The active ingredient of PROAIR HFA (albuterol sulfate) Inhalation Aerosol is albuterol sulfate, a racemic salt, of albuterol. Albuterol sulfate has the chemical name α¹­[( tert-butylamino) methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate (2:1) (salt), and has the following chemical structure:

The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C₁₃H₂₁NO₃)_2•H₂SO₄. Albuterol sulfate is a white to off-white crystalline powder. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate is the official generic name in the United States, and salbutamol sulfate is the World Health Organization recommended generic name. PROAIR HFA Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline suspension of albuterol sulfate in propellant HFA-134a (1, 1, 1, 2-tetrafluoroethane) and ethanol.

Prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing three sprays into the air, away from the face. After priming, each actuation delivers 108 mcg albuterol sulfate, from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). Each canister provides 200 actuations (inhalations).

This product does not contain chlorofluorocarbons (CFCs) as the propellant.

Bronchospasm

PROAIR HFA Inhalation Aerosol is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease.

Exercise-Induced Bronchospasm

PROAIR HFA Inhalation Aerosol is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

Bronchospasm

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

Exercise-Induced Bronchospasm

The usual dosage for adults and children 4 years of age or older is two inhalations 15 to 30 minutes before exercise.

Administration Information

Administer PROAIR HFA by oral inhalation only. Shake well before each spray. To maintain proper use of this product and to prevent medication build-up and blockage, it is important to follow the cleaning directions carefully.

Priming: Prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing three sprays into the air, away from the face.

Cleaning: As with all HFA-containing albuterol inhalers, to maintain proper use of this product and to prevent medication build-up and blockage, it is important to keep the plastic mouthpiece clean. The inhaler may cease to deliver medication if the plastic actuator mouthpiece is not properly cleaned and dried. To clean: Wash the plastic mouthpiece with warm running water for 30 seconds, shake off excess water, and air dry thoroughly at least once a week. If the mouthpiece becomes blocked, washing the mouthpiece will remove the blockage. If it is necessary to use the inhaler before it is completely dry, shake off excess water, replace canister, spray twice into the air away from face, and take the prescribed dose. After such use, the mouthpiece should be rewashed and allowed to air dry thoroughly. [see Patient Counseling Information].

Dosage Forms & Strengths

PROAIR HFA is an inhalation aerosol. PROAIR HFA is supplied as an 8.5 g/200 actuations pressurized aluminum canister with a red plastic actuator and white dust cap each in boxes of one. Each actuation delivers 120 mcg of albuterol sulfate from the canister valve and 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base).

Storage & Handling

PROAIR HFA (albuterol sulfate) Inhalation Aerosol is supplied as a pressurized aluminum canister with a red plastic actuator and white dust cap each in boxes of one. Each canister contains 8.5 g of the formulation and provides 200 actuations (NDC 59310579-20). Each actuation delivers 120 mcg of albuterol sulfate from the canister valve and 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base).

SHAKE WELL BEFORE USE. Store between 15° and 25°C (59° and 77°F). Contents under pressure. Do not puncture or incinerate. Protect from freezing temperatures and prolonged exposure to direct sunlight. Exposure to temperatures above 120oF may cause bursting. For best results, canister should be at room temperature before use. Avoid spraying in eyes. Keep out of reach of children.

See FDA-Approved Patient Labeling for priming and cleaning instructions.

The red actuator supplied with PROAIR HFA Inhalation Aerosol should not be used with the canister from any other inhalation aerosol products. The PROAIR HFA Inhalation Aerosol canister should not be used with the actuator from any other inhalation aerosol products.

The labeled amount of medication in each actuation cannot be assured after 200 actuations, even though the canister may not be completely empty. Discard the inhaler (canister plus actuator) after 200 actuations have been used. Never immerse the canister into water to determine how full the canister is (“float test”).

PROAIR HFA Inhalation Aerosol does not contain chlorofluorocarbons (CFCs) as the propellant.

