^ Paradoxical Bronchospasm
Albuterol Sulfate HFA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Albuterol Sulfate 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.
^ Monoamine Oxidase Inhibitors And Tricyclic Antidepressants
Albuterol Sulfate 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.
^ Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Frequency of Use
Inform patients that the action of Albuterol Sulfate HFA should last up to 4 to 6 hours. Do not use Albuterol Sulfate HFA more frequently than recommended. Instruct patients not to increase the dose or frequency of doses of Albuterol Sulfate HFA without consulting the physician. Instruct patients to seek medical attention immediately if treatment with Albuterol Sulfate HFA becomes less effective for symptomatic relief, symptoms become worse, and/or they need to use the product more frequently than usual.
Priming
Instruct patients to prime Albuterol Sulfate 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 Albuterol Sulfate 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, instruct patients to wash the actuator with warm water and let it air-dry completely at least once a week. Inform patients that detailed cleaning instructions are included in the Patient Information leaflet.
Paradoxical Bronchospasm
Inform patients that Albuterol Sulfate HFA can produce paradoxical bronchospasm. Instruct them to discontinue Albuterol Sulfate HFA if paradoxical bronchospasm occurs [see Warnings and Precautions (5.1)].
Concomitant Drug Use
Advise patients that while they are using Albuterol Sulfate HFA, other inhaled drugs and asthma medications should be taken only as directed by the physician.
Common Adverse Effects
Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, and nervousness.
Pregnancy Exposure Registry
Inform women there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications, including Albuterol Sulfate HFA, during pregnancy and that they can enroll in the Pregnancy Exposure Registry by calling 1-877-311-8972 or by visiting https://mothertobaby.org/ongoing-study/asthma [see Use in Specific Populations ( 8.1)] .
Manufactured for:
Prasco Laboratories
Mason, OH 45040 USA
Manufactured by:
GlaxoSmithKline
Research Triangle Park, NC 27709
VNT-PS:4PI
^ Description
The active component of Albuterol Sulfate 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 13H 21NO 3) 2•H 2SO 4. It is soluble in water and slightly soluble in ethanol.
The World Health Organization recommended name for albuterol base is salbutamol.
Albuterol Sulfate HFA is a blue plastic inhaler with a blue cap containing a pressurized metered-dose aerosol canister fitted with a counter. Each canister contains a microcrystalline suspension of albuterol sulfate in propellant HFA‑134a (1,1,1,2‑tetrafluoroethane). It contains no other excipients.
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).
Prime Albuterol Sulfate 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 Albuterol Sulfate HFA, release 4 sprays into the air away from the face, shaking well before each spray. Avoid spraying in eyes.
^ Clinical 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 albuterol sulfate HFA in 248 subjects treated with albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate HFA and a CFC 11/12‑propelled albuterol inhaler were comparable. Table 1lists 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 albuterol sulfate HFA and more frequently in the group treated with albuterol sulfate HFA than in the HFA-134a placebo inhaler group.
Adverse reactions reported by <3% of the adult and adolescent subjects receiving albuterol sulfate HFA and by a greater proportion of subjects receiving albuterol sulfate HFA than receiving HFA-134a placebo inhaler and that have the potential to be related to albuterol sulfate HFA include diarrhea, laryngitis, oropharyngeal edema, cough, lung disorders, tachycardia, and extrasystoles. Palpitations and dizziness have also been observed with albuterol sulfate 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 albuterol sulfate HFA in subjects between birth and 4 years of age. The results of these trials did not establish the efficacy of albuterol sulfate HFA in this age group [see Use in Specific Populations ( 8.4)] . Since the efficacy of albuterol sulfate HFA has not been demonstrated in children between birth and 48 months of age, the safety of albuterol sulfate 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.
^ Overdosage
The expected signs and symptoms with overdosage of albuterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis).
As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of Albuterol Sulfate HFA Inhalation Aerosol.
Treatment consists of discontinuation of Albuterol Sulfate HFA 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 Albuterol Sulfate HFA.
^ Lactation
Risk Summary
There are no available data on the presence of albuterol or the components of Albuterol Sulfate HFA in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, are likely to be correspondingly low [see Clinical Pharmacology ( 12.3)] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Albuterol Sulfate HFA and any potential adverse effects on the breastfed child from Albuterol Sulfate HFA or from the underlying maternal condition.
