamol, the adrenergic

drugs should be used with caution. Such

concomitant use must be individualized and

not given on a routine basis. If regular

coadministration is required then

alternative therapy must be considered.


May effectively

antagonise the

action of


Beta-adrenergic blocking drugs, especially the

non-cardioselective ones, such as

propranolol, should not usually be prescribed



May lead to

ECG changes



although the


significance of

these effects is not


The ECG changes and/or hypokalemia that

may result from the administration of non-

potassium sparing diuretics (such as loop or

thiazide diuretics) can be acutely worsened

by beta-agonists, especially when the

recommended dose of the beta-agonist is

exceeded. Caution is advised in the

coadministration of beta-agonists with non-

potassium sparing diuretics.

Proper name



Clinical comment


May lead to

decrease in serum

digoxin levels.

The clinical

significance of

these findings for

patients with


airways disease

who are


salbutamol and

digoxin on a

chronic basis is


Mean decreases of 16-22% in serum

digoxin levels were demonstrated after

single dose intravenous and oral

administration of salbutamol, respectively, to

normal volunteers who had received digoxin

for 10 days. It would be prudent to carefully

evaluate serum digoxin levels in patients who

are currently receiving digoxin and


Ipratropium bromide.

Acute angle


glaucoma has been

reported with


A small number of cases of acute angle

closure glaucoma have been reported in

patients treated with a combination of

nebulized salbutamol and ipratropium

bromide. Therefore, a combination of

nebulized salbutamol with nebulized

anticholinergics should be used cautiously.

Patients should receive adequate

instruction in correct administration and be

warned not to let the solution or mist enter

the eye.

Legend: CS=Class Statement


Dosing Considerations

The dosage should be individualized, and the patient’s response should be monitored by the

prescribing physician on an ongoing basis.

In patients with asthma, if salbutamol is required for relief of symptoms more than twice a

day on a regular daily basis or for an extended period of time, anti-inflammatory therapy

(e.g. Corticosteroid) should be part of the regimen.

Increasing demand for Teva-Salbutamol

(salbutamol sulphate) Solution in bronchial asthma is

usually a sign of worsening asthma and indicates that the treatment plan should be reviewed.

If a previously effective dose fails to provide the usual relief, or the effects of a dose last for

less than three hours, patients should seek prompt medical advice since this is usually a

sign of worsening asthma.

As there may be adverse effects associated with excessive dosing the dosage or frequency of

administration should only be increased on medical advice. However, if a more severe attack has

not been relieved by the usual dose, additional doses may be required. In these cases, patients

should immediately consult their doctors or the nearest hospital.


P.F. may be preferred in the treatment of severe

bronchospasm associated with exacerbations of chronic bronchitis and bronchial asthma.

Recommended Dose and Dosage Adjustment




and Adolescents ≥ 13 years of age


Patients requiring single doses of 2.5 mg or 5.0 mg

may be administered the contents of a single unit dose (TEVA-SALBUTAMOL STERINEBS


2.5 mg or 5.0 mg of salbutamol). Treatment may be repeated 4 times a day if necessary.

Children (5 - 12 years):

Children requiring single doses of 2.5 mg may be administered the

contents of a single unit dose (TEVA-SALBUTAMOL STERINEBS

2.5 mg of Salbutamol).

For more refractory cases children may use a 5 mg unit dose (see dosage above). Treatment may

be repeated 4 times a day if necessary.

If a more severe attack has not been relieved by a treatment, further treatments may be required.

In these cases, patients should immediately consult their doctor or the nearest hospital.

Missed Dose

If a single dose is missed, instruct the patient to take the next dose at the time when it is due or if

they become wheezy.


To ensure administration of the proper dose of the drug, the patient should be instructed by the

physician or other health professional in the proper use of the nebulizer system or respirator


Salbutamol is to be used only under the direction of a physician employing either a respirator or

nebulizer. Salbutamol can be taken by either the nebulization or intermittent positive pressure

ventilation method. The solution must not be injected or swallowed. When used in a nebulizer

delivery may be by a mouthpiece, a face mask, T piece or via an endotracheal tube. The

nebulizer should be connected to a compressed air or oxygen pump. Gas flow should be in the

range of 6 to 10 L/minute. With an average volume of 3 mL, a single treatment lasts

approximately 10 minutes. It is advisable to prepare one dose at a time of salbutamol or to utilize

the Unit Dose presentation.