Mktd by: Teva Specialty Pharmaceuticals LLC, Horsham, PA 19044. Mfd by: IVAX Pharmaceuticals Ireland, Waterford, Ireland. FDA revision date: 9/16/2008

Use of PROAIR HFA may be associated with the following:

• Paradoxical bronchospasm [see WARNINGS AND PRECAUTIONS]
• Cardiovascular Effects [see WARNINGS AND PRECAUTIONS]
• Immediate hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
• Hypokalemia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

A total of 1090 subjects were treated with PROAIR HFA Inhalation Aerosol, or with the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol, during the worldwide clinical development program.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult and Adolescents 12 Years of Age and Older: The adverse reaction information presented in the table below concerning PROAIR HFA Inhalation Aerosol is derived from a 6-week, blinded study which compared PROAIR HFA Inhalation Aerosol (180 mcg four times daily) with a double-blinded matched placebo HFA-Inhalation Aerosol and an evaluator-blinded marketed active comparator HFA-134a albuterol inhaler in 172 asthmatic patients 12 to 76 years of age. The table lists the incidence of all adverse events (whether considered by the investigator drug related or unrelated to drug) from this study which occurred at a rate of 3% or greater in the PROAIR HFA Inhalation Aerosol treatment group and more frequently in the PROAIR HFA Inhalation Aerosol treatment group than in the matched placebo group. Overall, the incidence and nature of the adverse events reported for PROAIR HFA Inhalation Aerosol and the marketed active comparator HFA-134a albuterol inhaler were comparable.

Adverse Experience Incidences (% of Patients) in a Six-Week Clinical Trial*

Adverse events reported by less than 3% of the patients receiving PROAIR HFA Inhalation Aerosol but by a greater proportion of PROAIR HFA Inhalation Aerosol patients than the matched placebo patients, which have the potential to be related to PROAIR HFA Inhalation Aerosol, included chest pain, infection, diarrhea, glossitis, accidental injury (nervous system), anxiety, dyspnea, ear disorder, ear pain, and urinary tract infection.

In small cumulative dose studies, tremor, nervousness, and headache were the most frequently occurring adverse events.

Pediatric Patients 4 to 11 Years of Age: Adverse events reported in a 3-week pediatric clinical trial comparing the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol (180 mcg albuterol four times daily) to a matching placebo HFA inhalation aerosol occurred at a low incidence rate (no greater than 2% in the active treatment group) and were similar to those seen in adult and adolescent trials.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of PROAIR HFA. 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. Reports have included rare cases of aggravated bronchospasm, lack of efficacy, asthma exacerbation (reported fatal in one case), muscle cramps, and various oropharyngeal side-effects such as throat irritation, altered taste, glossitis, tongue ulceration, and gagging.

The following adverse events have been observed in postapproval use of inhaled albuterol: urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles). In addition, albuterol, 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.

Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with PROAIR HFA Inhalation Aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

Beta-Blockers

Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as PROAIR HFA Inhalation Aerosol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta­adrenergic-blocking agents in patients with asthma. In this setting, consider cardioselective beta-blockers, although they should be administered with caution.

Diuretics

The ECG changes and/or hypokalemia which 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. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium sparing diuretics. Consider monitoring potassium levels.

Digoxin

Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and PROAIR HFA Inhalation Aerosol.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

PROAIR HFA Inhalation Aerosol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the cardiovascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

Included as part of the PRECAUTIONS section.

Paradoxical Bronchospasm

PROAIR HFA Inhalation Aerosol can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, PROAIR HFA Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister.

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 PROAIR HFA Inhalation Aerosol 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 antiinflammatory treatment, e.g., corticosteroids.

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 antiinflammatory agents, e.g., corticosteroids, to the therapeutic regimen.

Cardiovascular Effects

PROAIR HFA Inhalation Aerosol, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of PROAIR HFA Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. 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. The clinical significance of these findings is unknown. Therefore, PROAIR HFA Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Do Not Exceed Recommended Dose

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.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of albuterol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving PROAIR HFA Inhalation Aerosol.

Coexisting Conditions

PROAIR HFA Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia

As with other beta-agonists, PROAIR HFA Inhalation Aerosol 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.

Patient Counseling Information

See FDA-Approved Patient Labeling

Patients should be given the following information:

Frequency of Use

The action of PROAIR HFA Inhalation Aerosol should last for 4 to 6 hours. Do not use PROAIR HFA Inhalation Aerosol more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of PROAIR HFA Inhalation Aerosol without consulting the physician. If patients find that treatment with PROAIR HFA Inhalation Aerosol becomes less effective for symptomatic relief, symptoms become worse, and/or they need to use the product more frequently than usual, they should seek medical attention immediately.

