Albuterol

1 INDICATIONS AND USAGE VENTOLIN HFA is a beta 2 -adrenergic agonist indicated for: Treatment or prevention of bronchospasm in adult and pediatric patients aged 4 years and older with reversible obstructive airway disease. Prevention of exercise-induced bronchospasm in adult and pediatric patients aged 4 years and older.

1.1Bronchospasm

VENTOLIN HFA is indicated for the treatment or prevention of bronchospasm in adult and pediatric patients aged 4 years and older with reversible obstructive airway disease.

1.2Exercise-Induced Bronchospasm

VENTOLIN HFA is indicated for the prevention of exercise-induced bronchospasm in adult and pediatric patients aged 4 years and older.

For oral inhalation only. Treatment or prevention of bronchospasm in adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation every 4 to 6 hours. For some patients, 1 inhalation every 4 hours may be sufficient. Prevention of exercise-induced bronchospasm in adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation 15 to 30 minutes before exercise. 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. Cleaning information: At least once a week, wash the actuator with warm water and let it air-dry completely.

2.1Recommended Dosage for Bronchospasm

(Acute Episodes or Symptoms Associated with Bronchospasm) Adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation repeated every 4 to 6 hours; in some patients, 1 inhalation every 4 hours may be sufficient. More frequent administration or a greater number of inhalations is not recommended.

2.2Recommended Dosage for Prevention of Exercise-Induced Bronchospasm

Adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation 15 to 30 minutes before exercise.

2.3Administration Information

VENTOLIN HFA should be administered by the orally inhaled route only. 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. Avoid spraying in eyes. 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.

Life-threatening paradoxical bronchospasm may occur. Discontinue VENTOLIN HFA immediately and institute alternative therapy. Need for more doses of VENTOLIN HFA than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. VENTOLIN HFA is not a substitute for corticosteroids. Cardiovascular effects may occur. Use with caution in patients sensitive to sympathomimetic drugs and patients with cardiovascular or convulsive disorders. ( 5.4 , 5.7 ) Excessive use may be fatal. Do not exceed recommended dose. Immediate hypersensitivity reactions may occur. Discontinue VENTOLIN HFA immediately. Hypokalemia and changes in blood glucose may occur. ( 5.7 , 5.8 )

5.1Paradoxical Bronchospasm

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

5.2Deterioration 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 VENTOLIN HFA than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

5.3Use 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.

5.4Cardiovascular Effects

VENTOLIN HFA, like all other beta 2 -adrenergic agonists, can produce clinically significant cardiovascular effects in some patients such as changes in pulse rate or blood pressure. If such effects occur, VENTOLIN HFA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression.

The clinical relevance of these findings is unknown. Therefore, VENTOLIN HFA, like all other sympathomimetic amines, should be used with caution in patients with underlying cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.5Do 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.

5.6Hypersensitivity Reactions,

including Anaphylaxis Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of VENTOLIN HFA .

5.7Coexisting Conditions

VENTOLIN HFA, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.8Hypokalemia Beta-adrenergic

agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects . The decrease in serum potassium is usually transient, not requiring supplementation.

4 CONTRAINDICATIONS VENTOLIN HFA is contraindicated in patients with a history of hypersensitivity to any of the ingredients . Hypersensitivity to any ingredient.

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy. For more information, contact the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists at 1‑877-311-8972 or visit https://mothertobaby.org/ongoing-study/asthma. Risk Summary There are no randomized clinical studies of use of albuterol sulfate during pregnancy.

Available data from epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are, however, clinical considerations in pregnant women with asthma. Administration of VENTOLIN HFA to mice and rabbits during the period of organogenesis revealed evidence of adverse developmental outcomes (cleft palate in mice, delayed ossification in rabbits) at less than the maximum recommended human daily inhaled dose (MRHDID).

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or Delivery: Because of the potential for beta-agonist interference with uterine contractility, use of VENTOLIN HFA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. VENTOLIN HFA has not been approved for the management of pre-term labor.

Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Human Data: While available studies cannot definitively establish the absence of risk, published data from epidemiological studies and case reports have not consistently demonstrated an association with use of VENTOLIN HFA during pregnancy and major birth defects, specific birth defects, or miscarriage. The available studies have methodologic limitations, including inconsistent comparator groups, definitions of outcomes, and assessment of disease impact.

Animal Data: In a study in pregnant mice, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure less than the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol, another beta 2 -agonist. In a study in pregnant rabbits, orally administered albuterol sulfate produced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg).

In a study in pregnant rabbits, an albuterol/HFA-134a formulation administered by inhalation produced enlargement of the frontal portion of the fetal fontanelles at approximately one third of the MRHDID on a mg/m 2 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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Paradoxical bronchospasm Cardiovascular effects Hypersensitivity reactions, including anaphylaxis Hypokalemia Most common adverse reactions (incidence ≥3%) are throat irritation, viral respiratory infections, upper respiratory inflammation, cough, and musculoskeletal pain. To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflects exposure to VENTOLIN HFA in 248 subjects 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 subjects with asthma aged 12 years 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 subjects are based upon 1 clinical trial in which 46 subjects with asthma aged 4 to 11 years 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.

Adult and Adolescent Subjects Aged 12 Years and Older The two 12-week, randomized, double-blind trials in 610 adult and adolescent subjects 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 trials that occurred at a rate of ≥3% in the group treated with VENTOLIN HFA and more frequently in the group treated with VENTOLIN HFA than in the HFA-134a placebo inhaler group.

Table 1. Adverse Reactions with VENTOLIN HFA with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects Adverse Reaction Percent of Subjects 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 Adverse reactions reported by <3% of the adult and adolescent subjects receiving VENTOLIN HFA and by a greater proportion of subjects 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. Palpitations and dizziness have also been observed with VENTOLIN HFA. Pediatric Subjects Aged 4 to 11 Years Results from the 2-week clinical trial in pediatric subjects with asthma aged 4 to 11 years showed that this pediatric population had an adverse reaction profile similar to that of the adult and adolescent populations.

Three trials have been conducted to evaluate the safety and efficacy of VENTOLIN HFA in subjects between birth and 4 years of age. The results of these trials did not establish the efficacy of VENTOLIN HFA in this age group . 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 younger than 4 years was comparable to that observed in the older pediatric subjects and in adults and adolescents.

Where adverse reaction incidence rates were greater in subjects younger than 4 years compared with older subjects, the higher incidence rates were noted in all treatment arms, including placebo. These adverse reactions included upper respiratory tract infection, nasopharyngitis, pyrexia, and tachycardia.

6.2Postmarketing Experience In

addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of albuterol sulfate. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to albuterol or a combination of these factors.

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.