Like other sympathomimetics, albuterol can cause various adverse cardiovascular effects. Although incidences of the adverse effects are often unavailable, systemic albuterol formulations are generally expected to have a higher incidence of adverse effects compared to inhaled formulations. Hypertension (1% to less than 5% incidence from data of various inhaled formulations), angina, palpitations (less than 1% to less than 10%, various formulations), sinus tachycardia (1% to 10%), chest pain (unspecified) (less than 3%), or arrhythmia exacerbation or precipitation have been reported, especially in patients with preexisting cardiovascular disease. Peripheral vasodilation (e.g., hypotension) can also occur from beta-2 stimulation of the vasculature. Albuterol 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 albuterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, ST-T wave changes (e.g., flattening of the T wave, ST segment depression) and QT prolongation. Arrhythmias such as atrial fibrillation, supraventricular tachycardia (SVT), and extrasystole have been reported with albuterol use. Cardiac effects may be related to sympathomimetic effects and/or beta-agonist-induced hypokalemia. Albuterol can cause hyperglycemia and hypokalemia. Both of these effects occur from stimulation of beta-2 receptors, resulting in gluconeogenesis and intracellular movement of potassium. These effects occur most commonly with inhalation (via nebulization) of relatively large doses of albuterol (e.g., 5 to 10 mg).[28532] [40947] [43993] [44010]

Paradoxical bronchospasm can occur after treatment with albuterol and can be life threatening. If this occurs albuterol should be discontinued immediately. Rare cases of anaphylactoid reactions have been reported with beta-agonist therapy. Immediate hypersensitivity reactions may occur after administration of racemic albuterol, as demonstrated by rare cases of anaphylaxis, angioedema, bronchospasm, oropharyngeal swelling, rash (unspecified), and urticaria. Stevens-Johnson syndrome and erythema multiforme have been reported rarely in children who received albuterol.[44003] In clinical trials of albuterol inhalation, bronchospasm (8% to 15.4%), asthma exacerbation, allergic reactions (0.9% to 6%), and urticaria (0.9% to 1.7%) were reported.[28532] [43674] [43993] Use of albuterol inhalation solution produces adverse effects similar to those observed with the inhalation aerosol.[40947]

Central nervous system (CNS) adverse reactions are common with the use of both oral and inhaled albuterol. Tremor is one of the most common adverse effects and has been reported in less than 1% to 20% of patients who received inhaled albuterol in clinical trials. In controlled trials of albuterol oral extended-release tablets, tremor was reported in 24.2% of patients overall; however, the incidence of tremor increased with increasing age with up to 37.9% of adults aged 41 to 50 years experiencing tremor. Other adverse effects associated with albuterol use include headache (3% to 7% with inhaled formulations, 18.8% with extended-release tablet), migraine (1% to 2%), nervousness (1% to 15%), dizziness (3% to 7% and less than 5% with inhaled formulations, 1.5% with extended-release tablets), and insomnia (1% to 3.1%).[43674] [43993] [44002] [44010] Anxiety (less than 3%) and nightmares (1%) have also been reported with some formulations of albuterol inhalation aerosol.[28532] [40947] Emotional lability was reported in 1% of children 2 to 6 years of age receiving albuterol oral solution and agitation, aggressive behavior, and lightheadedness were reported in 1% or less of children 4 to 11 years of age receiving albuterol inhalation aerosol.[40947] [44003] Gastrointestinal (GI) adverse effects associated with both oral and inhaled albuterol include nausea (less than 15%) and vomiting (4.2% to 7%). Throat irritation (6% to 10%), dyspepsia (less than 5%), abdominal pain (3%), diarrhea (less than 3%), tooth discoloration (1%), eructation (less than 3%), and flatulence (less than 3%) have all been reported with inhaled albuterol therapy.[28532] [40947] [31823] Appetite stimulation (3%), abdominal pain (less than 1%), and decreased appetite (1%) have been reported in clinical trials of patients receiving albuterol oral solution. Dry mouth (xerostomia) (less than 3%), throat hoarseness, and unusual taste have also been reported with albuterol therapy.[44003] Other adverse effects occurring with albuterol therapy include epistaxis (1% to 3%) and cough (5% or less).[33925] [40947]

Musculoskeletal pain (3% to 5%), hyperkinesis (4% or less), weakness (2% or less), malaise (1.5%), ataxia (less than 3%), vertigo (less than 3%), rigors (less than 3%), edema (less than 3%), increased sweating (hyperhidrosis) (less than 3%), drowsiness (less than 3%), dysphonia (less than 3%, inhaled formulations) and excitability (2%) have been reported with albuterol use during clinical trials.[28532] [33925] [44002] [44003] [49953] Some adverse effects appear to occur more frequently in young children (2 to 6 years of age) than in older children or adults especially excitability, which occurred in roughly 20% of young children receiving albuterol oral solution in clinical trials.[44003] Muscle cramps (2.7% or less) have been reported with inhaled and oral dosage forms. In controlled trials of albuterol extended-release tablets, the incidence of muscle cramps increased with age (12 to 20 years, 1.2%; 21 to 30 years, 2.6%; 31 to 50 years, 6.9%). Less frequent adverse reactions occurring in less than 1% of patients include flushing, restlessness, irritability, and urinary retention.[44010] Hyperactivity has been reported with postmarketing experience.[49951] A case of hypokalemic periodic muscle paralysis, possibly precipitated by inhaled albuterol, was reported in a patient with a medical history of hypokalemic periodic paralysis (HPP).[56005]

Metabolic acidosis has been reported in post-marketing experience with albuterol inhalation solution and aerosol. A causal relationship has not been established.[43674] [49951] The potential for this effect following the use of oral albuterol dosage forms is unknown.

Infectious and respiratory adverse effects have been reported with inhaled albuterol therapy. In clinical trials of Accuneb (albuterol solution for nebulizer inhalation), otitis media (0.9% to 4.3% vs 0% placebo), gastroenteritis (0.9% to 3.4% vs 0.9% placebo), cold symptoms (3.4% vs 1.7% placebo), flu syndrome (2.6% vs 1.7% placebo), lymphadenopathy (0.9% to 2.6% vs 1.7% placebo), skin/appendage infection (1.7% vs 0% placebo), and bronchitis (0.9% to 1.7% vs 0.9% placebo) were all reported.[43674] Other infectious and respiratory adverse events reported with inhaled albuterol therapy include respiratory tract infection (7% to 21%), pharyngitis (7% to 14%), rhinitis (4% to 16%), fever (6%, reported with albuterol HFA MDI formulation), dyspnea (less than 3%), laryngitis (less than 3%, reported with inhalational formulations), ear disorder (less than 3%), ear pain or otalgia (less than 3%), glossitis (less than 3%), tinnitus (less than 3%), urinary tract infection (less than 3%), increased sputum (1.5%), wheezing (1% to 1.5%), nasopharyngitis (2%), oropharyngeal pain (2%), and nasal congestion (1%).[28532] [31823] [43993] [59350] Conjunctivitis has also been reported in 1% of patients receiving albuterol oral solution.[44003] Eye irritation may occur if formulations for inhalation are inadvertently sprayed in the eyes; patients should prime inhalers into the air and away from the eyes or face.

Paradoxical bronchospasm can occur after treatment with albuterol and can be life-threatening. If this occurs, albuterol should be discontinued immediately and supportive care provided as necessary. Paradoxical bronchospasm, when it occurs, frequently occurs with the first use of a new canister or vial of inhaled formulations of albuterol. Additionally, increased albuterol use may indicate asthma destabilization. Asthma may deteriorate acutely over a period of hours or chronically over several days or weeks. If deterioration of asthma occurs during therapy with albuterol, appropriate evaluation of the patient and the treatment strategy is warranted, giving special consideration to corticosteroid therapy. Albuterol has no anti-inflammatory activity and is not a substitute for inhaled or oral corticosteroid therapy. The use of beta-agonists 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. Corticosteroids should not be stopped or reduced when albuterol therapy is instituted.[31823] [43674] [44010] [49951] [59350] [64470] Do not exceed recommended dosages of beta-agonists; 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 after an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.[31823] [43674] [49951] [59350] [64470]