Priming and Cleaning

Priming: Priming is essential to ensure appropriate albuterol content in each actuation. Instruct patients to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing three sprays into the air, away from the face.

Cleaning: To ensure proper dosing and prevent actuator orifice blockage, instruct patients to wash the red plastic actuator mouthpiece and dry thoroughly at least once a week. Detailed cleaning instructions are included in the illustrated Information for the Patient leaflet.

Paradoxical Bronchospasm

Inform patients that ProAir HFA Inhalation Aerosol can produce paradoxical bronchospasm. Instruct patients to discontinue ProAir HFA Inhalation Aerosol if paradoxical bronchospasm occurs.

Concomitant Drug Use

While patients are taking PROAIR HFA Inhalation Aerosol, other inhaled drugs and asthma medications should be taken only as directed by a physician.

Common Adverse Events

Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Pregnancy

Patients who are pregnant or nursing should contact their physician about the use of PROAIR HFA Inhalation Aerosol.

General Information on Use

Effective and safe use of PROAIR HFA Inhalation Aerosol includes an understanding of the way that it should be administered.

Shake well before each spray.

Use PROAIR HFA Inhalation Aerosol only with the actuator supplied with the product. Discard the canister after 200 sprays have been used. Never immerse the canister in water to determine how full the canister is (“float test”).

In general, the technique for administering PROAIR HFA Inhalation Aerosol to children is similar to that for adults. Children should use PROAIR HFA Inhalation Aerosol under adult supervision, as instructed by the patient's physician.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately 15 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 6 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg (approximately 1,600 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 740 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In a 22-month study in Golden Hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 210 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 100 times the maximum recommended daily inhalation dose for children on a mg/m² basis).

Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1strain mouse micronucleus assay.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 310 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects: Pregnancy Category C:

There are no adequate and well-controlled studies of PROAIR HFA Inhalation Aerosol or albuterol sulfate in pregnant women. During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity. PROAIR HFA Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately eight-tenths of the maximum recommended human dose (MRHD) for adults on a mg/m² basis and in 10 of 108 (9.3%) fetuses at approximately 8 times the MRHD. Similar effects were not observed at approximately one-thirteenth of the MRHD. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).

In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 630 times the MRHD.

In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 65 times the MRHD [see Nonclinical Toxicology].

Labor and Delivery

Because of the potential for beta-agonist interference with uterine contractility, use of PROAIR HFA Inhalation Aerosol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.PROAIR HFA Inhalation Aerosol has not been approved for the management of pre-term labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta₂-agonists, including albuterol.

Nursing Mothers

Plasma levels of albuterol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components of PROAIR HFA Inhalation Aerosol are excreted in human milk.

Caution should be exercised when PROAIR HFA Inhalation Aerosol is administered to a nursing woman. Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of PROAIR HFA Inhalation Aerosol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of PROAIR HFA Inhalation Aerosol for the treatment or prevention of bronchospasm in children 12 years of age and older with reversible obstructive airway disease is based on one 6-week clinical trial in 116 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, and one single-dose crossover study comparing doses of 90, 180, and 270 mcg with placebo in 58 patients [see Clinical Studies]. The safety and effectiveness of PROAIR HFA Inhalation Aerosol for treatment of exercise-induced bronchospasm in children 12 years of age and older is based on one single-dose crossover study in 24 adults and adolescents with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see Clinical Studies].

The safety of PROAIR HFA Inhalation Aerosol in children 4 to 11 years of age is based on one 3-week clinical trial in 50 patients 4 to 11 years of age with asthma using the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol comparing doses of 180 mcg four times daily with placebo. The effectiveness of PROAIR HFA Inhalation Aerosol in children 4 to 11 years of age is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of PROAIR HFA 90 mcg and 180 mcg with placebo in 55 patients with asthma and a 3-week clinical trial using the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol in 95 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol four times daily with placebo [see Clinical Studies].

The safety and effectiveness of PROAIR HFA Inhalation Aerosol in pediatric patients below the age of 4 years have not been established.

Geriatric Use

Clinical studies of PROAIR HFA Inhalation Aerosol 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, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see WARNINGS AND PRECAUTIONS].

All beta₂-adrenergic agonists, including albuterol, 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.

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 PROAIR HFA Inhalation Aerosol.

Treatment consists of discontinuation of PROAIR HFA Inhalation Aerosol together with 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 PROAIR HFA Inhalation Aerosol.

The oral median lethal dose of albuterol sulfate in mice is greater than 2,000 mg/kg (approximately 6,800 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 3,200 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3,000 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 1,400 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In young rats, the subcutaneous median lethal dose is approximately 2,000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 6,400 times the maximum recommended daily inhalation dose for children on a mg/m² basis). The inhalation median lethal dose has not been determined in animals.

PROAIR HFA Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol and any other PROAIR HFA Inhalation Aerosol components. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate [see WARNINGS AND PRECAUTIONS].

Mechanism of Action

Albuterol sulfate is a beta₂-adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta2-adrenergic receptors on airway smooth muscle. Activation of beta2-adrenergic receptors leads to the activation of adenylcyclase 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. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. 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 predominantreceptors 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 [see WARNINGS AND PRECAUTIONS].

Albuterol 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 isoproterenol at comparable doses while producing fewer cardiovascular effects. However, inhaled albuterol, 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 [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

The systemic levels of albuterol are low after inhalation of recommended doses. In a crossover study conducted in healthy male and female volunteers, high cumulative doses of PROAIR HFA Inhalation Aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak plasma concentrations (Cmax) and systemic exposure (AUCinf) of approximately 4,100 pg/mL and 28,426 pg/mL*hr, respectively compared to approximately 3,900 pg/mL and 28,395 pg/mL*hr, respectively following the same dose of an active HFA-134a albuterol inhaler comparator. The terminal plasma half-life of albuterol delivered by PROAIR HFA Inhalation Aerosol was approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences between the products.

The pharmacokinetic profile of PROAIR HFA Inhalation Aerosol was evaluated in a two-way cross-over study in 11 healthy pediatric volunteers, 4 to 11 years of age. A single dose administration of PROAIR HFA Inhalation Aerosol (180 mcg albuterol base) yielded a least square mean (SE) Cmax and AUC_0-∞ of 1,100 (1.18) pg/mL and 5,120 (1.15) pg/mL*hr, respectively. The least square mean (SE) terminal plasma half-life of albuterol delivered by PROAIR HFA Inhalation Aerosol was 166 (7.8) minutes.

Metabolism and Elimination: Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol 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)-albuterol enantiomers, with (S)-albuterol 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)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3.

The primary route of elimination of albuterol 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 albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)­albuterol in the urine.

Geriatric, Pediatric, Hepatic/Renal Impairment: No pharmacokinetic studies for PROAIR HFA Inhalation Aerosol have been conducted in neonates or elderly subjects.

The effect of hepatic impairment on the pharmacokinetics of PROAIR HFA Inhalation Aerosol has not been evaluated.

The effect of renal impairment on the pharmacokinetics of albuterol 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 albuterol clearance. Caution should be used when administering high doses of PROAIR HFA Inhalation Aerosol to patients with renal impairment [see Use in Special Populations].

Animal Toxicology and/or Pharmacology

Preclinical: Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol 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), albuterol 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.

Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (380 - 1300 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 chlorofluorocarbons (CFCs), which have been used extensively in metered-dose inhalers.

In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 - 27 minutes in animals and 5 - 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

Reproductive Toxicology Studies: A study in CD-1 mice given albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). The drug did not induce cleft palate formation at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg of isoproterenol (positive control).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 fetuses (37%) when albuterol sulfate was administered orally at 50 mg/kg (approximately 630 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

In an inhalation reproduction study in Sprague-Dawley rats, the albuterol sulfate/HFA-134a did not exhibit any teratogenic effects at 10.5 mg/kg (approximately 65 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

Clinical Studies

Bronchospasm Associated with Asthma

Adult and Adolescent Patients 12 Years of Age and Older: In a 6-week, randomized, double-blind, placebo-controlled trial, PROAIR HFA Inhalation Aerosol (58 patients) was compared to a matched placebo HFA inhalation aerosol (58 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. An evaluator-blind marketed active comparator HFA-134a albuterol inhaler arm (56 patients) was included.

