General Administration Information
For storage information, see the specific product information within the How Supplied section.
Oral Inhalation Administration
Oral Inhalation (inhalation aerosol; metered-dose inhaler [MDI])
-Instruct the patient and/or caregiver on proper inhalation technique. Make sure the canister is firmly seated in the plastic mouthpiece actuator before each use. Shake the inhaler well. Prime the inhaler prior to the initial use by releasing 4 sprays into the air, away from the eyes and face. If not used for more than 3 days, re-prime the inhaler.
-For patients of any age unable to coordinate inhalation and actuation, a spacer or valved holding chamber (VHC) may be beneficial.
-The choice of using a mouthpiece versus a face mask with a spacer/VHC device must be made based on the skills and understanding of each individual patient. However, in general, children younger than 4 years require administration with a tight-fitting face mask and spacer/VHC device to achieve optimal delivery. If a face mask is used, allow 5 to 6 inhalations per actuation. Administer 1 puff at a time.
-If the patient is using other inhalers, instruct them to use levalbuterol first and wait 5 minutes, then use other inhalers as directed.
-After administration, instruct patient to rinse mouth with water to minimize dry mouth.
-The blue actuator (mouthpiece) supplied with levalbuterol (Xopenex HFA) should not be used with any other product canisters; conversely, actuators from other products should not be used with the levalbuterol (Xopenex HFA) canister.
-The dose indicator on the canister indicates the number of remaining inhalations. The dose indication display will move every tenth actuation. Towards the end of the usable inhalations, the color behind the number in the dose indicator window will change to red. Discard when the dose indicator display window shows zero.
-Clean the plastic mouthpiece of the inhaler at least once a week. After removing the medication canister wash the mouthpiece in warm running water. Shake excess water from the mouthpiece. Allow the actuator to air-dry completely. Blockage from medicine build up is more likely to occur if the actuator is not allowed to air-dry thoroughly. If build-up occurs, then washing the actuator will remove the blockage.
-To avoid the spread of infection, do not use the inhaler for more than one person.
Inhalation Solution for Nebulization
-For 3 mL inhalation solution vials: No dilution is necessary; the single-dose vials are ready-to-use.
-For 0.5 mL inhalation solution concentrate vials: Squeeze entire contents of vial into nebulizer reservoir; then, dilute solution to a final volume of 3 mL with sterile 0.9% NaCl Injection, and gently swirl nebulizer reservoir to mix.
-NOTE: For dosages less than 1.25 mg, the 3 mL inhalation solution vials must be used.
-Deliver solution by nebulization over 5 to 15 minutes.
-According to the manufacturer, the compatibility of levalbuterol inhalation solution with other drugs administered by nebulization has not been established; however, clinical guidelines state that levalbuterol nebulizer solution and budesonide suspension for nebulization are compatible in the same nebulizer.
-Safety and efficacy have been established when administered via PARI LC Jet or PARI LC Plus nebulizers and via PARI Master Dura-Neb 2000 or Dura-Neb 3000 compressors.
-The choice of using a mouthpiece versus a face mask must be made based on the skills and understanding of each individual patient.
-Using the 'blow by' technique (i.e., holding the face mask or open tube near the patient's nose and mouth) is not recommended.
-To avoid microbial contamination, aseptic technique should be used each time a multi-dose bottle is opened. Precautions should be taken to prevent contact of dropper tip with any surface, including nebulizer reservoir and ventilatory equipment. Each multi-dose bottle should be used for only 1 patient.
-Discard the vial if the solution is not colorless.
-Storage: Protect from light.-For 3 mL inhalation solution vials: Unit-dose vials should be stored in the protective foil pouch. If a vial is removed from the pouch and not used immediately, protect from light and use within 1 week. Once the protective foil pouch is opened use all contained vials within 2 weeks.
-For 0.5 mL inhalation solution concentrate vials: Use the contents of the vial immediately after the foil pouch is opened; do not store for future use.
During clinical trials of nebulized levalbuterol in patients < 6 years (n = 379), treatment-emergent asthma exacerbations (10-14% vs. 4% placebo and 6% albuterol) or asthma-related adverse reactions (10% vs. 4% placebo) and treatment discontinuations due to asthma (3-12% vs. 0-2% placebo and 4% albuterol) occurred at a higher frequency in levalbuterol-treated patients compared to the control group. Those receiving levalbuterol inhalation aerosol (n = 65; age < 4 years) also had a higher frequency of asthma-related adverse reactions (12%) and treatment discontinuations due to asthma (2%) compared to placebo (4% and 0%, respectively). Other adverse reactions were consistent with those see in patients >= 6 years of age.
