Product Monograph - Ventolin Diskus
Recent Major Label Changes
| 4 Dosage and Administration, 4.2 Recommended Dose and Dosage Adjustment | 2025-09 |
|---|---|
| 4 Dosage and Administration, 4.5 Missed Dose | 2025-09 |
| 7 Warnings and Precautions, Respiratory | 2025-09 |
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 ............................................................................................................... 5
6 Dosage Forms, Strengths, Composition, and Packaging .............................................. 6
7 Warnings and Precautions ......................................................................................... 6
7.1 Special Populations ................................................................................................ 8
7.1.1 Pregnancy ........................................................................................................... 8
7.1.2 Breastfeeding ..................................................................................................... 8
7.1.3 Pediatrics ............................................................................................................ 8
7.1.4 Geriatrics ............................................................................................................ 9
8 Adverse Reactions ..................................................................................................... 9
8.1 Adverse Reaction Overview ................................................................................... 9
8.2 Clinical Trial Adverse Reactions ............................................................................. 9
9 DRUG INTERACTIONS .............................................................................................. 10
9.4 Drug-Drug Interactions ........................................................................................ 10
9.5 Drug-Food Interactions ........................................................................................ 11
9.6 Drug-Herb Interactions ........................................................................................ 11
9.7 Drug-Laboratory Test Interactions....................................................................... 12
10 Clinical Pharmacology ............................................................................................. 12
10.1 Mechanism of Action ........................................................................................... 12
10.3 Pharmacokinetics ................................................................................................. 12
11 Storage, Stability and Disposal ................................................................................. 13
Part 2: Scientific Information .............................................................................................. 14
13 Pharmaceutical Information .................................................................................... 14
14 Clinical Trials ........................................................................................................... 14
14.1 Clinical Trials by Indication .................................................................................. 14
15 Microbiology ........................................................................................................... 16
16 Non-Clinical Toxicology ........................................................................................... 16
Patient Medication Information ......................................................................................... 19
Part 1: Healthcare Professional Information
1 Indications
Adults and Children (4 years and older):
VENTOLIN DISKUS (salbutamol sulfate) inhalation powder 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).
- Patients with IgE mediated allergic reactions to lactose (which contains milk protein) or milk.
- 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 DISKUS 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 inhaled salbutamol treatment 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
| Relief of acute Episodes of Bronchospasm* | Prevention of Bronchospasm** | Prevention of Exercise – induced Bronchospasm | Maximum Daily Dose (Total daily dose should not exceed) | |
|---|---|---|---|---|
| Adults and Children (4 years and older) | One Inhalation (200 mcg) as needed. | One Inhalation (200 mcg) every 4 to 6 hours, as needed, to a maximum of three to four times per day. | One Inhalation (200 mcg) 15 minutes before exercise. | Four Inhalations (800 mcg). |
* 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 DISKUS more than twice a week on an “as needed” basis may be at risk for overuse of VENTOLIN DISKUS 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 DISKUS inhalation powder 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 DISKUS inhaler.
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 DISKUS inhalation powder.
| 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
VENTOLIN DISKUS inhalation powder is a disposable blue-coloured plastic inhaler device containing a foil strip with 60 blisters. Each blister contains 200 mcg of salbutamol (as sulfate) as active ingredient.
7 Warnings and Precautions
General
Patients should always carry their VENTOLIN DISKUS inhalation 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 physician should be consulted immediately.
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.
| Route of Administration | Dosage Form / Strength / Composition | Non-medicinal Ingredients |
| Oral Inhalation | Powder for inhalation / 200 mcg / salbutamol | Lactose (which contains milk protein) |
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 with 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 DISKUS inhalation powder 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 DISKUS inhalation powder 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 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 DISKUS 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 DISKUS. 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 DISKUS.
- Deterioration of Asthma
Asthma may deteriorate over time. If the patient needs to use VENTOLIN DISKUS 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 VENTOLIN DISKUS treatment 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 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 DISKUS inhalation powder for relief of bronchospasm during labour should be restricted to those patients in whom the benefits clearly outweigh the risk.
7.1.2 Breastfeeding
It is not known whether salbutamol sulfate is excreted in breast milk after inhalation at recommended doses. Because of the potential for tumorigenicity shown 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 sulfate in breast milk has a harmful effect on the neonate.