When salbutamol is administered through intermittent positive pressure ventilation, the

inspiratory pressure is usually 10-20 cm H

O and the duration of administration varies from 5 to

20 minutes, depending upon the patient and the control of the apparatus. This length of

administration provides a more gradual and more complete lysis of bronchospasm. In several

cases it has been reported that the use of intermittent positive pressure ventilation in acute

asthma attacks was related to lethal episodes of hypoxia and pneumothorax. This method of drug

administration may be ineffective in patients with severe obstruction and may greatly increase

airway resistance and possibly induce severe hypercapnia and hypoxia. It is highly desirable to

monitor arterial blood gases during intermittent positive pressure ventilation therapy. When there

is a risk of anoxia through hypoventilation, oxygen should be added to the inspired air.

As many nebulizers operate on a continuous flow basis, it is likely that nebulized drug will be

released in the local environment. Salbutamol should therefore be administered in a well

ventilated room, particularly in hospitals when several patients may be using nebulizers at the

same time.

Salbutamol is to be used with a nebulizer, under the direction of a physician. Salbutamol is

intended to be used undiluted. However, if prolonged delivery time is desirable (more than 10

minutes) dilution using sterile normal saline as a diluent may be required.

Cleansing and maintenance of the nebulizer must be carefully exercised by strict adherence to

the manufacturer's instructions.


For management of a suspected drug overdose, contact your regional Poison Control Centre.

Symptoms and signs

The most common signs and symptoms of overdose with salbutamol are transient beta agonist

pharmacologically mediated events (see Warning and Precautions and Adverse Reactions).

Overdosage may cause tachycardia, cardiac arrhythmia, hypokalemia, hypertension and, in

extreme cases, sudden death. 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.


Consideration should be given to discontinuation of treatment and appropriate symptomatic

therapy. To antagonise the effect of salbutamol, the judicious use of a cardioselective beta-

adrenergic blocking agent (e.g. metoprolol, atenolol) may be considered, bearing in mind the

danger of inducing an asthmatic attack.

During continuous administration of salbutamol solution, any sign of overdosage can usually be

counteracted by withdrawal of the drug


Mechanism of Action

Salbutamol produces bronchodilation through stimulation of beta

-adrenergic receptors in

bronchial smooth muscle, thereby causing relaxation of bronchial muscle fibres. This action is

manifested by an improvement in pulmonary function as demonstrated by spirometric

measurements. Although beta

-receptors are the predominant adrenergic receptors in bronchial

smooth muscle and beta

-receptors are the predominant receptors in the heart, there are also


-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors.

The precise function of these receptors has not been established, but they raise the possibility that

even highly selective beta

-agonists may have cardiac effects.

At therapeutic doses, salbutamol

has little action on the beta

- adrenergic receptors in cardiac muscle.

A measurable decrease in airway resistance is typically observed within 5 to 15 minutes after

inhalation of salbutamol. The maximum improvement in pulmonary function usually occurs 60

to 90 minutes after salbutamol treatment, and significant bronchodilator activity has been

observed to persist for 3 to 6 hours.


After inhalation of recommended doses of salbutamol, plasma drug levels are very low. When

100 mcg of tritiated salbutamol aerosol was administered to two normal volunteers, plasma

levels of drug-radioactivity were insignificant at 10, 20 and 30 minutes following inhalation. The

plasma concentration of salbutamol may be even less as the amount of plasma drug-radioactivity

does not differentiate salbutamol from its principal metabolite, a sulphate ester. In a separate

study, plasma salbutamol levels ranged from less than 0.5 ng/mL to 1.6 ng/mL in ten asthmatic

children one hour after inhalation of 200 micrograms of salbutamol.

Five asthmatic patients were given tritium-labelled salbutamol from the nebulizer of an

intermittent positive pressure ventilator. In all patients, there was a rapid initial rise in plasma

concentration of total radioactivity. In four of the five patients, there was a further rise in plasma

concentration to a peak at 2 to 4 hours. All patients showed an improvement in FEV

with peak

improvement at 30 minutes to 2 hours. An average of 12.5% of the initial dose was recovered in

the urine. Of the radioactivity recovered, 88% was recovered in the first 24 hours. The metabolite

in the urine was the same as that in the plasma. During the first 2 hours, the ratio of free

salbutamol to metabolite average 2:1, whereas by 8 hours, the ratio was 9:11, and thereafter this

reversed ratio was maintained.