^3 Dosage Forms And Strengths
Inhalation aerosol: 108 mcg of albuterol sulfate (90 mcg of albuterol base) from the mouthpiece per actuation. Blue plastic inhaler with a blue cap containing a pressurized metered-dose aerosol canister containing 200 metered inhalations and fitted with a counter.
^ Bronchospasm Associated With Asthma
Adult and Adolescent Subjects Aged 12 Years and Older
The efficacy of albuterol sulfate HFA was evaluated in two 12-week, randomized, double-blind, placebo-controlled trials in subjects aged 12 years and older with mild to moderate asthma. These trials included a total of 610 subjects (323 males, 287 females). In each trial, subjects received 2 inhalations of albuterol sulfate HFA, CFC 11/12-propelled albuterol, or HFA-134a placebo 4 times daily for 12 weeks’ duration. Subjects taking the HFA-134a placebo inhaler also took albuterol sulfate HFA for asthma symptom relief on an as-needed basis. Some subjects who participated in these clinical trials were using concomitant inhaled steroid therapy. Efficacy was assessed by serial forced expiratory volume in 1 second (FEV 1). In each of these trials, 2 inhalations of albuterol sulfate HFA produced significantly greater improvement in FEV 1over the pretreatment value than placebo. Results from the 2 clinical trials are described below.
In a 12-week, randomized, double-blind trial, albuterol sulfate HFA (101 subjects) was compared with CFC 11/12-propelled albuterol (99 subjects) and an HFA-134a placebo inhaler (97 subjects) in adolescent and adult subjects aged 12 to 76 years with mild to moderate asthma. Serial FEV 1measurements [shown below as percent change from test-day baseline at Day 1 (n = 297) and at Week 12 (n = 249)] demonstrated that 2 inhalations of albuterol sulfate HFA produced significantly greater improvement in FEV 1over the pretreatment value than placebo.
FEV 1as Percent Change from Predose in a Large, 12-Week Clinical Trial
Day 1
Week 12
In the responder population (≥15% increase in FEV 1within 30 minutes postdose) treated with albuterol sulfate HFA, the mean time to onset of a 15% increase in FEV 1over the pretreatment value was 5.4 minutes, and the mean time to peak effect was 56 minutes. The mean duration of effect as measured by a 15% increase in FEV 1over the pretreatment value was approximately 4 hours. In some subjects, duration of effect was as long as 6 hours.
The second 12-week randomized, double-blind trial was conducted to evaluate the efficacy and safety of switching subjects from CFC 11/12-propelled albuterol to albuterol sulfate HFA. During the 3-week run-in phase of the trial, all subjects received CFC 11/12-propelled albuterol. During the double-blind treatment phase, albuterol sulfate HFA (91 subjects) was compared to CFC 11/12-propelled albuterol (100 subjects) and an HFA-134a placebo inhaler (95 subjects) in adult and adolescent subjects with mild to moderate asthma. Serial FEV 1measurements demonstrated that 2 inhalations of albuterol sulfate HFA produced significantly greater improvement in pulmonary function than placebo. The switching from CFC 11/12-propelled albuterol inhaler to albuterol sulfate HFA did not reveal any clinically significant changes in the efficacy profile.
In the 2 adult trials, the efficacy results from albuterol sulfate HFA were significantly greater than placebo and were clinically comparable to those achieved with CFC 11/12-propelled albuterol, although small numerical differences in mean FEV 1response and other measures were observed. Physicians should recognize that individual responses to beta-adrenergic agonists administered via different propellants may vary and that equivalent responses in individual patients should not be assumed.
Pediatric Subjects Aged 4 to 11 Years
The efficacy of albuterol sulfate HFA was evaluated in one 2-week, randomized, double-blind, placebo-controlled trial in 135 pediatric subjects aged 4 to 11 years with mild to moderate asthma. In this trial, subjects received albuterol sulfate HFA, CFC 11/12-propelled albuterol, or HFA-134a placebo. Serial pulmonary function measurements demonstrated that 2 inhalations of albuterol sulfate HFA produced significantly greater improvement in pulmonary function than placebo and that there were no significant differences between the groups treated with albuterol sulfate HFA and CFC 11/12-propelled albuterol. In the responder population treated with albuterol sulfate HFA, the mean time to onset of a 15% increase in peak expiratory flow rate (PEFR) over the pretreatment value was 7.8 minutes, and the mean time to peak effect was approximately 90 minutes. The mean duration of effect as measured by a 15% increase in PEFR over the pretreatment value was greater than 3 hours. In some subjects, duration of effect was as long as 6 hours.
