Baca Respiclick Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults and Children (4 years and older)

BACA RESPICLICK^TM (salbutamol) inhalation powder is indicated for

• the treatment and/ or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease.
• the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

Geriatrics (> 65 years of age):

There are limited data available on the use of BACA RESPICLICK in patients over 65 years old.

Pediatrics (˂ 4 years of age):

The efficacy and safety of BACA RESPICLICK in children below the age of 4 years has not been established.

CONTRAINDICATIONS

• Patients with known hypersensitivity to salbutamol or to any ingredient in the formulation or component of the container (see DOSAGE FORMS, COMPOSITION AND PACKAGING).
• Patients with severe hypersensitivity to milk protein.
• As a tocolytic in patients at risk of premature labour or threatened abortion.

WARNINGS AND PRECAUTIONS

General

Patients should always carry their BACA RESPICLICK (salbutamol) 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, healthcare professionals should be consulted immediately.

Excessive Use and Use with other Sympathomimetic

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.

DO NOT EXCEED RECOMMENDED DOSE.

Concomitant use of BACA RESPICLICK with other sympathomimetic agents is not recommended since the combined use may lead to deleterious cardiovascular effects. If concomitant use is necessary, this should take place only under strict medical supervision.

Use of Anti-Inflammatory Agents

The use of beta-adrenergic-agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.

Cardiovascular

Like other beta-adrenergic agonists, BACA RESPICLICK can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with beta agonists. 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. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST-segment depression. Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin. Cardiac arrest was noticed in several instances.

Endocrine and Metabolism

As with other beta-agonists, BACA RESPICLICK may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. 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.

BACA RESPICLICK, like all sympathomimetic amines, should be used with caution in patients with hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous salbutamol have been reported to aggravate preexisting diabetes mellitus and lead to the development of ketoacidosis. Concurrent administration of corticosteroids can exaggerate this effect.

Hypersensitivity Reactions

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

BACA RESPICLICK contains small amounts of lactose, which may contain trace levels of milk proteins. Hypersensitivity reactions including anaphylaxis, angioedema, pruritus, and rash have been reported with the use of therapies containing lactose. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving BACA RESPICLICK.

Neurologic

Care should be taken with patients with convulsive disorders.

Respiratory

Deterioration of Asthma

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of BACA RESPICLICK than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

Paradoxical Bronchospasm

As with other inhaled medications, paradoxical bronchospasm may occur that may be life threatening. If paradoxical bronchospasm occurs, characterized by an immediate increase in wheezing after dosing, BACA RESPICLICK should be discontinued immediately and alternative therapy instituted e.g. a different fast-acting inhaled bronchodilator to relieve acute asthmatic symptoms.

Special Populations

Pregnant Women: There are no adequate and well-controlled studies of BACA RESPICLICK or salbutamol sulphate in pregnant women. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity (see Toxicology, Teratogenicity studies). Seven patients became pregnant during clinical trials, including 5 patients treated with drug and 2 patients treated with placebo. One patient treated with placebo had a miscarriage.

Post-Marketing Experience in Pregnant Women: Human data are available from voluntary safety reporting during worldwide marketing experience. However, because these reactions are reported voluntarily from a population of unknown size; it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

During post marketing experience, various structural abnormalities, including cleft palate and limb defects, have been reported in the offspring of patients treated with salbutamol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of structural abnormalities can be discerned, and no relationship between salbutamol use and congenital anomalies has been established.

Since the data are insufficient to determine if there is any added risk to the fetus from salbutamol, BACA RESPICLICK should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor or Delivery: Because of the potential for beta-agonist interference with uterine contractility, use of BACA RESPICLICK for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

BACA RESPICLICK is contraindicated for the management of pre-term labour. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labour with beta₂-agonists, including salbutamol.

Nursing Women: It is not known whether salbutamol sulphate is excreted in human milk. There are no available data to assess the presence or absence of salbutamol in human milk, effects on the breast-fed child, or the effect of salbutamol on milk production. 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 drugs 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.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for salbutamol and any potential adverse effects on the breastfed child from salbutamol or from the underlying maternal condition.

