Ventolin HFA Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections (as indicated in section 2.1. of the PM Guidance) or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................. 2

Table of Contents ................................................................................................................. 2

Part 1: Healthcare Professional Information.......................................................................... 4

1 Indications ................................................................................................................ 4

1.1 Pediatrics ................................................................................................................ 4

2 Contraindications ...................................................................................................... 4

4 Dosage and Administration ....................................................................................... 4

4.1 Dosing Considerations ........................................................................................... 4

4.2 Recommended Dose and Dosage Adjustment ...................................................... 5

4.4 Administration ....................................................................................................... 5

5 Overdosage ............................................................................................................... 6

6 Dosage Forms, Strengths, Composition and Packaging ............................................... 6

7 Warnings and Precautions ......................................................................................... 7

7.1 Special Populations ................................................................................................ 9

7.1.1 Pregnancy ........................................................................................................... 9

7.1.2 Breast-feeding .................................................................................................... 9

7.1.3 Pediatrics ............................................................................................................ 9

7.1.4 Geriatrics .......................................................................................................... 10

8 Adverse Reactions ................................................................................................... 10

8.1 Adverse Reaction Overview ................................................................................. 10

8.2 Clinical Trial Adverse Reactions ........................................................................... 11

9 Drug Interactions .................................................................................................... 11

9.4 Drug-Drug Interactions ........................................................................................ 11

9.5 Drug-Food Interactions ........................................................................................ 13

9.6 Drug-Herb Interactions ........................................................................................ 13

9.7 Drug-Laboratory Test Interactions....................................................................... 13

10 Clinical Pharmacology ............................................................................................. 13

10.1 Mechanism of Action ........................................................................................... 13

10.3 Pharmacokinetics ................................................................................................. 14

11 Storage, Stability, and Disposal ................................................................................ 14

12 Special Handling Instructions ................................................................................... 14

Part 2: Scientific Information .............................................................................................. 15

13 Pharmaceutical Information .................................................................................... 15

14 Clinical Trials ........................................................................................................... 15

14.1 Clinical Trials by Indication .................................................................................. 15

15 Microbiology ........................................................................................................... 17

16 Non-Clinical Toxicology ........................................................................................... 17

Patient Medication Information ......................................................................................... 20

Part 1: Healthcare Professional Information

1 Indications

Adults and Children (4 years and older):

VENTOLIN HFA (salbutamol pressurised inhalation, suspension) is indicated for:

• the symptomatic relief and prevention of bronchospasm due to bronchial asthma, chronic bronchitis and other chronic bronchopulmonary disorders in which bronchospasm is a complicating factor.
• the prevention of exercise-induced bronchospasm.

1.1 Pediatrics

Pediatrics (< 4 years of age): The safety and efficacy in children below the age of 4 years has not been established.

2 Contraindications

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container (see 6 Dosage Forms, Strengths, Composition, and Packaging).
• As a tocolytic in patients at risk of premature labour or threatened abortion.

4 Dosage and Administration

4.1 Dosing Considerations

The dosage should be individualised, and the patient's response should be monitored by the prescribing physician on an ongoing basis.

Increasing demand for VENTOLIN HFA in bronchial asthma is usually a sign of poorly controlled or worsening asthma and indicates that the patient should be re-evaluated, the treatment plan should be reviewed and the regular asthma controller treatment should be optimized. If treatment with VENTOLIN HFA alone is not adequate to control asthma, concomitant anti-inflammatory therapy should be part of the treatment regimen.

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 physicians or the nearest hospital.

4.2 Recommended Dose and Dosage Adjustment

* If a more severe attack has not been relieved by the usual dose, further inhalations may be needed every 4 to 6 hours. More frequent or a larger number of inhalations is not recommended. In these cases, patients should immediately consult their physicians or the nearest hospital.

**Patients who are taking VENTOLIN HFA more than twice a week on an “as needed” basis may be at risk for overuse of VENTOLIN HFA. A reassessment of the patient's therapy plan may be required. Bronchodilators should not be the only or main treatment in patients with persistent asthma.

4.4 Administration

VENTOLIN HFA is administered by the inhaled route only. To ensure administration of the proper dose of the drug, the patient should be instructed by the physician or other healthcare professional on the proper use of the pressurised inhalation, suspension.

Inhaler actuation should be synchronised with inspiration to ensure optimum delivery of drug to the lungs. In patients who find coordination of a pressurised metered dose inhaler difficult, a spacer may be used with VENTOLIN HFA.

The use of open mouth technique to administer VENTOLIN HFA has not been investigated in clinical trials.

Priming: It is recommended to test spray VENTOLIN HFA into the air four times, away from the face, before using for the first time and in cases where the aerosol has not been used for more than 5 days.