^ Recommended 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.
^ Cardiovascular Effects
Albuterol Sulfate 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, Albuterol Sulfate 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, Albuterol Sulfate HFA, like all other sympathomimetic amines, should be used with caution in patients with underlying cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
^ Pediatric Use
The safety and effectiveness of albuterol sulfate HFA for treatment or prevention of bronchospasm and for prevention of exercised-induced bronchospasm in pediatric patients aged 4 years and older have been established. Use of albuterol sulfate HFA for this indication is supported by evidence from adequate and well-controlled studies of two 12-week clinical trials in subjects aged 12 years and older with asthma and one 2-week clinical trial in subjects aged 4 to 11 years with asthma [see Adverse Reactions ( 6.1), Clinical Studies ( 14.1)] .
The safety and effectiveness of albuterol sulfate HFA in pediatric patients younger than 4 years have not been established. Three trials have been conducted to evaluate the safety and efficacy of albuterol sulfate HFA in subjects younger than 4 years and the findings are described below.
Two 4-week randomized, double-blind, placebo-controlled trials were conducted in 163 pediatric subjects aged from birth to 48 months with symptoms of bronchospasm associated with obstructive airway disease (presenting symptoms included: wheeze, cough, dyspnea, or chest tightness). Albuterol sulfate HFA or placebo HFA was delivered with either an AeroChamber Plus Valved Holding Chamber or an Optichamber Valved Holding Chamber with mask 3 times daily. In one trial, albuterol sulfate HFA 90 mcg (n = 26), albuterol sulfate HFA 180 mcg (n = 25), and placebo HFA (n = 26) were administered to children aged between 24 and 48 months. In the second trial, albuterol sulfate HFA 90 mcg (n = 29), albuterol sulfate HFA 180 mcg (n = 29), and placebo HFA (n = 28) were administered to children aged between birth and 24 months. Over the 4-week treatment period, there were no treatment differences in asthma symptom scores between the groups receiving albuterol sulfate HFA 90 mcg, albuterol sulfate HFA 180 mcg, and placebo in either trial.
In a third trial, albuterol sulfate HFA was evaluated in 87 pediatric subjects younger than 24 months for the treatment of acute wheezing. Albuterol sulfate HFA was delivered with an AeroChamber Plus Valved Holding Chamber in this trial. There were no significant differences in asthma symptom scores and mean change from baseline in an asthma symptom score between albuterol sulfate HFA 180 mcg and albuterol sulfate HFA 360 mcg.
In vitro dose characterization studies were performed to evaluate the delivery of albuterol sulfate HFA via holding chambers with attached masks. The studies were conducted with 2 different holding chambers with masks (small and medium size). The in vitro study data when simulating patient breathing suggest that the dose of albuterol sulfate HFA presented for inhalation via a valved holding chamber with mask will be comparable to the dose delivered in adults without a spacer and mask per kilogram of body weight ( Table 2). However, clinical trials in children younger than 4 years described above suggest that either the optimal dose of albuterol sulfate HFA has not been defined in this age group or albuterol sulfate HFA is not effective in this age group. The safety and effectiveness of albuterol sulfate HFA administered with or without a spacer device in children younger than 4 years have not been demonstrated.
^4 Contraindications
Albuterol Sulfate HFA is contraindicated in patients with a history of hypersensitivity to any of the ingredients [see Warnings and Precautions ( 5.6), Description ( 11)] .
^ 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.
^ Postmarketing 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 albuterol sulfate 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.
^ Animal Toxicology And/or Pharmacology
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 beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.
^ How Supplied/storage And Handling
Albuterol Sulfate HFA Inhalation Aerosol is supplied in the following box of 1 as a pressurized aluminum canister fitted with a counter and supplied with a blue plastic actuator with a blue cap:
NDC 80425-0359-01 18-g canister containing 200 actuations
Each inhaler is packaged with a Patient Information leaflet.
The blue actuator supplied with Albuterol Sulfate HFA should not be used with any other product canisters, and actuators from other products should not be used with an Albuterol Sulfate HFA canister.
Counter
Albuterol Sulfate HFA has a counter attached to the canister. The counter starts at 204 and counts down each time a spray is released. The correct amount of medication in each actuation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000.
Contents Under Pressure
Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire or incinerator.
Storage
Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use.
^ Recommended 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.
^ Geriatric Use
Clinical trials of albuterol sulfate HFA did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the 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.
^ Coexisting Conditions
Albuterol Sulfate 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.
^ 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 and 6 times the MRHDID for adults and children, respectively, on a mg/m 2basis). 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 1,900 and 740 times the MRHDID for adults and children, respectively, on a mg/m 2basis). 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 250 and 100 times the MRHDID for adults and children, respectively, on a mg/m 2basis).
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 AH1 strain mouse micronucleus assay.
Fertility and reproductive performance in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 380 times the MRHDID for adults on a mg/m 2basis).
^ Hypersensitivity Reactions, Including Anaphylaxis
Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Albuterol Sulfate HFA [see Contraindications ( 4)] .
^ Hypokalemia
Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology ( 12.1)] . The decrease in serum potassium is usually transient, not requiring supplementation.
^ 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 Albuterol Sulfate 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.
^ Administration Information
Albuterol Sulfate HFA should be administered by the orally inhaled route only.
Priming
Priming Albuterol Sulfate HFA is essential to ensure appropriate albuterol content in each actuation. Prime Albuterol Sulfate 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 Albuterol Sulfate 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.
^ Beta-adrenergic Receptor Blocking Agents
Beta-blockers not only block the pulmonary effect of beta-agonists, such as albuterol sulfate HFA, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.
^ Pregnancy
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. (See Clinical Considerations.)
Administration of albuterol sulfate 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). (See Data.)
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 Albuterol Sulfate HFA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Albuterol sulfate 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 albuterol sulfate 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 2basis 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 2basis 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 2basis 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 2basis.
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.
^ Bronchospasm
Albuterol Sulfate HFA Inhalation Aerosol is indicated for the treatment or prevention of bronchospasm in adult and pediatric patients aged 4 years and older with reversible obstructive airway disease.
^ Exercise-induced Bronchospasm
Albuterol Sulfate HFA is indicated for the prevention of exercise-induced bronchospasm in adult and pediatric patients aged 4 years and older.
^6 Adverse Reactions
The following clinically significant adverse reactions are described elsewhere in the labeling:
^7 Drug Interactions
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.
^ Pharmacokinetics
The systemic levels of albuterol are low after inhalation of recommended doses. A trial conducted in 12 healthy male and female subjects using a higher dose (1,080 mcg of albuterol base) showed that mean peak plasma concentrations of approximately 3 ng/mL occurred after dosing when albuterol was delivered using propellant HFA-134a. The mean time to peak concentrations (T max) was delayed after administration of Albuterol Sulfate HFA (T max = 0.42 hours) as compared with CFC-propelled albuterol inhaler (T max = 0.17 hours). Apparent terminal plasma half-life of albuterol is approximately 4.6 hours. No further pharmacokinetic trials for albuterol sulfate HFA were conducted in neonates, children, or elderly subjects.
^ 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.
^ Exercise-induced Bronchospasm
One controlled clinical trial in adult subjects with asthma (N = 24) demonstrated that 2 inhalations of albuterol sulfate HFA taken approximately 30 minutes prior to exercise significantly prevented exercise-induced bronchospasm (as measured by maximum percentage fall in FEV 1following exercise) compared with an HFA-134a placebo inhaler. In addition, albuterol sulfate HFA was shown to be clinically comparable to a CFC 11/12-propelled albuterol inhaler for this indication.
^ 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.
^ Mechanism Of Action
In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2-adrenergic receptors compared with isoproterenol. Although beta 2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1-adrenoceptors are the predominant receptors in the heart, there are also beta 2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2-agonists may have cardiac effects.
Activation of beta 2-adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles 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.
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. Controlled clinical studies and other clinical experience have shown that 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 ( 5.4)] .
^ Non–potassium-sparing Diuretics
The ECG changes and/or hypokalemia that may result from the administration of non—potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of Albuterol Sulfate HFA with non–potassium-sparing diuretics.