Approximately 10% of an inhaled salbutamol dose is deposited in the lungs. Eighty-five per cent

of the remaining salbutamol administered from a metered-dose inhaler is swallowed, however,

since the dose is low (100 to 200 mcg), the absolute amount swallowed is too small to be of

clinical significance. Salbutamol is only weakly bound to plasma proteins. Results of animal

studies indicate that following systemic administration, salbutamol does not cross the blood-

brain barrier but does cross the placenta using an

in vitro

perfused isolated human placenta

model. It has been found that between 2% and 3% of salbutamol was transferred from the

maternal side to the fetal side of the placenta.

Salbutamol is metabolized in the liver. The principal metabolite in humans is salbutamol-o-

sulphate, which has negligible pharmacologic activity. Salbutamol may also be metabolized by

oxidative deamination and/or conjugation with glucuronide.

Salbutamol is longer acting than isoprenaline in most patients by any route of administration

because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-

O-methyl transferase. Salbutamol and its metabolites are excreted in the urine (>80%) and the

feces (5% to 10%). Plasma levels are insignificant after administration of aerosolized

salbutamol; the plasma half-life ranges from 3.8 to 7.1 hours.


Keep out of the sight and reach of children.


P.F. Store between 2 to 25°C. Leave product in the

carton when not used.

In the home, the unit dose preparation (TEVA-SALBUTAMOL STERINEBS

) which is pre-

diluted and ready to use, is the most convenient preparation. Any unused solution in the

nebulizer should be discarded.



P.F. (Salbutamol Sulphate Solution) contains

salbutamol sulphate in an aqueous solution, equivalent to 1.0 mg or 2.0

mg of salbutamol base

per mL. It contains salbutamol sulphate as salbutamol base 1 mg/mL or 2 mg/ml with normal

saline solution of sodium chloride (0.9%) in sterile water for inhalation. Sulphuric acid may be

included to adjust pH.


P.F. is supplied in nebules containing 2.5 mL unit

doses. Each individual carton contains 20 plastic sterinebs with enclosed leaflet.



Drug Substance

Proper name:

salbutamol sulphate

Chemical name:

1,3-Benzenedimethanol, α1-[[(1,1-dimethylethyl)amino]methyl]-4-


Molecular formula and molecular mass:

S ; 576.7

Structural formula:

Physicochemical properties:


White to almost white powder. It is odourless or almost odourless.


Soluble in 4 parts of water; slightly soluble in ethanol

(96%), in chloroform and in ether.

pH value:

pKa values:

9.3 and 10.3

Distribution Coefficient:

The distribution coefficient of salbutamol between two phases of

octanol and water, as determined by HPLC, is log D=-0.5 at pH

7.42 at room temperature.

Melting Point:

Approximately 155

C, with decomposition.


In controlled clinical trials, the onset of improvement in pulmonary function was within 15

minutes, as determined by both maximum mid-expiratory flow rate (MMEF) and FEV


measurements also showed that near maximum improvement in pulmonary function generally

occurs within 60 to 90 minutes following two inhalations of salbutamol and that clinically

significant improvement generally continues for three to four hours in most patients. In clinical

trials some patients with asthma showed a therapeutic response (defined as maintaining FEV

values 15% or more above baseline) that was still apparent at six hours. Continued effectiveness

of salbutamol was demonstrated over a 13-week period in these same trials.

In clinical studies, two inhalations of salbutamol taken approximately 15 minutes before exercise

prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV


80% of baseline values in the majority of patients. One of these studies also evaluated the

duration of the prophylactic effect to repeated exercise challenges which was evident at four

hours in the majority of patients and at six hours in approximately one third of the patients.

The ability of salbutamol to produce bronchodilation in humans has been demonstrated in many

spirometric and plethysmographic studies. Following a challenge with acetylcholine aerosol, in a

study examining the effects of salbutamol in airway resistance following challenge testing in 12

patients, the mean airway resistance increased 250%. After salbutamol aerosol (200

micrograms), the mean airway resistance decreased to 78% of the initial value. Challenges with

grass pollen or house dust aerosols in five and eight patients, respectively, increased activity

resistance 265% and 255%, respectively. Administration of salbutamol decreased airway

resistance to initial levels.

Controlled clinical studies and other clinical experience have shown that inhaled salbutamol, like

other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some

patients, as measured by pulse rate, blood pressure, symptoms, and/or ECG changes.