Serial FEV₁ measurements, shown below as percent change from test-day baseline at Day 1 and at Day 43, demonstrated that two inhalations of PROAIR HFA Inhalation Aerosol produced significantly greater improvement in FEV₁ over the pre-treatment value than the matched placebo, as well as a comparable bronchodilator effect to the marketed active comparator HFA-134a albuterol inhaler.

FEV1 as Mean Percent Change from Test-Day Pre-Dose in a 6-Week Clinical Trial Day 1

Day 43

In this study, 31 of 58 patients treated with PROAIR HFA Inhalation Aerosol achieved a 15% increase in FEV₁ within 30 minutes post-dose on Day 1. In these patients, the median time to onset, median time to peak effect, and median duration of effect were 8.2 minutes, 47 minutes, and approximately 3 hours, respectively. In some patients, the duration of effect was as long as 6 hours.

In a placebo-controlled, single-dose, crossover study, PROAIR HFA Inhalation Aerosol, administered at albuterol doses of 90, 180 and 270 mcg, produced bronchodilator responses significantly greater than those observed with a matched placebo HFA inhalation aerosol and comparable to a marketed active comparator HFA-134a albuterol inhaler.

Pediatric Patients 4 to 11 Years of Age: In a 3-week, randomized, double-blind, placebo-controlled trial, the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol (50 patients) was compared to a matched placebo HFA inhalation aerosol (45 patients) in asthmatic children 4 to 11 years of age at a dose of 180 mcg albuterol four times daily. Serial FEV₁ measurements, expressed as the maximum percent change from testday baseline in percent predicted FEV₁ at Day 1 and at Day 22 observed within two hours postdose, demonstrated that two inhalations of HFA albuterol sulfate produced significantly greater improvement in FEV₁ over the pre-treatment value than the matched placebo.

In this study, 21 of 50 pediatric patients treated with the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol achieved a 15% increase in FEV₁ within 30 minutes post-dose on Day 1. In these patients, the median time to onset, median time to peak effect and median duration of effect were 10 minutes, 31 minutes, and approximately 4 hours, respectively. In some pediatric patients, the duration of effect was as long as 6 hours.

In a placebo-controlled, single-dose, crossover study in 55 pediatric patients 4 to 11 years of age, PROAIR HFA Inhalation Aerosol, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo HFA inhalation aerosol. Serial FEV₁ measurements, expressed as the baseline-adjusted percent predicted FEV₁ observed over 6 hours post-dose, demonstrated that one and two inhalations of PROAIR HFA Inhalation Aerosol produced significantly greater bronchodilator responses than the matched placebo.

Exercise-Induced Bronchospasm

In a randomized, single-dose, crossover study in 24 adults and adolescents with exercise-induced bronchospasm (EIB), two inhalations of PROAIR HFA taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as maintenance of FEV₁ within 80% of post-dose, pre-exercise baseline values) in 83% (20 of 24) of patients as compared to 25% (6 of 24) of patients when they received placebo.

Some patients who participated in these clinical trials were using concomitant steroid therapy.

PROAIR® HFA
(albuterol sulfate) Inhalation Aerosol

Read this leaflet carefully before you start to use PROAIR HFA.

Keep this leaflet because it has important summary information about PROAIR HFA. Your healthcare provider has more information or advice.

Read the new leaflet that comes with each refill of your prescription because there may be new information.

What is PROAIR HFA?

PROAIR HFA is a kind of medicine called a fast-acting bronchodilator. Fast-acting bronchodilators help to quickly open the airways in your lungs so that you can breathe more easily.

Each dose of PROAIR HFA should last up to 4 to 6 hours.

Take PROAIR HFA as directed by your doctor. Do not take extra doses or take more often without asking your doctor.

Get medical help right away if PROAIR HFA no longer helps your symptoms. Also get medical help if your symptoms get worse or if you need to use your inhaler more often.

While you are using PROAIR HFA, use other inhaled medicines and asthma medicines only as directed by your doctor. Tell your doctor if you are pregnant or nursing, and ask about the use of PROAIR HFA.

Possible side effects of taking PROAIR HFA include fast or irregular heartbeat, chest pain, shakiness, and nervousness. With the first use of a new canister, worsening of wheezing may occur.

