VENTOLIN HFA

The active component of VENTOLIN HFA is albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta 2 -adrenergic bronchodilator. Albuterol sulfate has the chemical name α 1 -[( tert -butylamino)methyl]-4-hydroxy- m -xylene-α, α′-diol sulfate (2:1)(salt) and the following chemical structure: Albuterol sulfate is a white crystalline powder with a molecular weight of 576.7, and the empirical formula is (C 13 H 21 NO 3 ) 2 •H 2 SO 4 . It is soluble in water and slightly soluble in ethanol. The World Health Organization recommended name for albuterol base is salbutamol. VENTOLIN HFA is a pressurized metered-dose aerosol unit fitted with a counter. VENTOLIN HFA is intended for oral inhalation only. Each unit contains a microcrystalline suspension of albuterol sulfate in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients. Priming VENTOLIN HFA is essential to ensure appropriate albuterol content in each actuation. To prime the inhaler, release 4 sprays into the air away from the face, shaking well before each spray. The inhaler should be primed before using it for the first time, when it has not been used for more than 2 weeks, or when it has been dropped. After priming, each actuation of the inhaler delivers 120 mcg of albuterol sulfate, USP in 75 mg of suspension from the valve and 108 mcg of albuterol sulfate, USP from the mouthpiece (equivalent to 90 mcg of albuterol base from the mouthpiece). Each 18-g canister provides 200 inhalations. Each 8-g canister provides 60 inhalations. This product does not contain chlorofluorocarbons (CFCs) as the propellant. Chemical structure

VENTOLIN HFA is a beta 2 -adrenergic agonist indicated for: • Treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. (1.1) • Prevention of exercise-induced bronchospasm in patients 4 years of age and older. (1.2) 1.1 Bronchospasm VENTOLIN ® HFA is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. 1.2 Exercise-Induced Bronchospasm VENTOLIN HFA is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

Administer VENTOLIN HFA by oral inhalation only. Shake VENTOLIN HFA well before each spray. FOR ORAL INHALATION ONLY. • Treatment or prevention of bronchospasm in adults and children 4 years of age and older: 2 inhalations every 4 to 6 hours. For some patients, 1 inhalation every 4 hours may be sufficient. (2.1) • Prevention of exercise-induced bronchospasm in adults and children 4 years of age and older: 2 inhalations 15 to 30 minutes before exercise. (2.2) • Priming information: Prime VENTOLIN HFA before using for the first time, when the inhaler has not been used for more than 2 weeks, or when the inhaler has been dropped. To prime VENTOLIN HFA, release 4 sprays into the air away from the face, shaking well before each spray. (2.3) • Cleaning information: At least once a week, wash the actuator with warm water and let it air-dry completely. (2.3) 2.1 Bronchospasm For treatment of acute episodes of bronchospasm or prevention of symptoms associated with bronchospasm, the usual dosage for adults and children is 2 inhalations repeated every 4 to 6 hours; in some patients, 1 inhalation every 4 hours may be sufficient. More frequent administration or a larger number of inhalations is not recommended. 2.2 Exercise-Induced Bronchospasm The usual dosage for adults and children 4 years of age and older is 2 inhalations 15 to 30 minutes before exercise. 2.3 Administration Information Priming: Priming VENTOLIN HFA is essential to ensure appropriate albuterol content in each actuation. Prime VENTOLIN HFA before using for the first time, when the inhaler has not been used for more than 2 weeks, or when the inhaler has been dropped. To prime VENTOLIN HFA, release 4 sprays into the air away from the face, shaking well before each spray. Cleaning: To ensure proper dosing and to prevent actuator orifice blockage, wash the actuator with warm water and let it air-dry completely at least once a week. Dose Counter: VENTOLIN HFA has a dose counter attached to the canister that starts at 204 or 64 and counts down each time a spray is released [see Dosage Forms and Strengths (3)] . When the counter reads 020, the patient should contact the pharmacist for a refill of medication or consult the physician to determine whether a prescription refill is needed. VENTOLIN HFA comes in a moisture-protective foil pouch, which should be removed prior to use. Discard VENTOLIN HFA when the counter reads 000 or 12 months after removal from the moisture-protective foil pouch, whichever comes first [see Dosage Forms and Strengths (3)] . See Patient Information tear-off leaflet for instructions on how to prime and clean the inhaler to ensure proper dosing and to prevent actuator orifice blockage.