When salbutamol was administered as a metered-dose inhaler preparation to six normal

volunteers, at doses of three or seven inhalations of 100 micrograms, it was observed that three

inhalations of salbutamol did not alter serum potassium while seven inhalations resulted in a

decrease in serum potassium from 4.4 to 3.8 mEq/L. Thus, recommended doses of salbutamol

aerosol (two inhalations) would not be expected to alter serum potassium levels.

A double-blind placebo controlled comparison of the bronchodilator effects of salbutamol,

inhaled either as a dry powder or as a conventional aerosol, was carried out in 20 adult patients

with chronic bronchial asthma. All treatments were significantly better than placebo. There was

no significant difference between responses to any of the three dry powder doses (100 mcg, 200

mcg, 300 mcg) but the average response to 200 mcg aerosol was significantly greater than that to

200 mcg dry powder.

Salbutamol dry powder (400 mcg) and conventional aerosol (200 mcg) were administered to 10

adult asthmatics. There was no statistically significant difference between the improvement in

obtained 10 minutes after administration of either the dry powder or the aerosol


Salbutamol was administered as a dry powder (50 mcg, 100 mcg, 200 mcg, 400 mcg) and as an

aerosol (200 mcg) to 10 adult asthmatics. The greatest responses were obtained with salbutamol

400 mcg administered as a dry powder. No effect on blood pressure or pulse rate was observed.

Daily improvement in PEFR in response to single doses of inhaled salbutamol (200 mcg dry

powder and 100 mcg conventional aerosol) was measured in nine asthmatic children (aged 5-13

years) for six weeks. The order of administration of powder and aerosol was reversed at the end

of three weeks. There was no statistically significant difference between the increase in PEFR 5

minutes after either 200 mcg dry powder or after 100 mcg aerosol. The total mean increases in

PEFR 10 minutes after inhalation of powder and aerosol (weeks 1-3) and inhalation of aerosol

and powder (weeks 4-6) were not significantly different.

In a double-blind placebo-controlled study, salbutamol (200 mcg) completely prevented

exercise-induced bronchospasm in three of five children, and greatly reduced the effects in the

other two patients.

Administration of 10 mg salbutamol as a 0.5% solution through IPPV from a Bennett ventilator,

given in a 3 minute period, resulted in a 40% increase of FEV

with maximum effect in about 90

minutes. The average duration of effect was 3 hours. The heart rate had an average increase of 9

beats/minute, peaking after 25 minutes, and lasting for about 36 minutes. No ECG changes were


Salbutamol solution 0.5% was self-administered at home via a portable nebulizer, without IPPV,

by 28 adult patients with severe chronic asthma. The dose was 0.5 mL (2.5 mg salbutamol) in 4.5

mL normal saline, 2 to 4 times daily, and the duration of treatment period ranged from 0.9 to 2.7

years (mean 1.7 years). For each patient the treatment period was compared retrospectively with

a control period of the same duration preceding nebulizer therapy. No statistically significant

differences between treatment and control periods were found for pulmonary function tests

performed before and after 5 puffs of a salbutamol pressurized aerosol, or for number of out-

patient emergency department visits, hospitalizations, sick leaves, and days hospitalized.

However, there were significant reductions during the treatment period in the duration of sick

leaves and medical ward treatments, while half of the patients reported that it was easier to sleep

and two-thirds said it was easier to exercise.

In 10 pediatric studies, a total of 189 patients up to 14 years of age were treated with salbutamol

solution 0.5% administered via a portable nebulizer. In most cases, the dose was between 0.5 mL

and 1.0 mL per treatment, diluted with normal saline, bringing the total volume to 2.0 mL.

Children with asthma had very good results from the treatment, while children with bronchitis or

bronchiolitis did not respond well. Salbutamol was very well tolerated in these studies. One

author reported 2 cases of skeletal muscle tremor, but drew attention to the fact that both patients

received concurrent oral bronchodilator. Otherwise, the only reported side effect was occasional

mild tachycardia.


Clinical Pharmacology

Prolonged use of salbutamol in most patients caused no significant changes in ECG pattern,

blood sugar, liver and kidney functions and hematological values.

The hemodynamic effects of intravenous salbutamol were studied in patients with mitral valve

disease. At the dose of l mcg/kg, salbutamol reduced mean aortic pressure by 7 mmHg, increased

the cardiac output by 0.6 L/minute and reduced systemic vascular resistance by 7 units. It caused

no change in left ventricular ejection time. At the dose of 2 mcg/kg, salbutamol increased the

mean oxygen uptake by 21 mL/minute, narrowing the mean arteriovenous oxygen difference by

10 mL/minute. Salbutamol has no effect on the pulmonary ventilation/perfusion ratio, therefore,

unlike isoprenaline, it does not increase hypoxia during acute asthmatic attacks.

Animal Pharmacology

In vitro

studies and

in vivo

pharmacologic studies have demonstrated that salbutamol has a

preferential effect on beta

-adrenergic receptors compared with isoprenaline. While it is

recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth

muscle, recent data indicate that there is a population of beta

-receptors in the human heart

existing in a concentration between 10% and 50%. The precise function of these, however, is not

yet established.

The pharmacologic effects of beta-adrenergic agonist drugs, including salbutamol, are at least in

part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase,

the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-

adenosine monophosphate (cAMP). Increased cAMP levels are associated with relaxation of

bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity

from cells, especially from mast cells.

The muscle-relaxing effect of salbutamol was found to be more prolonged than when the effect

was induced by isoprenaline. As suggested from the results of experiments in isolated animal

tissues, salbutamol has been shown to produce a substantial bronchodilator effect in the intact

animal. In the anaesthetised guinea pig, salbutamol completely prevents acetylcholine-induced

bronchospasm at the dose of 100 micrograms/kg intravenously.

Administration of salbutamol aerosol at a dose of 250 microgram/mL for one minute to guinea

pigs prevented acetylcholine-induced bronchospasm without any chronotropic effect. A

prolonged bronchodilator effect of salbutamol compared to isoprenaline (in terms of mean times

to dyspnea following acetylcholine challenge) was observed following oral administration of

salbutamol to conscious guinea pigs. The protective action of salbutamol in this case persisted

for up to six hours.

In anaesthetised cats and dogs, salbutamol prevented the bronchospasm elicited by vagal

stimulation without any significant effect on heart rate and blood pressure. Comparative tests of

salbutamol and isoprenaline in isolated dog papillary muscle, guinea pig atrial muscle and human

heart muscle have shown that the effect of salbutamol on beta

- adrenergic receptors in the heart

is minimal.

In a number of studies using guinea pig atria, it was found that on a weight-to-weight basis,

salbutamol was from 2,000 to 2,500 times less active in terms of inotropic effect and 500 times

less active in terms of chronotropic effect than isoprenaline. Compared to orciprenaline,

salbutamol was about 40 times less active in terms of inotropic effect and four times less potent

in terms of chronotropic effect. Salbutamol has been shown to be one-fifth as potent a

vasodilator in skeletal muscle as isoprenaline, as measured by effects on hind limb blood flow in

the anaesthetised dog. In the perfused rabbit ear, salbutamol was shown to possess only one-tenth

the activity of isoprenaline in terms of vasodilating effect. In dogs, salbutamol was shown to

increase coronary blood flow, which was subsequently shown to be the result of a direct

coronary vasodilating effect of salbutamol.

In six dogs with right-sided cardiac by-pass, salbutamol, given at the dose of

25 micrograms/kg, improved left ventricular efficiency and increased coronary blood flow.

Recent studies in minipigs, rodents, and dogs recorded the occurrence of cardiac arrhythmias and

sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and

methylxanthines were administered concurrently. The significance of these findings when

applied to humans is currently unknown.

Animal studies show that salbutamol does not pass the blood brain barrier.


Acute Toxicity

Species (n)

Oral LD


Intravenous LD


Mouse (10)

>2000 mg/kg

72 mg/kg

Rat (10)

>2000 mg/kg

60 mg/kg

Rat (n)

Intraperitoneal LD


Newborn (155)

216 mg/kg

Weanling (100)

524 mg/kg

2 week old (90)

437 mg/kg

The rate of respiration in test animals initially increased, but subsequently became abnormally

slow and deep. Death, preceded by convulsions and cyanosis, usually occurred within four hours

after drug administration.

Rabbits, cats and dogs survived a single dose of 50 mg/kg salbutamol.

Intermediate (Four Months) Toxicity

Rats received salbutamol twice daily, in oral doses from 0.5 to 25 mg/kg, on an increasing scale.

The only significant hematological changes were a small increase in hemoglobin and packed cell

volume. BUN and SGOT values were elevated while blood glucose and plasma protein levels

remained unchanged. Pituitaries had increased amount of PAS-positive material in the cleft at the

higher dose levels.