Pediatrics (˂ 4 years of age):

The safety and effectiveness of BACA RESPICLICK in pediatric patients below the age of 4 years have not been established.

Geriatrics (> 65 years of age):

Clinical studies of BACA RESPICLICK did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. As with other beta₂-agonists, special caution should be observed when using BACA Respiclick in elderly patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug (see WARNINGS and PRECAUTIONS, CARDIOVASCULAR).

All beta₂-adrenergic agonists, including salbutamol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Monitoring and Laboratory Tests

Monitoring Control of Asthma

Failure to respond for at least three hours to a previously effective dose of BACA Respiclick indicates a deterioration of the condition and the physician should be contacted promptly. Patients should be warned not to exceed the recommended dose.

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. 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 doctor should be consulted immediately. Sudden or progressive deterioration in asthma control is potentially life threatening; the treatment plan must be re-evaluated, and consideration be given to corticosteroid therapy (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

Adverse Drug 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 WARNINGS and PRECAUTIONS, Endocrine and Metabolism).

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 stimulants. 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.

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

A total of 1289 subjects were treated with BACA RESPICLICK (salbutamol) during the clinical development program. The most common adverse reactions (≥1%) were back pain, pain, gastroenteritis viral, sinus headache, and urinary tract infection.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adults and Adolescents 12 years of Age and Older:

A total of 1456 adult and adolescents patients were included in the clinical program of whom 1120 received treatment with salbutamol.

The safety data described below for BACA RESPICLICK in adults and adolescents 12 years of age and older is derived from the 12-week double blind placebo-controlled trials which compared BACA RESPICLICK 194 mcg administered four times daily with a double-blinded matched placebo in 653 asthmatic patients 12 to 76 years of age. Table 1 displays the adverse reactions with an incidence ≥ 1% in BACA RESPICLICK treated patients and greater than placebo-treated patients.

Table 1: Adverse Reactions Experienced by ≥1.0% of Adult and Adolescent Patients in the

BACA RESPICLICK Group and Greater Than Placebo in three 12-Week Clinical Trials^*

*All adverse events (whether considered by the investigator drug related or unrelated to drug) which occurred at an incidence rate of greater than or equal to 1.0% in the BACA RESPICLICK group and greater than placebo.

In a long-term study of 168 patients treated with BACA RESPICLICK for up to 52 weeks (including a 12-week double-blind period), the most commonly reported adverse events greater than or equal to 5% were upper respiratory infection, nasopharyngitis, sinusitis, bronchitis, cough, oropharyngeal pain, headache, and pyrexia.

In a small cumulative dose study, tremor, palpitations, and headache were the most frequently occurring (≥5%) adverse events.

Pediatric Patients Aged 4 to 11 Years:

The safety data for BACA RESPICLICK in pediatric patients 4 to 11 years of age is derived from the double-blind placebo controlled trial of 3 weeks which compared BACA RESPICLICK 194 mcg administered 4 times daily with a double blinded matched placebo in 185 asthmatic patients.

Table 2: Adverse Reactions Experienced by ≥2.0% of Patients 4 to 11 Years of Age in the

BACA RESPICLICK Group and Greater Than Placebo in the 3 Week Trial

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Cardiac disorders: Palpitations

Gastrointestinal disorders: Dry mouth

General disorders and administration site conditions: Feeling jittery

Nervous system disorders: Headache, migraine and tremor

Respiratory, thoracic, and mediastinal disorders: Dysphonia and oropharyngeal pain.

Post-Market Adverse Drug Reactions

The following adverse events have been reported during postapproval use of salbutamol products: urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), rare cases of aggravated bronchospasm, muscle cramps, and various oropharyngeal side-effects such as throat irritation, altered taste. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In addition, salbutamol, like other sympathomimetic agents, can cause adverse reactions such as: angina, hypertension or hypotension, palpitations, central nervous system stimulation, insomnia, headache, nervousness, tremor, muscle cramps, drying or irritation of the oropharynx, hypokalemia, hyperglycemia, and metabolic acidosis.

DRUG INTERACTIONS

Drug-Drug Interactions

Table 3 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

BACA RESPICLICK (salbutamol) inhalation powder is not recommended for children under 4 years of age.