The inhaler contains enough salbutamol for 200 actuations (puffs) only. After 200 actuations (puffs), the inhaler can continue to spray but without the prescribed dose of salbutamol. Methods such as shaking, weighing or submerging inhalers are not accurate for determining that an inhaler is empty of the prescribed dose of salbutamol. Maintaining a record of the number of actuations (puffs) administered to the patient should be considered, towards avoiding inadvertent use of an empty inhaler. Keeping a back-up inhaler could be considered. If the patient has more than one inhaler, it is recommended to keep track of each inhaler separately.

5 Overdosage

Symptoms and signs

The most common signs and symptoms of overdose with salbutamol are transient beta agonist pharmacologically mediated events (see 7 Warnings and Precautions and 8.1 Adverse Reaction Overview). 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.

Treatment

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. There is insufficient evidence to determine if dialysis is beneficial for overdosage of VENTOLIN HFA.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

Description

VENTOLIN HFA is a pressurized metered dose inhaler (MDI) consisting of an aluminum canister fitted with a metering valve. Each canister is fitted into the supplied blue plastic actuator. A blue dust cap is fitted over the actuator's mouthpiece when not in use. Each depression of the valve delivers 100 mcg of salbutamol (as sulfate).

VENTOLIN HFA contains a micro-crystalline suspension of salbutamol sulfate in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no excipients. Each actuation delivers 100 mcg of salbutamol (as sulfate). This product does not contain chlorofluorocarbons (CFCs) as the propellant.

VENTOLIN HFA is available in 200 dose formats.

VENTOLIN HFA does not incorporate a dose counter to display the number of doses remaining in the inhaler.

7 Warnings and Precautions

General

Patients should always carry their VENTOLIN HFA 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 physician should be consulted immediately.

The inhaler contains enough salbutamol for 200 actuations (puffs) only. After 200 actuations (puffs), the inhaler can continue to spray but without the prescribed dose of salbutamol. Methods such as shaking, weighing or submerging inhalers are not accurate for determining that an inhaler is empty of the prescribed dose of salbutamol. Maintaining a record of the number of actuations (puffs) administered to the patient should be considered, towards avoiding inadvertent use of an empty inhaler. Keeping a back-up inhaler could be considered. If the patient has more than one inhaler, it is recommended to keep track of each inhaler separately.

Cardiovascular

In individual patients, any beta₂-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 suspected.

Endocrine and Metabolism

• Metabolic Effects

In common with other beta-adrenergic agents, salbutamol sulfate can induce reversible metabolic changes such as potentially serious hypokalemia, particularly following nebulised 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 situations.

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

Care should be taken with patients with hyperthyroidism.

Immune

• Hypersensitivity

Immediate hypersensitivity reactions may occur after administration of salbutamol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, hypotension, anaphylaxis and oropharyngeal edema.

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

Monitoring and Laboratory Tests

In accordance with the present practice for asthma treatment, patient response should be monitored clinically and by lung function tests.

Neurologic

Care should be taken with patients with convulsive disorders.

Respiratory

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. VENTOLIN HFA should be discontinued immediately, the patient assessed and if necessary, alternative therapy instituted (see 8.1 Adverse Reaction Overview).

• Monitoring Control of Asthma

Failure to respond for at least three hours to a previously effective dose of VENTOLIN HFA 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.

Failure to respond to treatment with VENTOLIN HFA may signal a need for urgent medical advice or treatment.

The increasing use of fast-acting, short duration inhaled beta₂-adrenergic agonists to control symptoms indicates deterioration of asthma control and the patient’s therapy plan should be reassessed by a physician.

Patients who are taking VENTOLIN HFA more than twice a week on an “as needed” basis, not counting prophylactic use prior to a known trigger should be re-evaluated (i.e., daytime symptoms, nighttime awakening, and activity limitation due to asthma) for proper treatment adjustment as these patients are at risk for overuse of VENTOLIN HFA. A reassessment of the patient's therapy plan may be required.

In worsening asthma, it is inadequate to increase beta₂-agonist use only, especially over an extended period of time. In the case of acute or rapidly worsening dyspnea, a physician 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 4.1 Dosing Considerations).

Overuse of short-acting beta-agonists may mask the progression of the underlying disease and contribute to deteriorating asthma control, leading to an increased risk of severe asthma exacerbations and mortality.

Patients who are prescribed regular asthma anti-inflammatory therapy (e.g., inhaled corticosteroids) should be advised to continue taking their anti-inflammatory medication even when symptoms improve, and they no longer require VENTOLIN HFA.

• Deterioration of Asthma

Asthma may deteriorate over time. If the patient needs to use VENTOLIN HFA more often than usual, this may be a sign of worsening asthma. This requires re-evaluation of the patient and treatment plan and consideration of adjusting the asthma maintenance therapy. If treatment with VENTOLIN HFA alone is not adequate to control asthma, concomitant anti-inflammatory therapy should be part of the treatment regimen. It is essential that the physician instructs the patient on the need for further evaluation if the patient’s asthma becomes worse (see 4 Dosage and Administration).