Salbutamol was given to dogs twice daily, in oral doses from 0.05 to 12.5 mg/kg, on an

increasing scale. The rate of increase of hemoglobin and packed cell volume was depressed,

particularly at higher doses. Leukocyte count decreased after sixteen weeks of treatment at each

dose level. Platelet count was increased after eight weeks at the highest dose. No significant

biochemical effects were observed. The only significant histological change was the appearance

of corpora amylacea in the stomach which was attributed to altered mucus secretion. Inhalation

of 1000 mcg of salbutamol aerosol twice daily for three months did not produce any

morphological changes in the lungs, trachea, lymph nodes, liver or heart.

Long-Term Toxicity

Fifty female, Charles River CD Albino rats received salbutamol orally at 2, 10 and

50 mg/kg/day for one hundred and four weeks; fifty female Charles River CD Sprague-Dawley-

derived rats received 20 mg/kg/day salbutamol orally for fifty weeks, and fifty female Charles

River Long-Evans rats received 20 mg/kg/day salbutamol orally for ninety-six weeks. These rat

studies demonstrated a dose-related incidence of mesovarian leiomyomas. No similar tumors

were seen in mice.


In vitro

tests involving four micro-organisms revealed no mutagenic activity.


In a two-year study in the rat, salbutamol sulphate caused a significant dose-related increase in

the incidence of benign leiomyomas of the mesovarium at doses corresponding to 111, 555, and

2,800 times the maximum human inhalation dose. In another study, the effect was blocked by the

co-administration of propranolol. The relevance of these findings to humans is not known. An

18-month study in mice and a lifetime study in hamsters revealed no evidence of tumorigenicity.

Teratogenicity Studies

Salbutamol has been shown to be teratogenic in mice when given in doses corresponding to 14

times the human aerosol dose; when given subcutaneously in doses corresponding to 0.2 times

the maximum human (child weighing 21 kg) oral dose; and when given subcutaneously in doses

corresponding to 0.4 times the maximum human oral dose.

A reproduction study in CD-1 mice given salbutamol at doses of 0.025, 0.25, and

2.5 mg/kg subcutaneously, corresponding to 1.4, 14, and 140 times the maximum human aerosol

dose respectively, showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg and in

10 of 108 (9.3%) fetuses at 2.5 mg/kg. No cleft palates were observed at a dose of 0.025 mg/kg

salbutamol. Cleft palate occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg isoprenaline

(positive control).

In rats, salbutamol treatment given orally at 0.5, 2.32, 10.75 and 50 mg/kg/day throughout

pregnancy resulted in no significant fetal abnormalities. However, at the highest dose level there

was an increase in neonatal mortality. Reproduction studies in rats revealed no evidence of

impaired fertility.

Salbutamol had no adverse effect when given orally to Stride Dutch rabbits, at doses of 0.5, 2.32

and 10.75 mg/kg/day throughout pregnancy. At a dose of 50 mg/kg/day, which represents 2800

times the maximum human inhalation dose and 78 times the maximum human oral dose

cranioschisis was observed in 7 of 19 (37%) fetuses.


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Product Monograph for

VENTOLIN, revised October 2. 2014. GlaxoSmithKline Inc.







(salbutamol sulphate solution)

This leaflet is part III of a three-part "Product

Monograph" for TEVA-SALBUTAMOL


P.F. and is designed specifically for

Consumers. This leaflet is a summary and will not

tell you everything about TEVA-SALBUTAMOL


P.F. Please read this insert carefully

before you start your medicine. Contact your doctor

or pharmacist if you have any questions about the

drug. This medicine is for you only. Only your doctor

can prescribe it for you. Never give it to someone

else. It may harm them even if his/her symptoms are

the same as yours.


What the medication is used for:


P.F. is used

in Adults and Children 5 years or older. It treats

severe, worsening breathing problems

(bronchospasm) associated with:

Chronic bronchitis

Bronchial Asthma

Bronchospasm is a sudden worsening of shortness of

breath and wheezing.

The safety and effectiveness of TEVA-


P.F. in children

below the age of 5 years are not known.

What it does:

It can relieve chest tightness and wheezing if you

have asthma or another chest illness.

Salbutamol is one of a group of medicines called

bronchodilators. Salbutamol relaxes the muscles in

the walls of the small air passages in the lungs. This

helps to open up the airways and so helps to relieve

chest tightness, wheezing and cough so that you can

breathe more easily.