The dosage for BACA RESPICLICK should be individualized and the patient’s response should be monitored by a prescribing physician on an ongoing basis.

Increasing demand for inhaled salbutamol in bronchial asthma is usually a sign of poorly controlled or worsening asthma and indicates that the patient should be reevaluated and the treatment plan should be reviewed. If inhaled salbutamol treatment alone is not adequate to control asthma, concomitant anti-inflammatory therapy should be part of the treatment regimen (e.g., corticosteroids).

If a previously effective dose fails to provide the usual relief or the effects of a dose last for less than three hours, patients should seek prompt medical advice since this is usually a sign of worsening asthma.

As there may be adverse effects associated with excessive dosing, the dosage or frequency of administration should only be increased on medical advice. However, if a more severe attack has not been relieved by the usual dose, additional doses may be required. In these cases, patients should immediately consult their doctors or the nearest hospital.

Recommended Dose and Dosage Adjustment

Bronchospasm:

For treatment of acute episodes of bronchospasm or prevention of symptoms associated with bronchospasm, the recommended dosage for adults and children 4 years of age or older is 2 inhalations (2 x 97 mcg) repeated every 4 to 6 hours. More frequent administration or a larger number of inhalations is not recommended. In some patients, 1 inhalation (97 mcg) every 4 hours may be sufficient.

Maximum daily dose: 776 mcg, equivalent to 8 inhalations.

Exercise-Induced Bronchospasm:

For prevention of exercise-induced bronchospasm, the recommended dosage for adults and children 4 years of age or older is 2 inhalations (2 x 97 mcg) 15 to 30 minutes before exercise. Maximum daily dose: 776 mcg, equivalent to 8 inhalations.

Missed Dose

If a single dose is missed, instruct the patient to take the next dose when it is due or if they become wheezy.

Administration

BACA RESPICLICK should be administered by the orally inhaled route only in patients aged 4 years and older.

The healthcare professional should instruct the patient as per the following points:

• BACA RESPICLICK does not require priming.
• Do not use BACA RESPICLICK with a spacer or volume holding chamber.

• Do not open your BACA RESPICLICK cap unless you are taking your medication.

  Repeated opening and closing the green cap without taking medication will waste medication and may damage the inhaler.

• Immediately replace inhaler if mouthpiece cover is damaged or broken.

• Counter: The BACA RESPICLICK inhaler has a counter.

  o

Patients should never try to alter the numbers for the counter.

o

13 months after opening the foil pouch, when the counter displays 0 or after the expiration date on the product,

• Cleaning:

  o

o

OVERDOSAGE

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

Symptoms and Signs

The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g. seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia.

Hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of BACA RESPICLICK.

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.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma (See Warnings and Precautions).

Treatment

Discontinue BACA RESPICLICK treatment and consider administration of appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of BACA RESPICLICK.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Salbutamol is a beta₂-adrenergic agonist. It acts as a functional antagonist to relax the smooth muscle of all airways, from the trachea to the terminal bronchioles, irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges.

The pharmacologic effects of salbutamol are attributable to activation of beta₂-adrenergic receptors on airway smooth muscle. Activation of beta₂-adrenergic receptors leads to the activation of adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3’,5’ adenosine monophosphate (cyclic AMP). This increase of cyclic AMP is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

While it is recognized that beta₂-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta₂-adrenergic receptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta₂-agonists may have cardiac effects.

Salbutamol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than the non-selective β₁- β₂–agonist isoproterenol at comparable doses while producing fewer cardiovascular effects. However, inhaled salbutamol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

Pharmacodynamics

Primary Pharmacodynamics: Following 97 or 194 mcg single-dose inhalation, the bronchodilatory effect of BACA RESPICLICK was significantly greater than placebo in patients 12 years of age and older (N=71) and pediatric patients 4 to 11 years of age (N=61) with persistent asthma.

Secondary Pharmacodynamics: As with other beta₂-adrenergic agonists, BACA RESPICLICK prolonged QT intervals following a 1552 mcg cumulative dose.

Pharmacokinetics

Absorption: Salbutamol was rapidly absorbed into the systemic circulation with peak plasma concentrations occurring at half an hour following single- or multiple-dose oral inhalation(s) of BACA RESPICLICK.