7.1.3 Pediatrics
Pediatrics (4 years and older): The application of this inhalation system in children depends on the ability of the individual child to learn the proper use of the inhaler. During inhalation, children should be assisted or supervised by an adult who knows the proper use of the inhaler.
Rarely, in children, hyperactivity occurs and occasionally, sleep disturbances, hallucination or atypical psychosis have been reported.
Pediatrics (< 4 years of age): Safety and efficacy in children below 4 years of age have not been established.
7.1.4 Geriatrics
As with other beta2-agonists, special caution should be observed when using VENTOLIN DISKUS 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.
The adverse reactions to salbutamol are similar in nature to reactions to other sympathomimetic agents, although the incidence of certain cardiovascular effects is lower with salbutamol.
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, vertigo, central nervous system stimulation, hyperactivity in children, unusual taste, drying or irritation of the oropharynx, palpitations, transient muscle cramps, insomnia, 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.
Clinical trials with VENTOLIN DISKUS (salbutamol sulfate) inhalation powder 200 mcg in 268 adolescents and adults and 142 children aged 4 to 11 years demonstrated generally similar adverse event profiles in both patient populations. The most common adverse events were headache and throat irritation. Combined results are shown in the following table:
Table 2 Adverse Experiences With ≥3% Incidence in Two 4-Week Chronic Dosing Studies With Patients 4 Years of Age and Older
| Adverse Experience | Placebo* | VENTOLIN DISKUS* Inhalation Powder 200 mcg four times daily | VENTOLIN Inhalation Aerosol* 200 mcg four times daily |
|---|---|---|---|
| Number of patients | 136 | 139 | 135 |
| Central nervous system | |||
| Headache | 10% | 13% | 9% |
| Gastrointestinal | |||
| Nausea and vomiting | 2% | 4% | 1% |
| General | |||
| Fever | 1% | 3% | 1% |
| Muscle pain | <1% | 3% | 1% |
| Musculoskeletal pain | 1% | 3% | 0 |
| Oropharyngeal | |||
| Throat irritation | 3% | 6% | 3% |
| Respiratory system | |||
| Upper respiratory tract infections | 6% | 6% | 7% |
| Ear, nose, and throat infections | 1% | 0% | 3% |
* Patients in all groups could use VENTOLIN Inhalation Aerosol 100 mcg prn as rescue medication.
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
| Drug type | Ref | Effect | Clinical comment |
| Monoamine oxidase inhibitors or tricyclic antidepressants. | CS | May potentiate action of salbutamol on cardiovascular system. | Salbutamol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants. |
| Other inhaled sympathomimetic bronchodilators or epinephrine. | CS | May lead to deleterious cardiovascular effects. | Other inhaled sympathomimetic bronchodilators or epinephrine should not be used concomitantly with salbutamol sulfate. If additional adrenergic drugs are to be administered by any route to the patient using inhaled salbutamol sulfate, 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. |
| Beta-blockers | CS | May effectively antagonize the action of salbutamol. | Beta-adrenergic blocking drugs, especially the non-cardioselective ones, such as propranolol, should not usually be prescribed together. |
| Diuretics | CS | May lead to ECG changes and/or hypokalemia, although the clinical significance of these effects is not known. | 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. |
| Digoxin | CS | May lead to decrease in serum digoxin levels. The clinical significance of these findings for patients with obstructive airways disease who are receiving salbutamol sulfate and digoxin on a chronic basis is unclear. | 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 salbutamol sulfate. |
Legend: CS = Case Study
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 percent 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.
11 Storage, Stability and Disposal
Keep out of the sight and reach of children. Do not store above 30°C. Keep in a dry place. Protect from frost and light.
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:
Physical Form: White to almost white powder.
Solubility: Soluble in water and slightly soluble in ethanol.
14 Clinical Trials
14.1 Clinical Trials by Indication
In separate 4-week, randomized, double-blind, active and placebo-controlled trials, 142 asthma patients 4 to 11 years of age and 268 asthma patients 12 to 75 years of age were evaluated for the bronchodilator efficacy of VENTOLIN DISKUS (salbutamol sulfate) inhalation powder 200 mcg four times daily (49 pediatric and 90 adolescent/adult patients) in comparison to VENTOLIN (salbutamol sulfate) Inhalation Aerosol 200 mcg four times daily (48 pediatric and 87 adult/adolescent patients) and placebo (45 pediatric and 91 adolescent/adult patients). Thirty-seven percent of pediatric patients and 47% of adolescent/adults were taking concurrent inhaled corticosteroids. On Treatment Day 1 and at Treatment Week 4, serial FEV1 measurements in patients ≥6 years of age (shown below as percent change from test-day baseline at Treatment Week 4) and serial peak expiratory flow rate (PEFR) measurements in patients 4 to 11 years of age demonstrated that one inhalation of VENTOLIN DISKUS inhalation powder produced significantly greater improvement in pulmonary function than placebo. There was no gender- or age-related differences in safety or efficacy of VENTOLIN DISKUS inhalation powder as compared to placebo.
Compared to two inhalations of VENTOLIN Inhalation Aerosol, one inhalation of VENTOLIN DISKUS inhalation powder produced significantly comparable improvements in pulmonary function. In children, VENTOLIN DISKUS inhalation powder appeared to provide slightly better results, while in adolescent /adults, VENTOLIN Inhalation Aerosol appeared to provide slightly better results. Therefore, while
VENTOLIN DISKUS inhalation powder was comparable to VENTOLIN Inhalation Aerosol in clinical studies, it should not be assumed that VENTOLIN Inhalation Aerosol and VENTOLIN DISKUS inhalation powder will produce clinically equivalent outcomes in all patients.
Percent Change From Same Day Baseline in FEV1 From Two 4-Week Clinical Trials in Patients ≥6 Years of Age: Treatment Week 4
In both adolescent /adult and pediatric studies, the majority of patients achieved ≥15% increase in FEV1 (or PEFR) within 15 minutes after inhalation of VENTOLIN DISKUS inhalation powder 200 mcg. Additional analyses were performed on all patients who responded within 30 minutes. For these patients, the median onset of effect ranged from 3 to 3.6 minutes, and the median duration of effect ranged from 2.9 to 4.9 hours. In some patients, duration of effect was as long as 6 hours. Greater than 90% of both adolescent/adult and pediatric patients complied with the dosing instructions of VENTOLIN DISKUS inhalation powder.
Similarly, the majority of patients in both the adolescent/adult and pediatric studies achieved ≥15% increase in FEV1 (or PEFR) within 15 minutes after inhalation of VENTOLIN Inhalation Aerosol 200 mcg. Additional analyses were performed on all patients who responded within 30 minutes. For these patients, the median onset of effect ranged from 3 to 4.2 minutes, and the median duration of effect ranged from 1.7 to 5.8 hours. In some patients, duration of effect was as long as 6 hours.
A single dose crossover trial compared 200 and 400 mcg VENTOLIN DISKUS inhalation powder with 100, 200, and 400 mcg VENTOLIN Inhalation Aerosol and placebo in patients 4 to 11 years of age with asthma. All treatments were significantly better than placebo in improving pulmonary function. Results of serial PEFR testing demonstrated that the peak effect within 30 minutes of dosing, expressed as percent change from test-day baseline, was 23.6% for VENTOLIN DISKUS inhalation powder 200 mcg, compared with 19.9% for VENTOLIN Inhalation Aerosol 200 mcg. In this single dose study, the majority of patients achieved ≥15% increase in PEFR within 30 minutes after inhalation of VENTOLIN DISKUS inhalation powder 200 mcg. For these patients, the median onset of effect was 3.6 minutes, and the median duration of effect was 5 hours. In some patients, duration of effect was as long as 6 hours.
A single dose crossover trial compared VENTOLIN DISKUS inhalation powder 200 mcg with VENTOLIN Inhalation Aerosol 200 mcg and placebo in patients 18 years of age and older with exercise-induced bronchospasm (EIB). Both treatments were comparable and significantly better than placebo in maintaining pulmonary function and protecting against EIB.
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 bypass, 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
| Species (n) | Oral LD50 | Intravenous LD50 |
|---|---|---|
| Mouse (10) | > 2000 mg/kg | 72 mg/kg |
| Rat (10) | > 2000 mg/kg | 60 mg/kg |
| Rat (n) | Intraperitoneal LD50 |
|---|---|
| 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.
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.