When it should not be used:


P.F. if:

you are allergic to it or any of the components of

its formulation (see What the important

nonmedicinal ingredients are).

your heart beats faster than normal.

for the treatment of preterm labour or


What the medicinal ingredient is:



contains the active ingredient, salbutamol sulphate.

What the important nonmedicinal ingredients are:

Sodium chloride, dilute sulphuric acid and water.

What dosage forms it comes in:



contains salbutamol sulphate equivalent to 1 mg/mL,

or 2.0 mg/mL salbutamol base.


P.F. are:


preservative free

unit doses (each ampoule contains 1 dose

that is ready for use)




P.F. talk to your doctor or pharmacist

You have ever had to stop taking another

medicine for this illness because you were

allergic to it or because it caused problems.

You are having treatment for a thyroid condition.

You are having treatment for high blood pressure

or a heart problem.

You have diabetes.

You have a past history of seizures.

You have low levels of potassium in your blood

(hypokalemia), especially if you are taking:

Drugs known as xanthine derivatives (such as


Steroids to treat asthma

Water pills (diuretics)

You are pregnant or intend to become pregnant.



P.F. during pregnancy may cause harm to your

baby. Your doctor will consider the benefit to

you and the risk to your baby of taking TEVA-


P.F. while

you're pregnant.

You are breastfeeding. It is not known if TEVA-


P.F. passes

into breast milk.

Rare cases of lactic acidosis (too much lactic acid in

the blood) have been reported in patients receiving

high doses of TEVA-SALBUTAMOL


P.F. If you suffer symptoms (see

Serious Side Effects Table), contact your doctor



If the relief of wheezing or chest tightness is not as

good as usual, or the effect lasts for less than three

hours, tell your doctor as soon as possible. If you

notice a sudden worsening of your shortness of

breath and wheeze shortly after taking your medicine,

tell your doctor as soon as possible. It may be that

your chest condition is worsening and you may need

to add another type of medicine to your treatment.

You should always carry other asthma medication

with you to use immediately in case you experience

an asthma attack.

Effects on Children

Children may experience:

Changes in sleep patterns

Changes in behaviour such as restlessness,

excitability ( hyperactivity)

Seeing or hearing things that are not there


As with most medicines, interactions with other

drugs are possible. Tell your doctor, nurse, or

pharmacist about all the medicines you take,

including drugs prescribed by other doctors,

vitamins, minerals, natural supplements, or

alternative medicines.

The following may interact with TEVA-




Allergy medication

Blood pressure-lowering drugs, including


Diuretics (“water pills”)

Bronchodilators used to open the airway

(such as other asthma medication)


Digoxin, a heart medication





only be inhaled

from a nebulizer. It must not be

injected or swallowed.

Do not let the TEVA-SALBUTAMOL


P.F. or the mist produced by the

nebulizer, get in your eyes.

Use your nebulizer in a well ventilated room. Some

of the mist will be released into the air and may be

breathed in by others.



only as directed by your doctor. During

administration your doctor may want to monitor your




P.F. may last for up to 6 hours and

should last at least 4 hours.

Call your doctor

immediately if the effect of your usual dose lasts

for less than 3 hours or if you suddenly get worse

shortness of breath and you wheeze after using




this is usually a sign of worsening asthma.

Do not

increase the dose or how often you take your

medicine without informing your doctor,

as this may

make you feel worse

. If symptoms get worse, tell

your doctor as soon as possible.


P.F., other medicines (including asthma medicines)

should only be used when prescribed by your doctor.

If you regularly use TEVA-SALBUTAMOL



P.F. two or more times a day, and

take no other asthma medication, you should talk

to your doctor who may want to reassess your

treatment plan. If you do not get relief from 3 or 4

treatments during a day, contact your physician.

Do not

exceed the prescribed dose or frequency of

administration without contacting your physician.

Usual dose:

Adults and Adolescents 13 years and older:

ampoule (either 2.5 mg or 5 mg), repeated 4 times a

day if necessary.

Children (5-12 years)

: 1 ampoule (2.5 mg), repeated

4 times a day if necessary.

Patients who have not improved on this dose, may

need 1 ampoule (5mg), repeated 4 times a day if






1. The contents of TEVA-SALBUTAMOL


P.F. are to be inhaled from a

nebulizer. Do not open the foil pack until the


P.F. are


2. Prepare the nebulizer for filling according to the

manufacturer’s instructions.