Distribution: The volume of distribution has not been determined for BACA RESPICLICK. Published literature suggests that salbutamol exhibits low in vitro plasma protein binding (10%).

Metabolism: Information available in the published literature suggests that the primary enzyme responsible for the metabolism of salbutamol in humans is SULTIA3 (sulfotransferase). When racemic salbutamol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-salbutamol enantiomers, with (S)-salbutamol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)-salbutamol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3. Elimination: The accumulation ratio (~1.6 fold) was observed following one week QID dosing. The corresponding effective half-life was approximately 5 hours, which was consistent with the elimination half-life following both single- or multiple-dose administration.

Excretion: The primary route of elimination of salbutamol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic salbutamol, between 25% and 46% of the (R)-salbutamol fraction of the dose was excreted as unchanged (R)-salbutamol in the urine.

Special Populations and Conditions

Age: No pharmacokinetic studies for BACA RESPICLICK have been conducted in neonates or elderly subjects. The systemic exposure in children 6 to 11 years of age is similar to that of adults following 194 mcg single dose inhalation of BACA RESPICLICK.

Sex: The influence of sex on the pharmacokinetics of BACA RESPICLICK has not been studied.

Race: The influence of race on the pharmacokinetics of BACA RESPICLICK has not been studied.

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of BACA RESPICLICK has not been evaluated.

Renal Insufficiency: The effect of renal impairment on the pharmacokinetics of salbutamol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in salbutamol clearance. Caution should be used when administering high doses of BACA RESPICLICK to patients with renal impairment.

STORAGE AND STABILITY

Store at room temperature between 15° and 30°C. Avoid exposure to extreme heat, cold, or humidity.

Keep out of reach and sight of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

BACA RESPICLICK is an inhalation driven dry powder inhaler for oral inhalation that contains a formulation of salbutamol sulphate and lactose monohydrate. Each inhaler contains 0.65 g of the formulation and provides 200 actuations.

Each actuation provides 117 mcg of salbutamol sulphate (equivalent to 97 mcg of salbutamol base) delivered ex valve, equal to 108 mcg of salbutamol sulphate (90 mcg of salbutamol base) delivered from the mouthpiece.

Each inhaler has a red cap and is packaged individually in a foil pouch in a carton. The inhaler has a counter.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Salbutamol Sulphate

Chemical name: Bis[1RS]-2-[1,1-dimethylethyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanol]sulphate

or

1,3-benzenedimethanol, α1-[[1,1-dimethylethyl)amino]methyl]-4-hydroxy-, sulphate (2:1) salt

or

α1-[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α, α’-diol sulphate (2:1) salt [Module 3, Section 3.2.S.1.1 Nomenclature]

Molecular formula and molecular mass: (C₁₃H₂₁NO₃)₂ . H₂SO₄ / 576.7 g/mol

Structural formula:

Physicochemical properties: A white or almost white crystalline powder. Freely soluble in water, practically insoluble or very slightly soluble in Methylene Chloride and Alcohol, slightly soluble in Chloroform and Ether. Does not show optical activity, as it is a racemic drug substance.

CLINICAL TRIALS

Bronchospasm Associated with Asthma

Adult and Adolescent Patients 12 Years of Age and Older

Patient Demographics and Trial design

The efficacy and safety of BACA RESPICLICK have been evaluated in two 12-week, randomized, double-blind, placebo-controlled studies of identical design (Study 1 and Study 2). BACA RESPICLICK (153 patients) was compared to a matched placebo dry powder inhaler (163 patients) in asthmatic patients 12 to 76 years of age at a dose of 194 mcg salbutamol four times daily (Table 4). Patients were maintained on inhaled corticosteroid treatment.

Table 4 - Summary of the Design and Patient Demographics of Studies 1 and 2 in Adults and Adolescents Patients with Bronchospasm (FAS)

Study results:

The primary efficacy variable was the baseline-adjusted FEV₁ AUC_0-6hr over the 12-week treatment period. In both studies, there was a statistically significant difference from placebo (See Tables 5 and 6).