The parts of your PROAIR HFA inhaler:

There are 2 main parts to your PROAIR HFA inhaler—the metal canister that holds the medicine and the red plastic actuator that sprays the medicine from the canister (see Figure 1).

The inhaler also has a cap that covers the mouthpiece of the actuator.

Do not use the PROAIR HFA actuator with a canister of medicine from any other inhaler. And do not use a PROAIR HFA canister with an actuator from any other inhaler.

How to Use Your PROAIR HFA

Before using your PROAIR HFA: If a child needs help using the inhaler, an adult should help the child use the inhaler. An adult should watch a child use the inhaler to be sure it is used correctly.

The inhaler should be at room temperature before you use it.

Check each time to make sure the canister fits firmly in the plastic actuator. Also look into the mouthpiece to make sure there are no foreign objects there, especially if the cap is not being used to cover the mouthpiece.

Priming your PROAIR HFA:

You must prime the inhaler to get the right amount of medicine. Prime the inhaler before you use it for the first time or if you have not used it for more than 14 days. To prime the inhaler, take the cap off the mouthpiece of the actuator. Then shake the inhaler well, and spray it into the air away from your face. Shake and spray the inhaler like this 2 more times to finish priming it.

Instructions for taking a dose from your PROAIR HFA:

Read through the 6 steps below before using PROAIR HFA. If you have any questions, ask your doctor or pharmacist.

1. Take the cap off the mouthpiece of the actuator. Shake the inhaler well before each spray.

2. Hold the inhaler with the mouthpiece down (see Figure 2). Breathe out through your mouthand push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your lips around it.

3. Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth (see Figure 3). Right after the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth.

4. Hold your breath as long as you can, up to 10 seconds, then breathe normally.

5. If your doctor has prescribed more sprays, wait 1 minute and shake the inhaler again. Repeat steps 2 through 4.

6. Put the cap back on the mouthpiece after every time you use the inhaler, and make sure it snaps firmly into place.

When to Replace Your PROAIR HFA

• Before you reach 200 sprays, you should refill your prescription or ask your doctor if you need another prescription for PROAIR HFA.
• Throw the inhaler away when you have used 200 sprays. You should not keep using the inhaler after 200 sprays even though the canister may not be completely empty because you cannot be sure you will receive any medicine.
• Do not use the inhaler after the expiration date, which is on the packaging it comes in.

How to Clean Your PROAIR HFA

It is very important to keep the plastic actuator clean so the medicine will not build-up and block the spray. Do not try to clean the metal canister or let it get wet. The inhaler may stop spraying if it is not cleaned correctly.

Wash the actuator at least once a week.

Cleaning instructions:

• Take the canister out of the actuator, and take the cap off the mouthpiece.
• Wash the actuator through the top with warm running water for 30 seconds (see Figure 4). Then wash the actuator again through the mouthpiece (see Figure 5).

• Shake off as much water from the actuator as you can. Look into the mouthpiece to make sure any medicine build-up has been completely washed away. If there is any build-up, repeat steps in Figures 4 and 5.
• Let the actuator air-dry completely, such as overnight (see Figure 6).

• When the actuator is dry, put the canister in the actuator and make sure it fits firmly. Shake the inhaler well and spray it twice into the air away from your face. Put the cap back on the mouthpiece.

If your actuator becomes blocked:

Blockage from medicine build-up is more likely to happen if you do not let the actuator air-dry completely. If the actuator gets blocked so that little or no medicine comes out of the mouthpiece (see Figures 7 and 8), wash the actuator as described in the “Cleaning Instructions” section above.

If you need to use your inhaler before the actuator is completely dry, shake as much water off the actuator as you can. Put the canister in the actuator and make sure it fits firmly. Shake the inhaler well and spray it twice into the air away from your face. Then take your dose as prescribed. Then clean and air-dry it completely.

Storing Your PROAIR HFA

Store between 15° and 25° C (59° and 77° F). Avoid exposure to extreme heat and cold. For best results, canister should be at room temperature.

Shake well before use.

Contents Under Pressure. Do not puncture. Do not store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Avoid spraying in eyes. Keep out of reach of children.