3. Open the foil pouch and remove the ampoules.




P.F. push one ampoule

downwards and away while holding

the remaining ampoules securely (diagram 2). Return

the remaining ampoules to the foil pouch and place

the foil pouch back into the carton.

5. Holding the top of the ampoule securely, twist the

body to open (diagram 3).

6. Place the open end of the ampoule well into the

nebulizer cup and squeeze slowly (diagram 4).

Ensure the contents are emptied into the nebulizer


7. Gently shake the nebulizer and connect it with the

mouthpiece or face mask. Connect the apparatus to

the air pump or oxygen and start the treatment.

8. Breathe calmly and evenly as much as possible

until no more mist is formed in the nebulizer

chamber. At this point, treatment is finished.

9. After use discard any solution remaining in the

nebulizer cup.



P.F should be used under the supervision of an adult

who understands the proper use of the nebulizer and

only as prescribed by the doctor.




P.F. and Nebulizer

Open only one foil pack at a time and use all 5

ampoules before opening the next foil pack. Record

the date when the foil pack is first opened. Always

place foil tray (covered with lid) back in the carton

after use.

To clean the Nebulizer:

Cleaning: After each use, clean the nebulizer as


Disassemble the supply tube and the nebulizer.

Wash in warm detergent solution. Rinse the tube

with water.

To wash the suction tubes:

Place 3 mL of detergent solution in the vial,

assemble the unit and operate for 2 minutes.

Disassemble and rinse the vial with warm

water, place 3 mL of warm water in the vial,

assemble the unit and operate for 2 minutes.

Disassemble and rinse with warm water.

To dry the external passage:

Connect the nebulizer tube to the pump with

the supply tube.

Turn on the pump and blow air through for 1

minute. If there is evidence of clogging,

clean the openings and tube connectors with

the detergent, then rinse with water.


Do not swallow or inject TEVA-SALBUTAMOL




P.F. is

inhaled into your lungs using a nebulizer.


In case of drug overdose, contact a health care

practitioner, hospital emergency department or

regional Poison Control Centre immediately, even if

there are no symptoms. Take this leaflet or your

medication with you so that the hospital or poison

control centre will know what you have taken.

If you accidentally take a

larger dose than


, you are more likely to get side effects

like a faster heart beat, headaches and feeling shaky

or restless. These effects usually wear off within a


few hours, but you should tell your doctor as soon as


Missed Dose:

If you forget to inhale a dose do not worry: inhale the

next dose at the time you would normally take it or

inhale a dose sooner than when it is due if you

become wheezy.



Side effects may include:

Effects on heart

Faster heart beat than usual



Effects on nervous system


Feeling a little shaky

Feeling anxious or irritable

Feeling tired or weak

Trouble sleeping (insomnia)

Hyperactivity in children

Dizziness, vertigo


Effects on muscles and joints

Muscle cramps

Other Effects

Nausea and vomiting

Chest pain or discomfort


Difficulty urinating

Unusual taste in your mouth

Dry or irritated throat



Symptom / effect

Talk with

your doctor or


Stop taking

drug and

call your

doctor or












wheezing or

tightness in the

chest or difficulty

in breathing (sign





Swelling of the

eyelids, face, lips,

tongue or throat,

accompanied by

difficulty in


speaking or

swallowing (signs

of angioedema).

Skin rash, skin

eruption or other

effect on the skin

or eyes, itching or

fever. Fainting

when the blood

pressure is too

low (sign of


Deep and rapid



abdominal pain,

weight loss,

fatigue, malaise

(sign of lactic


much lactic acid

in the blood).


Low level of

potassium in your




in Children:

or hear things that

are not there

This is not a complete list of side effects. If you have

any unexpected effects after receiving




contact your

doctor or pharmacist.






P.F. in a safe place, out of reach

and sight of children. Your medicines may harm




between 2-25°C. Leave product in the carton when

not used.

Reporting Side Effects

You can report any suspected side effects associated

with the use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction

Reporting (



reporting.html) for information on how to

report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical



You may need to read this leaflet again.



until you have

finished your medicine.

This document plus the full product monograph,

prepared for health professionals can be found by

contacting Teva Canada Limited by:

Phone: 1-800-268-4127 ext. 3;

Email:; or

Fax: 1-416-335-4472

This leaflet was prepared by:

Teva Canada Limited

30 Novopharm Court

Toronto, Ontario


M1B 2K9

Last revised: December 21, 2017

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