7.1 Special Populations

7.1.1 Pregnancy

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 fetus (see 16 Non-Clinical 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: Because of the potential for beta-agonist interference with uterine contractility, use of VENTOLIN HFA for relief of bronchospasm during labour should be restricted to those patients in whom the benefits clearly outweigh the risks.

7.1.2 Breast-feeding

Plasma levels of salbutamol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components are excreted in human milk. Because of the potential for tumorigenicity shown for salbutamol in some 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.

7.1.3 Pediatrics

Pediatrics (4 to < 12 years): The use of metered-dose inhalers in children depends on the ability of the individual child to learn the proper use of this device. Metered-dose inhalers with spacers are recommended for children under 5 years of age, especially for administration of inhaled corticosteroids. Conversion from a face mask to a mouthpiece is strongly encouraged as soon as the age and the cooperation of the child permit.

During inhalation, children should be assisted or supervised by an adult who knows the proper use of the device.

Rarely, in children, hyperactivity occurs and occasionally, sleep disturbances, hallucination or atypical psychosis have been reported.

Pediatrics (< 4 years of age): The safety and efficacy in children below the age of 4 years has not been established.

7.1.4 Geriatrics

As with other beta₂-agonists, special caution should be observed when using VENTOLIN HFA in elderly patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug.

8 Adverse Reactions

8.1 Adverse Reaction Overview

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 beta₂-agonist therapy primarily from parenteral and nebulised routes of administration (see 7 Warnings and Precautions, Endocrine and Metabolism, Metabolic Effects).

Peripheral vasodilation and a compensatory small increase in heart rate may occur in some patients. Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported, usually in susceptible patients.

Other adverse reactions associated with salbutamol 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 beta₂-adrenergic agonists. Adaptation occurs during the first few days of dosing and the tremor usually disappears as treatment continues.

In addition, salbutamol, like other sympathomimetic agents, can cause adverse effects such as 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 oropharynx, headache, palpitations, transient muscle cramps, insomnia, nausea, weakness and dizziness.

Immediate hypersensitivity reactions including angioedema, urticaria, bronchospasm, hypotension, rash, oropharyngeal oedema, anaphylaxis and collapse have been reported very rarely.

Rarely, in children, hyperactivity occurs and occasionally, sleep disturbances, hallucination or atypical psychosis have been reported.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Adverse reaction information concerning VENTOLIN HFA is derived from two 12-week, randomized, double-blind studies in 610 adolescent and adult asthmatic patients that compared VENTOLIN HFA, VENTOLIN inhalation aerosol (CFC formulation), and an HFA-134a placebo inhaler.

*This table includes all adverse events (whether considered by the investigator to be drug-related or unrelated to drug) that occurred at an incidence rate of at least 3% in the group treated with VENTOLIN HFA and more frequently in the group treated with VENTOLIN HFA than in the HFA-134a placebo inhaler group.

Overall, the incidence and nature of the adverse events reported for VENTOLIN HFA and VENTOLIN inhalation aerosol (CFC formulation) were similar. Results in a 2-week pediatric clinical study (n=35) showed that the adverse event profile was generally similar to that of the adult.

Adverse events reported by less than 3% of the adolescent and adult patients receiving VENTOLIN HFA and by a greater proportion of patients receiving VENTOLIN HFA than receiving HFA-134a placebo inhaler and that have the potential to be related to VENTOLIN HFA include diarrhea, laryngitis, cough, lung disorders, tachycardia, and extrasystoles. Palpitation and dizziness have also been observed with VENTOLIN HFA.

9 Drug Interactions

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 3 Established or Potential Drug-Drug Interactions

Legend: CS = Class Statement.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 Clinical Pharmacology

10.1 Mechanism of Action

Salbutamol produces bronchodilation through stimulation of beta₂-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 beta₂-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta₁-receptors are the predominant receptors in the heart, there are also beta₂-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 beta₂-agonists may have cardiac effects. At therapeutic doses, salbutamol has little action on the beta₁-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.

10.3 Pharmacokinetics

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 sulfate 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 mcg of salbutamol.

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-sulfate, 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.

Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (140 to 800 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These are similar to effects produced by the structurally related CFCs, which have been used extensively in metered-dose inhalers.

In animals and humans, propellant HFA-134a was eliminated rapidly in the breath, with no evidence of metabolism or accumulation in the body. Time to maximum plasma concentration (t_max) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

11 Storage, Stability, and Disposal

Replace the mouthpiece cover firmly and snap it into position. Keep out of the sight and reach of children. Store at a temperature between 15°C and 25°C.