For questions related to proper use and maintenance of your PROAIR HFA inhaler, please call Teva Specialty Pharmaceuticals customer service at 1-888-482-9522.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ALBUTEROL (SALBUTAMOL) HFA INHALER - ORAL

(al-BUE-ter-ol)(sal-BUE-tah-mol)

COMMON BRAND NAME(S): Proventil HFA, Ventolin HFA

USES: Albuterol (also known as salbutamol) is used to prevent and treat wheezing and shortness of breath caused by breathing problems (e.g., asthma, chronic obstructive pulmonary disease). It is also used to prevent asthma brought on by exercise. Albuterol belongs to a class of drugs known as bronchodilators. It works in the airways by opening breathing passages and relaxing muscles. Controlling symptoms of breathing problems can decrease time lost from work or school.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using this medication and each time you get a refill. Follow the illustrated directions for use of the inhaler. If any of the information is unclear, consult your doctor or pharmacist.

Follow the instructions for test sprays in the air (priming) if you are using a new canister, or if you have not used it for 2 weeks or longer, or if the inhaler has been dropped. Avoid spraying the medication in your eyes.

Before each dose, shake the inhaler well. Inhale this medication by mouth, usually every 4 to 6 hours as needed or as directed by your doctor. Dosage is based on your medical condition and response to treatment. Do not increase your dose or use it more frequently than prescribed without your doctor's approval.

If you are using this medication to prevent asthma brought on by exercise, inhale 2 puffs 15 to 30 minutes before exercise or as directed by your doctor.

If you find it difficult to use this inhaler correctly, it may help to use a spacer device with this inhaler. Ask your doctor or pharmacist for more information.

Clean and dry the inhaler at least once a week as directed in the Patient Information Leaflet. It should also be cleaned anytime it appears to be clogged or is not working properly.

If you use other asthma drugs (including inhaled medications), ask your doctor about how to properly use this medication with your other asthma medicines.

If this medication stops working well, or if your breathing symptoms become worse, or if you need to use this medication more frequently than usual, seek immediate medical attention.

Keep track of the number of inhalations you use, and discard the inhaler after you have used the labeled number of inhalations on the product package. Test sprays used to prime the inhaler should also be counted.

SIDE EFFECTS: Nervousness, shaking (tremor), mouth/throat dryness or irritation, cough, dizziness, headache, trouble sleeping, or nausea may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fast/pounding heartbeat, muscle cramps/weakness.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, irregular heartbeat.

Rarely, this medication has caused severe (rarely fatal), sudden worsening of breathing problems/asthma (paradoxical bronchospasm). If you experience sudden wheezing, seek immediate medical attention.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using albuterol, tell your doctor or pharmacist if you are allergic to it; or if you have had a serious reaction to similar drugs (e.g., metaproterenol, terbutaline); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart problems (e.g., irregular heartbeat, angina, heart attack), high blood pressure, diabetes, low levels of potassium in the blood, seizure, overactive thyroid (hyperthyroidism).

This drug may make you dizzy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are using this medication.

Caution is advised when using this drug in older adults since they may be more sensitive to its effects, especially the effects on the heart.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Avoid taking MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) within 2 weeks before, during, or after treatment with this medication. In some cases a serious, possibly fatal drug interaction may occur.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: adrenaline-like drugs (e.g., ephedrine, epinephrine), beta blockers (e.g., atenolol, propranolol), digoxin, tricyclic antidepressants (e.g., amitriptyline, nortriptyline), "water pills" (diuretics such as furosemide, hydrochlorothiazide).

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids) because they may contain ingredients that could increase heart rate or blood pressure. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: fast/pounding/irregular heartbeat, severe shaking (tremors), seizures.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., pulmonary function tests, blood pressure, levels of potassium in the blood) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Avoid allergens/irritants such as smoke, pollen, pet dander, dust, or molds that may worsen breathing problems.

Learn to use a peak flow meter, use it daily, and promptly report worsening breathing problems (such as readings in the yellow/red range, increased use of quick-relief inhalers).

Ask your doctor or pharmacist whether you should have an annual flu shot.

MISSED DOSE: If you are using this medication on a prescribed schedule and miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-77 degrees F (15-25 degrees C) away from light and moisture. It is best to store the inhaler with the mouthpiece down. Do not puncture the canister or expose it to high heat or open flame. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.