Albuterol is contraindicated in patients with albuterol hypersensitivity, levalbuterol hypersensitivity, or hypersensitivity to any component of the specific dosage formulation. Albuterol inhalation powder (i.e., ProAir RespiClick and ProAir Digihaler) is contraindicated in patients with severe milk protein hypersensitivity since the formulation contains lactose, which contains milk proteins.[59350] [64470] Immediate hypersensitivity reactions may occur after administration of racemic albuterol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.[31823] [43674] [44010] [49951] [59350] [64470]

Albuterol, like other sympathomimetic amines, should be used cautiously in patients with a history of seizure disorder, hyperthyroidism (thyrotoxicosis), or unusual responsiveness to other sympathomimetic amines.[28532] [49951]

Monitor heart rate and blood pressure in patients receiving high doses of albuterol for acute asthma exacerbations; cardiovascular adverse effects are more likely to occur when aggressive doses are used. Albuterol, like other beta2-agonists and sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency (coronary artery disease), cardiac arrhythmias, and hypertension. Albuterol can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, albuterol may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic (ECG) changes, such as flattening of the T wave, QT prolongation, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Beta-adrenergic agonist therapies like albuterol 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.[31823] [43674] [44010] [49951] [59350] [64470]

Use albuterol with caution in patients with diabetes mellitus. Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and diabetic ketoacidosis. Also, patients with diabetic ketoacidosis (DKA) typically have a severe electrolyte imbalance. Serum potassium concentrations must be closely monitored during the treatment of DKA and albuterol may contribute to changes in serum potassium concentrations.[31823] [43674] [44010] [49951] [59350] [64470]

There are no randomized clinical studies of use of albuterol during pregnancy. Available data from published 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. Poorly controlled or moderately controlled asthma represents risks in pregnant women; there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control.[31823] [43674] [44010] [49951] [59350] [64470] The National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group include short-acting inhaled beta-2 agonists (SABAs) as first-line therapy for mild intermittent asthma during pregnancy, if treatment is required. Inhalation therapy is preferred to oral albuterol treatment. Albuterol is preferred over other SABAs due to extensive safety-related information during pregnancy. However, there is no evidence of fetal injury with the use of other inhaled SABAs, and maintaining a previously established treatment regimen may be more beneficial to the patient.[31822] Due to the potential for beta-agonist interference with uterine contractility, the use of albuterol for acute relief of bronchospasm during labor and obstetric delivery should be restricted to those patients in whom the benefits clearly outweigh the risks. Additionally, albuterol is not approved for the management of pre-term labor; serious adverse events, including pulmonary edema, have been reported after treatment of premature labor with beta-2 agonists. A pregnancy registry is available to monitor pregnancy outcomes in women exposed to asthma medications, including levalbuterol. To enroll in MotherToBaby Pregnancy Studies' Asthma and Pregnancy Study, patients should call 1-877-311-8972 or visit www.mothertobaby.org/ongoing-study/asthma.[31823] [43674] [44010] [49951] [59350] [64470]

According to the National Asthma Education and Prevention Program (NAEPP) for managing asthma during pregnancy, there is currently no contraindication for the use of short-acting inhaled beta-2 agonists, including albuterol, during breast-feeding. Inhaled albuterol therapy is preferred over oral treatment.[31822] Systematic data regarding the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production are lacking. Plasma concentrations of albuterol after inhalation of therapeutic doses are very low in humans and substantially lower than systemically-administered albuterol. If present in breast milk, albuterol has low oral bioavailability in the infant.[31823] [43674] [44010] [49951] [59350] [64470]

Albuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitor therapy (MAOI therapy) or within 2 weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated.[31823] [59350]