12 Special Handling Instructions

The contents of VENTOLIN HFA are under pressure. The container may explode if heated. Do not place in hot water or near radiators, stoves or other sources of heat. Even when empty, do not puncture or incinerate container. As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Proper name: salbutamol sulfate

Chemical name: α¹-[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α, α’-diol sulfate (2:1) (salt)

Molecular formula and molecular mass: (C₁₃H₂₁NO₃)₂ ● H₂SO₄ 576.7

Structural formula:

Physicochemical properties:

Description: White to almost white powder.

Solubility: Soluble in water and slightly soluble in methanol.

pKa Values: 9.4 and 10.0.

Distribution Coefficient: The distribution coefficient between two phases of octanol and water, as determined by HPLC, at pH 9.9 is 0.23.

Melting Point Approximately 156°C.

14 Clinical Trials

14.1 Clinical Trials by Indication

In two 12-week, randomized, double-blind studies, VENTOLIN HFA pressurised inhalation, suspension (202 patients) was compared to VENTOLIN inhalation aerosol (CFC formulation) (207 patients) and an HFA-134a placebo inhaler (201 patients) in adolescent and adult patients with mild to moderate asthma. The studies were similar in design.

One study evaluated the safety and efficacy of VENTOLIN HFA in patients with asthma, and the second study evaluated the effects of switching from VENTOLIN inhalation aerosol (CFC formulation) to VENTOLIN HFA. Serial forced expiratory volume in 1 second (FEV₁) measurements (shown below as percent change from test-day baseline at week 12, n = 525) demonstrated that two inhalations of VENTOLIN HFA produced significantly greater improvement in pulmonary function than placebo and produced outcomes that were clinically comparable to VENTOLIN inhalation aerosol (CFC formulation). Patients taking the HFA-134a placebo inhaler also took VENTOLIN HFA for asthma symptom relief on an as-needed basis. These patients produced similar morning predose baseline FEV₁ values to patients taking VENTOLIN HFA and VENTOLIN inhalation aerosol (CFC formulation) taken four times daily (plus as-needed for asthma symptom relief) throughout the 12-week study period.

FEV₁ as Percent Change From Predose in Two Large, 12-Week Clinical Trials

VENTOLIN Inhalation Aerosol (CFC formulation), two inhalations four times daily (n = 185)

The median time to onset of a 15% increase in FEV₁ was 4.8 minutes, and the median time to peak effect was 48 to 60 minutes. The mean duration of effect as measured by a 15% increase in FEV₁ was approximately 3 hours. In some patients, duration of effect was as long as 6 hours.

In a 2-week, randomized, double-blind study, VENTOLIN HFA was compared to VENTOLIN inhalation aerosol (CFC formulation) and an HFA-134a placebo inhaler in 135 pediatric patients (4 to 11 years old) with mild to moderate asthma. Serial pulmonary function measurements demonstrated that two inhalations of VENTOLIN HFA produced significantly greater improvement in pulmonary function than placebo and that there were no significant differences between the groups treated with VENTOLIN HFA and VENTOLIN inhalation aerosol (CFC formulation).

The median time to onset of a 15% increase in peak expiratory flow rate (PEFR) was 5 to 10 minutes, and the median time to peak effect was approximately 60 minutes. The mean duration of effect as measured by a 15% increase in PEFR was 2.5 hours. In some patients, duration of effect was as long as 6 hours.

In a clinical study in adult patients with asthma, two inhalations of VENTOLIN HFA taken approximately 30 minutes prior to exercise significantly prevented exercise-induced bronchospasm (as measured by maximum percentage fall in FEV₁ following exercise) compared to an HFA-134a placebo inhaler. In addition, VENTOLIN HFA was shown to be clinically comparable to VENTOLIN inhalation aerosol (CFC formulation).

15 Microbiology

No microbiological information is required for this drug product.

16 Non-Clinical Toxicology

Animal Pharmacology

In vitro studies and in vivo pharmacologic studies have demonstrated that salbutamol has a preferential effect on beta₂-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 beta₂-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 mcg/kg intravenously.

Administration of salbutamol aerosol at a dose of 250 mcg/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 beta₁-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 mcg/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

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 CFC 11/12-propelled 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.

Mutagenicity

In vitro tests involving four micro-organisms revealed no mutagenic activity.

Carcinogenicity

In a two-year study in the rat, salbutamol sulfate 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, cranioschisis was observed in 7 of 19 (37%) fetuses.

A reproduction study in New Zealand White rabbits using salbutamol sulfate/HFA-134a formulation, revealed enlargement of the frontal portion of the fontanelles in 6 of 95 (6%) and 15 of 107 (14%) fetuses at 28 and 149 mcg/kg, respectively (approximately 2/5 and 2 times, respectively, the maximum recommended human daily dose on a mg/m² basis), giving plasma levels of approximately 12 and 60 ng/mL, respectively.