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APO-SALBUTAMOL INHALER

NAME OF THE MEDICINE
Chemical Name: RS)-2-tert-butylamino-1-(4-hydroxy-3-hydroxymethyl-phenyl) ethanol sulfate. C13H21NO3.½ H2SO4 Structural Formula:
CAS Registry Number: 51022-70-9
DESCRIPTION
Salbutamol sulfate is a white or almost white powder. It is soluble in water but is only slightly soluble in
alcohol, chloroform and ether. 1.2mg of salbutamol sulfate is equivalent to 1.0mg of salbutamol base.
APO-Salbutamol Inhaler contains microcrystalline salbutamol sulfate suspended in norflurane (1,1,1,2-
tetrafluoroethane), a CFC-free propellant which does not deplete ozone from the atmosphere. Each
metered dose delivers an amount of salbutamol sulfate equivalent to 100 µg of salbutamol. APO-
Salbutamol Inhaler also contains oleic acid and ethanol. APO-Salbutamol Inhaler is available in pack
sizes containing 200 doses.
PHARMACOLOGY
Salbutamol is a direct acting sympathomimetic agent which mainly has -adrenergic activity and a high
degree of selectivity for 2-adrenoceptors. As a predominantly 2-adrenoceptor stimulant, salbutamols’
bronchodilating action is relatively more prominent than its cardiac effects. Salbutamol is chemically
related to adrenaline, noradrenaline and isoprenaline but it has a longer duration of action than these
compounds. This is possibly due to its resistance to catechol-O-methyl transferase (COMT), an
inactivating enzyme which occurs in association with sympathetic receptors.
Pharmacodynamics
The -sympathetic agonists act primarily through activation of adenylate cyclase which catalyses the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Cyclic AMP mediates the effects of the -agonists on sympathetic receptors. Increased cAMP concentrations also inhibits release of mediators of immediate hypersensitivity from mast cells, as well as relaxing bronchial smooth muscle. Stimulation of 2-receptors causes relaxation of the smooth muscle of the bronchi, uterus and blood vessels, decreases the duration of skeletal muscle contraction and increases glycolysis and glycogenolysis. APO-Salbutamol Inhaler contains the sulfate salt of salbutamol, which has been shown to be clinically equivalent to salbutamol base when administered in equivalent doses by metered-dose inhaler. Pharmacokinetics
When APO-Salbutamol Inhaler is inhaled at the recommended doses salbutamol is delivered topically to
the lung such that its effects are apparent within minutes. Because of the small amount of drug
administered and due to its gradual absorption from bronchi, plasma levels of salbutamol are extremely
low after oral inhalation. Salbutamol is not metabolised in the lung.
Swallowed salbutamol is readily absorbed from the gastrointestinal tract and undergoes extensive pre-
systemic metabolism by conjugation to a 4'-0-sulfate ester in the gastrointestinal tract and the liver. Its
systemic bioavailability is about 50%.
Salbutamol and its metabolites are rapidly excreted in the urine and faeces. About 80% of a single dose
is recovered in urine within 24 hours. Following oral inhalation unchanged salbutamol accounts for
approximately 30% of the excreted dose in the urine. The elimination half-life of salbutamol is about 3-6
hours. Salbutamol is not significantly bound in plasma. The elimination of salbutamol may be altered by
changes to hepatic or renal function; consequently dosage reduction may be required in patients with
hepatic or renal impairment.