VENTOLIN HFA is contraindicated in patients with a history of hypersensitivity to albuterol or any other components of VENTOLIN HFA. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate. Hypersensitivity to albuterol sulfate or any of the ingredients of VENTOLIN HFA. (4)

Use of VENTOLIN HFA may be associated with the following: • Paradoxical bronchospasm [see Warnings and Precautions (5.1)] • Cardiovascular effects [see Warnings and Precautions (5.4)] • Immediate hypersensitivity reactions [see Warnings and Precautions (5.6)] • Hypokalemia [see Warnings and Precautions (5.8)] Most common adverse reactions (incidence ≥3%) are throat irritation, viral respiratory infections, upper respiratory inflammation, cough, and musculoskeletal pain. (6) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The safety data described below reflects exposure to VENTOLIN HFA in 248 patients treated with VENTOLIN HFA in 3 placebo-controlled clinical trials of 2 to 12 weeks’ duration. The data from adults and adolescents is based upon 2 clinical trials in which 202 patients with asthma 12 years of age and older were treated with VENTOLIN HFA 2 inhalations 4 times daily for 12 weeks’ duration. The adult/adolescent population was 92 female, 110 male and 163 white, 19 black, 18 Hispanic, 2 other. The data from pediatric patients are based upon 1 clinical trial in which 46 patients with asthma 4 to 11 years of age were treated with VENTOLIN HFA 2 inhalations 4 times daily for 2 weeks’ duration. The population was 21 female, 25 male and 25 white, 17 black, 3 Hispanic, 1 other. 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. Adults and Adolescents 12 Years of Age and Older: The two 12-week, randomized, double-blind studies in 610 adolescent and adult patients with asthma that compared VENTOLIN HFA, a CFC 11/12-propelled albuterol inhaler, and an HFA-134a placebo inhaler. Overall, the incidence and nature of the adverse reactions reported for VENTOLIN HFA and a CFC 11/12-propelled albuterol inhaler were comparable. Table 1 lists the incidence of all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these studies that occurred at a rate of 3% or greater in the group treated with VENTOLIN HFA and more frequently in the group treated with VENTOLIN HFA than in the HFA-134a placebo inhaler group. Table 1. Overall Adverse Reactions With ≥3% Incidence in 2 Large 12-Week Clinical Trials in Adolescents and Adults a Adverse Reaction Percent of Patients VENTOLIN HFA (n = 202) % CFC 11/12-Propelled Albuterol Inhaler (n = 207) % Placebo HFA-134a (n = 201) % Ear, nose, and throat Throat irritation 10 6 7 Upper respiratory inflammation 5 5 2 Lower respiratory Viral respiratory infections 7 4 4 Cough 5 2 2 Musculoskeletal Musculoskeletal pain 5 5 4 a This table includes all adverse reactions (whether considered by the investigator to be drug-related or unrelated to drug) that occurred at an incidence rate of at least 3.0% in the group treated with VENTOLIN HFA and more frequently in the group treated with VENTOLIN HFA than in the HFA-134a placebo inhaler group. Adverse reactions reported by less than 3% of the adolescent and adult patients receiving VENTOLIN HFA and by a greater proportion of patients receiving VENTOLIN HFA than receiving HFA-134a placebo inhaler and that have the potential to be related to VENTOLIN HFA include diarrhea, laryngitis, oropharyngeal edema, cough, lung disorders, tachycardia, and extrasystoles. Palpitation and dizziness have also been observed with VENTOLIN HFA. Pediatric Patients: Results from the 2-week pediatric clinical study in patients with asthma 4 to 11 years of age showed that this pediatric population had an adverse reaction profile similar to that of the adolescent and adult populations. Three studies have been conducted to evaluate the safety and efficacy of VENTOLIN HFA in patients between birth and 4 years of age. The results of these studies did not establish the efficacy of VENTOLIN HFA in this age-group [see Pediatric Use (8.4)] . Since the efficacy of VENTOLIN HFA has not been demonstrated in children between birth and 48 months of age, the safety of VENTOLIN HFA in this age-group cannot be established. However, the safety profile observed in the pediatric population under 4 years of age was comparable to that observed in the older pediatric patients and in adolescents and adults. Where adverse reaction incidence rates were greater in patients under 4 years of age compared with older patients, the higher incidence rates were noted in all treatment arms, including placebo. These adverse reactions included upper respiratory tract infection, nasopharyngitis, pyrexia, and tachycardia. 6.2 Postmarketing Experience In addition to the adverse reactions listed in section 6.1, the following adverse reactions have been identified during postapproval use of VENTOLIN 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. Cases of paradoxical bronchospasm, hoarseness, arrhythmias (including atrial fibrillation, supraventricular tachycardia), and hypersensitivity reactions (including urticaria, angioedema, rash) have been reported after the use of VENTOLIN HFA. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypokalemia, hypertension, peripheral vasodilatation, angina, tremor, central nervous system stimulation, hyperactivity, sleeplessness, headache, muscle cramps, drying or irritation of the oropharynx, and metabolic acidosis.

Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. • Beta-blockers: May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. Patients with asthma should not normally be treated with beta-blockers. (7.1) • Diuretics: Electrocardiographic changes and/or hypokalemia associated with diuretics may worsen with concomitant beta-agonists. Consider monitoring potassium levels. (7.2) • Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants: May potentiate effect of albuterol on the vascular system. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants. (7.4) 7.1 Beta-Blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as VENTOLIN HFA, but may produce severe bronchospasm in patients with asthma. 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 beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution. 7.2 Diuretics The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-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 relevance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics. Consider monitoring potassium levels. 7.3 Digoxin Mean decreases of 16% to 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 relevance of these findings for patients with obstructive airway disease who are receiving inhaled 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 albuterol. 7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants VENTOLIN HFA 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 vascular system may be potentiated. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants.