Proair HFA Information
Proair hfa (Albuterol sulfate) Dosage And Administration
Administer Proair hfa (Albuterol sulfate) 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:
Proair hfa (Albuterol sulfate) Dosage Forms & Strengths
Proair hfa (Albuterol sulfate) is an inhalation aerosol. Proair hfa (Albuterol sulfate) 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).
Proair hfa (Albuterol sulfate) Contraindications
Proair hfa (Albuterol sulfate) Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol and any other Proair hfa (Albuterol sulfate) Inhalation Aerosol components. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate .
Proair hfa (Albuterol sulfate) Adverse Reactions
Use of Proair hfa (Albuterol sulfate) may be associated with the following:
A total of 1090 subjects were treated with Proair hfa (Albuterol sulfate) Inhalation Aerosol, or with the same formulation of albuterol as in Proair hfa (Albuterol sulfate) 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:
Adverse events reported by less than 3% of the patients receiving Proair hfa (Albuterol sulfate) Inhalation Aerosol but by a greater proportion of Proair hfa (Albuterol sulfate) Inhalation Aerosol patients than the matched placebo patients, which have the potential to be related to Proair hfa (Albuterol sulfate) 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:
The following adverse reactions have been identified during postapproval use of Proair hfa (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. 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.
Proair hfa (Albuterol sulfate) Drug Interactions
Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with Proair hfa (Albuterol sulfate) Inhalation Aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.
Proair hfa (Albuterol sulfate) Use In Specific Populations
Teratogenic Effects: Pregnancy Category C:
There are no adequate and well-controlled studies of Proair hfa (Albuterol sulfate) 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 (Albuterol sulfate) 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/m 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 .
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 (Albuterol sulfate) Inhalation Aerosol are excreted in human milk.
Caution should be exercised when Proair hfa (Albuterol sulfate) 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 (Albuterol sulfate) 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.
The safety and effectiveness of Proair hfa (Albuterol sulfate) 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 . The safety and effectiveness of Proair hfa (Albuterol sulfate) 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 .
The safety of Proair hfa (Albuterol sulfate) 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 (Albuterol sulfate) Inhalation Aerosol comparing doses of 180 mcg four times daily with placebo. The effectiveness of Proair hfa (Albuterol sulfate) 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 (Albuterol sulfate) 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 (Albuterol sulfate) Inhalation Aerosol in 95 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol four times daily with placebo
The safety and effectiveness of Proair hfa (Albuterol sulfate) Inhalation Aerosol in pediatric patients below the age of 4 years have not been established.
Clinical studies of Proair hfa (Albuterol sulfate) 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 .
All beta-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.
Proair hfa (Albuterol sulfate) Overdosage
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 (Albuterol sulfate) Inhalation Aerosol.
Treatment consists of discontinuation of Proair hfa (Albuterol sulfate) 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 (Albuterol sulfate) 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/m basis and approximately 3,200 times the maximum recommended daily inhalation dose for children on a mg/m 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/m basis and approximately 1,400 times the maximum recommended daily inhalation dose for children on a mg/m 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/m basis and approximately 6,400 times the maximum recommended daily inhalation dose for children on a mg/m basis). The inhalation median lethal dose has not been determined in animals.
Proair hfa (Albuterol sulfate) Description
The active ingredient of Proair hfa (Albuterol sulfate) Inhalation Aerosol is albuterol sulfate, a racemic salt, of albuterol. Albuterol sulfate has the chemical name α-[(-butylamino) methyl]-4-hydroxy--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 (CHNO)•HSO. 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 (Albuterol sulfate) 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.
Proair hfa (Albuterol sulfate) Clinical Pharmacology
Albuterol sulfate is a beta-adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta-adrenergic receptors on airway smooth muscle. Activation of beta-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 beta-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta-adrenergic receptors. The precise function of these receptors has not been established .
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 .
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 (Albuterol sulfate) Inhalation Aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak plasma concentrations (C) and systemic exposure (AUC) 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 (Albuterol sulfate) Inhalation Aerosol was approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences between the products.
The pharmacokinetic profile of Proair hfa (Albuterol sulfate) 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 (Albuterol sulfate) Inhalation Aerosol (180 mcg albuterol base) yielded a least square mean (SE) C and AUC 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 (Albuterol sulfate) Inhalation Aerosol was 166 (7.8) minutes.
Metabolism and Elimination:
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:
The effect of hepatic impairment on the pharmacokinetics of Proair hfa (Albuterol sulfate) 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 (Albuterol sulfate) Inhalation Aerosol to patients with renal impairment .
Proair hfa (Albuterol sulfate) Nonclinical Toxicology
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/m basis and approximately 6 times the maximum recommended daily inhalation dose for children on a mg/m 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/m basis and approximately 740 times the maximum recommended daily inhalation dose for children on a mg/m 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/m basis and approximately 100 times the maximum recommended daily inhalation dose for children on a mg/m 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 AH1 strain 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/m basis).
Preclinical:
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 (T) 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 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/m 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/m 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.
Proair hfa (Albuterol sulfate) Clinical Studies
Adult and Adolescent Patients 12 Years of Age and Older:
Serial FEV measurements, shown below as percent change from test-day baseline at Day 1 and at Day 43, demonstrated that two inhalations of Proair hfa (Albuterol sulfate) Inhalation Aerosol produced significantly greater improvement in FEV 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.
In this study, 31 of 58 patients treated with Proair hfa (Albuterol sulfate) Inhalation Aerosol achieved a 15% increase in FEV 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 (Albuterol sulfate) 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 this study, 21 of 50 pediatric patients treated with the same formulation of albuterol as in Proair hfa (Albuterol sulfate) Inhalation Aerosol achieved a 15% increase in FEV 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 (Albuterol sulfate) Inhalation Aerosol, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo HFA inhalation aerosol. Serial FEV measurements, expressed as the baseline-adjusted percent predicted FEV observed over 6 hours post-dose, demonstrated that one and two inhalations of Proair hfa (Albuterol sulfate) Inhalation Aerosol produced significantly greater bronchodilator responses than the matched placebo.
In a randomized, single-dose, crossover study in 24 adults and adolescents with exercise-induced bronchospasm (EIB), two inhalations of Proair hfa (Albuterol sulfate) taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as maintenance of FEV 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) How Supplied/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 59310-579-20). 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).
Proair hfa (Albuterol sulfate) Patient Counseling Information
See FDA-Approved Patient Labeling ()
Patients should be given the following information:
Proair hfa (Albuterol sulfate)
Proair hfa (Albuterol sulfate)