CLINICAL STUDIES
In a 12-week, randomised, double-blind, double-dummy, active- and placebo-controlled study, 565 adult patients with asthma were evaluated for the bronchodilator efficacy of a non-CFC (norflurane) salbutamol pressurised inhaler (193 patients) in comparison to a CFC salbutamol pressurised inhaler (186 patients). Serial FEV1 (Forced Expiratory Volume) measurements demonstrated that two inhalations of a non-CFC (norflurane) salbutamol pressurised inhaler produced significantly greater improvement in pulmonary function than placebo and produced outcomes which were clinically comparable to a CFC salbutamol pressurised inhaler. The mean time to onset of a 15% increase in FEV1 was 6 minutes and the mean time to peak effect was 50 minutes. The mean duration of effect as measured by a 15% increase in FEV1 was 3 hours. No statistically significant or clinical meaningful differences were seen in the safety parameters, including the overall adverse event rates, heart rate, blood pressure, serum potassium or ECG interval changes between a non-CFC (norflurane) salbutamol pressurised inhalerand CFC-salbutamol pressurised inhaler. In a 4-week, randomised, open-label, parallel study, 63 children with asthma were evaluated for the bronchodilator efficacy of a non-CFC (norflurane) salbutamol pressurised inhaler (33 patients) in comparison to CFC-salbutamol pressurised inhaler (30 patients). Serial FEV1 measurements demonstrated that two inhalations of a non-CFC (norflurane) salbutamol pressurised inhalerproduced a clinically comparable bronchodilator effect compared to CFC salbutamol pressurised inhaler. Analysis of all safety parameters revealed that a non-CFC (norflurane) salbutamol pressurised inhalerhas a similar safety profile to CFC salbutamol pressurised inhaler. In the 12-month studies there were 337 adult patients assigned to a non-CFC (norflurane) salbutamol pressurised inhalerand 132 to CFC salbutamol pressurised inhaler (2 puffs twice daily and prn). There were no significant differences between a non-CFC (norflurane) salbutamol pressurised inhalerand CFC salbutamol pressurised inhaler treatment groups for total reported adverse events, clinically meaningful changes in laboratory tests or physical examinations (changes in pulse rate, blood pressure, serum potassium and ECG intervals). Baseline lung function, assessed as the FEV1 obtained at visits prior to dosing did not change in either group over the one year treatment periods. No significant differences in bronchodilator efficacy were found between a non-CFC (norflurane) salbutamol pressurised inhalerand CFC salbutamol pressurised inhaler throughout the studies. Forty eight asthmatic patients (adults) completed 16 puffs cumulative dose, cross-over studies comparing a non-CFC (norflurane) salbutamol pressurised inhalerto CFC salbutamol pressurised inhaler. The efficacy equivalence between a non-CFC (norflurane) salbutamol pressurised inhalerand CFC-salbutamol pressurised inhaler was confirmed by the comparable FEV1 responses, while equivalence in safety was confirmed by comparable falls in serum potassium, changes in vital signs (heart rate, blood pressure) and ECG intervals. INDICATIONS
Relief of bronchospasm in patients with asthma or chronic obstructive pulmonary disease, and for acute prophylaxis against exercise-induced asthma or in other situations known to induce bronchospasm. CONTRAINDICATIONS
Known hypersensitivity to salbutamol sulfate or other sympathomimetics, or to any other ingredients.

PRECAUTIONS
The results of animal experiments indicate that high dosages of some sympathomimetic agents may
cause cardionecrosis. In view of this evidence the possibility of cardiac lesions occurring in humans
cannot be excluded. The administration of APO-Salbutamol Inhaler by inhalation results in low salbutamol
plasma concentrations so the risk of this effect is correspondingly reduced.
APO-Salbutamol Inhaler contains norflurane, a CFC-free propellant. In animal studies norflurane has
been shown to have no significant pharmacological effects, except at very high exposure concentrations
when necrosis and a relatively weak cardiac sensitising effect were found. The potency of the cardiac
sensitisation of norflurane was less than that of trichlorofluoromethane (CFC-11). Large doses of CFC
propellants have been reported in animals to produce cardiac arrhythmias and sensitise their hearts to
adrenaline-induced arrhythmias. Data in humans are limited. Inhalations of the maximum recommended
dose of APO-Salbutamol Inhaler produce low concentrations of propellant in the plasma.
Excessive use of APO-Salbutamol Inhaler is potentially hazardous, both from the propellant as well as
from the possibility of overdose with the active medication. Patients should therefore be warned not to
exceed the recommended dose. Additionally, overuse of inhaled salbutamol may cause a worsening of
hypoxaemia.
Use with caution in the following circumstances:
Cardiac disease: When APO-Salbutamol Inhaler is used at the recommended doses the blood
concentrations of salbutamol are usually too low to produce a significant systemic effect. However,
prescribers should be aware of the possibility of the unwanted stimulation of cardiac adrenergic receptors
and care should be taken in patients with hypertension, coronary artery disease and myocardial
insufficiency.
Cardiac arrhythmias: Salbutamol may predispose to the occurrence of cardiac arrhythmias or may
exacerbate existing arrhythmias. This effect may be due to a direct chronotropic effect and to the
reduction of serum potassium. Care should be taken when using salbutamol in patients who have
arrhythmias or who are receiving drugs such as digitalis or diuretics which do not spare potassium.
Caution should also be taken when using salbutamol with anaesthetic agents which sensitise the
myocardium to sympathomimetic agents.
Hypokalaemia: Potentially serious hypokalaemia may result from
parenteral and nebulised administration. This effect may be potentiated in patients with hypoxia or those
treated concomitantly with theophylline, steroids or diuretics. Caution should be taken in these patients.
Diabetes mellitus: When given by inhalation at recommended doses salbutamol should have little or no
hyperglycaemic effect; however care should be taken initially in using salbutamol in diabetics.
Hyperthyroidism: Salbutamol should be used with caution in patients with thyrotoxicosis.

Carcinogenicity/Mutagenicity:
There are no reasons to consider norflurane as a potential mutagen, clastogen or carcinogen judging
from in-vitro and in-vivo studies which include long-term administration by inhalation in rodents.
Use in Pregnancy
There is no experience of APO-Salbutamol Inhaler in pregnant women. An inhalation reproductive study with APO-Salbutamol Inhaler in rats did not exhibit any teratogenic effects. Salbutamol does however cross the placenta. In some rodent studies large doses of salbutamol have been shown to be teratogenic although the relevance of these findings to humans is unknown. Safe use in pregnancy has not been
established; therefore APO-Salbutamol Inhaler should not be used during pregnancy unless the benefits
outweigh the potential risk.
Use in Lactation
There is no experience of APO-Salbutamol Inhaler in lactating women. It is unknown whether salbutamol
is excreted in breast milk. APO-Salbutamol Inhaler should therefore not be used in women who are
breast-feeding unless the benefits of therapy outweigh the potential risk to the infant.
Interactions with Other Medicines
Beta-adrenergic blockers specifically antagonise the action of salbutamol and other sympathomimetics
on the airways. Use of these drugs is also generally contraindicated in asthma because they tend to
increase airway resistance.
Concomitant use of theophylline (and other xanthine derivatives), steroids and diuretics may potentiate
salbutamol-induced hypokalaemia in acute severe asthma. In those circumstances and in other situations
(such as hypoxia) likely to potentiate salbutamol-induced hypokalaemia, serum potassium levels should
be monitored.
Instructions for Prescribers
Asthma management should be adjusted according to individual need based on lung function and clinical
monitoring. Increasing use of 2-agonist may be a sign of worsening asthma. Under these conditions a
re-assessment of the patient's therapy plan may be required and concomitant glucocorticosteroid therapy
should be considered. This is important since poor asthma control can result in potential life-threatening
situations and increased use of 2-agonists may cause deterioration of asthma control.
Patients should be informed of the importance of correct inhaler technique. To ensure correct use of
APO-Salbutamol Inhaler refer patients to the Patient Instruction Leaflet accompanying each unit. If
necessary, correct technique should be demonstrated to patients, particularly first-time users and those
with poor coordination.
It is advisable to check the patient's compliance and inhaler technique before increasing the dose.
Patients should be advised to seek medical advice when the bronchodilator effect is reduced and not to
increase the dose over that prescribed. Patients should be warned that excessive use of inhaled
salbutamol may result in significant adverse effects and/or loss of asthma control. Patients should also be
advised not to use other asthma medications at the same time as APO-Salbutamol Inhaler unless on
medical advice.
If using a spacer, the patient should be instructed to breathe in and out several times after each release
into the spacer. Any delay should be kept to a minimum. Because of electrostatic charge, leading to
adherence of drug particles to the wall of the spacer, spacers should be washed in warm water with
kitchen detergent and left to drain dry (without rinsing) before initial use and at least monthly thereafter. A
cloth should not be used to dry the spacer, as this can produce more static electricity.
ADVERSE EFFECTS
The adverse effects of salbutamol sulfate are generally extensions of its sympathomimetic actions. Their
rates of occurrence are dependent on route of administration as well as dose.
Clinical Trial Data
In a 12-week, double-blind, double-dummy study which compared a non-CFC (norflurane) salbutamol
pressurised inhaler, CFC salbutamol pressurised inhaler and a placebo (norflurane) inhaler in 565
asthmatic patients, the adverse events reported as probably or possibly related to study treatment, given
as 2 puffs four times daily for 12 weeks, and with an incidence of 1% or greater are presented in the table
below. A dash represents an incidence of less than 1%.
Adverse event
salbutamol
(norflurane)
inhaler
N=193
Application site disorders:
Autonomic Nervous system disorders:
Body as a whole – general disorders:
Central & Peripheral nervous system disorders:
Gastro-intestinal system disorders:
Heart rate and rhythm disorders:
Musculo-skeletal system disorders:
Psychiatric disorders:
Respiratory disorders:
Skin and appendages disorders:

Post Marketing Data
In a 3-month post-marketing surveillance study 5,402 patients receiving CFC-salbutamol pressurised
inhaler were switched to a non-CFC (norflurane) salbutamol pressurised inhaler. The reported adverse
reactions which were considered to be probably or possible related to treatment is presented below in the
following frequency categories within body system:
Central & peripheral nervous system disorders: Uncommon: headache, tremor, dizziness. Rare: paraesthesia, leg cramps, dysphonia. Respiratory system disorders: Uncommon: pharyngitis, bronchospasm, increased asthma symptoms, coughing. Rare: dyspnoea, acute asthma episode, upper respiratory tract infection, tracheitis, bronchitis, rhinitis. Uncommon: nausea. Rare: dry mouth, vomiting, stomatitis, abdominal pain, dyspepsia, tongue discolouration, anorexia. Body as a whole - general disorders: Uncommon: chest pain. Rare: inadequate response, decrease therapeutic response, rigours, malaise, fever, oedema. Heart rate and rhythm disorders: Uncommon: palpitation Application site disorders: Rare: inhalation site sensation, inhalation taste sensation, cough, increased asthma symptom, application site reaction, dysphonia. Musculo-skeletal disorders: Rare: myalgia, arthralgia Skin & appendages disorders: Rare: pruritus, rash, skin disorder Psychiatric disorders: Rare: nervousness, depression, paroniria, agitation, emotional lability (mood swing), abnormal thinking, euphoria. Resistance mechanism disorders: Rare: infection Myo endo pericardial & valve disorders: Rare: angina pectoris Platelet, bleeding & clotting disorders: Rare: epistaxis Reproductive disorders female: Rare: breast pain Autonomic nervous system disorders: Rare: flushing, saliva altered Special senses other, disorders: Rare: taste perversion
DOSAGE AND ADMINISTRATION
APO-Salbutamol Inhaler is therapeutically equivalent to CFC salbutamol pressurised inhalers. Patients can be switched from CFC salbutamol pressurised inhalers to APO-Salbutamol Inhaler at the same dose without loss of therapeutic effect. Adults: 1 to 2 inhalations every four hours as necessary to obtain relief of bronchospasm. If previously effective doses do not provide relief, other treatment should be instituted promptly. Children: As for adults. Elderly: Dosage should at first be lower than for younger adults but may be increased gradually to the usual adult level if necessary. Impaired Hepatic or Renal Function: Since salbutamol is extensively metabolised in the liver, any liver
function impairment may necessitate a reduction in dosage. Similarly impairment in renal function may
also require a dosage reduction since a large proportion of inhaled salbutamol is excreted in the urine.
Note: An increase in the use of salbutamol required to control asthma symptoms may indicate a
deterioration in the patients’ asthma. If so, a re-assessment of the patients’ treatment regimen may be
required. Should inhalation therapy fail to relieve asthma symptoms, other treatments should be
implemented immediately in order to avoid a potential medical emergency.
Patients who are unable to successfully coordinate actuation of the metered dose inhaler with inhalation
(including virtually all children) will benefit from substituting their conventional press and breathe metered
dose inhaler with an Autohaler, or using a spacer device.
Where a spacer is considered necessary the AeroChamberPlus has been shown to be compatible with
APO-Salbutamol Inhaler. Use of an AeroChamberPlus spacer with APO-Salbutamol Inhaler reduces the
amount of drug deposited in the oropharynx without affecting drug deposition in the lungs. A change in
the make of spacer or a change in the formulation of the drug used may be associated with alterations in
the amount of drug delivered to the lungs, the clinical significance of which is uncertain. In these
situations the patient should be monitored for any loss of asthma control. For instructions on the proper
use of spacers refer to Instructions for Prescribers.


OVERDOSAGE
Symptoms:
The symptoms of overdose are the same as the adverse effects of salbutamol, the most significant being
tachycardia and/or muscle tremor. With the metered dose inhalers some toxicity may be due to the
aerosol propellant.
Treatment:
Monitor biochemical abnormalities particularly hypokalaemia. Hypokalaemia should be treated with
potassium replacement if necessary.
PRESENTATION AND STORAGE CONDITIONS
APO-Salbutamol Inhaler: Each unit delivers salbutamol sulfate equivalent to salbutamol 100 µg per
metered dose. APO-Salbutamol Inhaler 200 dose delivers 200 doses. Each unit is supplied with an
actuator.
APO-Salbutamol Inhaler should be stored below 30°C, away from direct heat or sunlight. As the canister
is pressurised, no attempt should be made to puncture it or dispose of it by burning.
NAME AND ADDRESS OF SUPPLIER
Apotex Pty Ltd
66 Waterloo Road
North Ryde NSW 2113
Australia
Apotex Pty Ltd is the licensee of the registered trade marks APO and APOTEX from the registered
proprietor, Apotex Inc.
POISONS SCHEDULE OF THE MEDICINE
S3: Pharmacy Only Medicine.
Date of TGA approval : 20 August 2010

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