Table 5: Phase 3 Studies 1 and 2: Baseline-Adjusted FEV₁ AUC_0-6hr (L*Hour) over the

12‑Week Treatment Period (FAS)

FEV₁ AUC_0‑6hr=baseline‑adjusted area under the FEV₁ (forced expiratory volume in 1 second) curve over 6 hours; FAS=Full analysis set; SB MDPI=Salbutamol Multidose Dry Powder Inhaler; QID=4 times a day; N=number of patients included in the FAS; n=number of patients included in the analysis.

Table 6: Phase 3 Studies 1 and 2: FEV₁ AUC_0-6hr (L*Hour) Difference between

Salbutamol MDPI versus Placebo Over the 12‑Week Treatment Period (FAS)

FEV₁ AUC_0‑6hr=baseline‑adjusted area under the FEV₁ (forced expiratory volume in 1 second) curve over 6 hours; FAS=Full analysis set; MDPI=Multidose Dry Powder Inhaler; QID=4 times a day.

Serial FEV₁ measurements, as shown in Figures 1 and 2, demonstrated that two inhalations of BACA RESPICLICK produced significantly greater improvement in FEV₁ AUC_0-6hr over the pre-treatment value than placebo in Study 1. Consistent results were observed in Study 2.

Figure 1. Mean Day 1 Change from Baseline FEV₁ by Treatment and Time point (Study 1-Full Analysis Set)

Figure 2: Mean Day 85 Change from Baseline FEV₁ by Treatment and Time point (Study 1-Full Analysis Set)

In Study 1, 44 of 78 patients treated with BACA RESPICLICK achieved a 15% increase in FEV₁ within 30 minutes post-dose on Day 1. The median time to onset was 5.7 minutes, and median duration of effect as measured by a 15% increase was approximately 2 hours. Consistent results were observed in Study 2.

The secondary endpoints in Study 1 and 2 were FEV₁ AUC_0-6hr on days 1, 8 and 85 demonstrated the bronchodilatory effect of BACA RESPICLICK was largely maintained during the 12 week treatment period.

Pediatric Patients 4 to 11 Years of Age

In a 3-week, randomized, double-blind, placebo-controlled trial, BACA RESPICLICK (92 patients) was compared to a matched placebo (92 patients) in asthmatic children 4 to 11 years of age at a dose of 194 mcg salbutamol four times daily. Serial FEV₁ measurements, expressed as the baseline-adjusted percent-predicted FEV₁ AUC_0-6h over the 3-week treatment period, demonstrated that 2 inhalations of BACA RESPICLICK produced significantly greater improvement in FEV₁ over the pre-treatment value than the matched placebo.

In this study, 48 of 92 patients treated with BACA RESPICLICK achieved a 15% increase in FEV₁ within 30 minutes post-dose on Day 1. The median time to onset was 5.9 minutes, and the median duration of effect as measured by a 15% increase was approximately 1 hour.

Exercise-Induced Bronchospasm

In a randomized, single-dose, crossover study in 38 adult and adolescent patients with exercise-induced bronchospasm (EIB), two inhalations of BACA RESPICLICK taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as the maintenance of FEV₁ within 80% of post-dose, pre-exercise baseline values) in 97% (37 of 38) of patients as compared to 42% (16 of 38) of patients when they received placebo.

Patients who participated in these clinical trials were allowed to use concomitant steroid therapy.

DETAILED PHARMACOLOGY

Intravenous studies in rats with salbutamol sulphate have demonstrated that salbutamol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), salbutamol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when β‑agonists and methylxanthines were administered concurrently. The clinical significance of these findings is unknown.

TOXICOLOGY

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 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 sulphate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at doses corresponding to 111, 555, and

2,800 times the maximum human inhalation dose. In another study, the effect was blocked by the co-administration of propranolol. The relevance of these findings to humans is not known. An 18-month study in mice and a lifetime study in hamsters revealed no evidence of tumorigenicity.

Teratogenicity

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.

REFERENCES

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2. 2. Salbutamol: A review. Drugs 1971; 4:274-302.
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4. 4. US-FDA Prescribing Information ProAir Respiclick dated September 2016.
5. 5.

   Health Canada Product Monograph NOVO-SALBUTAMOL HFA dated 22 September

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