The most common adverse reactions associated with levalbuterol use are related to its sympathomimetic effects, although certain cardiovascular effects may be less common with levalbuterol than with sympathomimetics that have less selectivity for beta2-adrenergic receptors. In general, the sympathomimetic effects of levalbuterol are dose-related.
Central nervous system (CNS) adverse reactions are common with levalbuterol inhalation solution (0.63 or 1.25 mg doses). Restlessness or nervousness (2.8-9.6%) and tremor (6.8%) are the most common adverse effects reported in adolescents and adults. In children 4-11 years old, the most common side effect is headache (7.6-11.9). Dizziness (1.4-2.7%), anxiety (<= 2.7%), insomnia (< 2%), migraine (<= 2.7%), and vertigo are less frequent reactions reported in adults or children receiving levalbuterol.
Like other sympathomimetics, levalbuterol can cause various adverse cardiovascular effects including hypertension, angina, palpitations, and sinus tachycardia (2.7-2.8%). Although infrequent, peripheral vasodilation (hypotension, syncope) can also occur from beta2-stimulation of vasculature. Arrhythmia exacerbation or precipitation, such as atrial fibrillation, supraventricular tachycardia (SVT), and extrasystole have been reported with levalbuterol use. 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. Cardiac effects may be related to sympathomimetic effects and/or beta-agonist-induced hypokalemia. Stimulation of beta2-receptors results in gluconeogenesis and intracellular movement of potassium, which may cause hyperglycemia and hypokalemia. These effects occur most commonly with inhalation (via nebulization) of high doses of beta-agonists. Clinically significant effects are uncommon after administration of levalbuterol at recommended doses. In clinical trials, the effects on heart rate, plasma glucose, and plasma potassium were generally diminished after 4 weeks (compared to day 1) in all treatment groups.
As with other inhaled beta-2 agonists, paradoxical bronchospasm can occur after treatment with levalbuterol and can be life-threatening. If this occurs, discontinue levalbuterol immediately and institute alternative therapy. Rare cases of anaphylactoid reactions, angioedema, bronchospasm, and oropharyngeal edema have been reported with levalbuterol use. In clinical trials, rash (unspecified) was reported in <= 7.5% of patients, and urticaria was reported in <= 3% of patients.
Respiratory and/or infectious adverse events reported with inhaled levalbuterol therapy include viral infection (6.9-12.3%) and rhinitis (2.7-11.1%). Similarly, the most frequent adverse reactions in adolescents and adults receiving 90 mcg of levalbuterol inhalation aerosol are asthma (9.4%), pharyngitis (7.9%), and rhinitis (7.4%). In children 4-11 years receiving levalbuterol, the most common side effects are asthma (9-9.1%), fever (3-9.1%), pharyngitis (3-10.4%), viral infection (7.6-9%), and rhinitis (6.1-10.4%). Less frequent reactions reported in adults or children receiving levalbuterol via oral inhalation include increased cough (<= 4.1%), sinusitis (1.4-4.2%), influenza syndrome (<= 4.2%), epistaxis (< 2%), and lymphadenopathy (<= 3%). Throat irritation and hoarseness may also occur after beta-agonist oral inhalation. Dyspnea has been reported with post-marketing use. Conjunctivitis has also been reported (< 2%); however, in clinical practice, this is sometimes due to incorrect administration technique.
Muscle cramps (leg cramps) (<= 2.7%), pain (<= 4%), asthenia (weakness) (3%), myalgia (< 2%), and turbinate edema (1.4-2.8%) have been reported in adults or children receiving levalbuterol via oral inhalation. Accidental injury (4.5-9.2%) is one of the most common adverse events reported in children 4-11 years of age. Other adverse events reported less frequently (< 2%) in clinical trials include paresthesias and chest pain (unspecified).
Gastrointestinal (GI) adverse effects have been reported with levalbuterol. In children 4-11 years of age receiving inhaled levalbuterol, the most common side effects reported in clinical trials were diarrhea (1.5-6%) and vomiting (11%). Abdominal pain (1.5%) was reported in children 6-11 years of age receiving levalbuterol inhalational solution. Less frequent reactions reported in adults or children receiving levalbuterol via oral inhalation were constipation (< 2%), dyspepsia (<= 2.7%), dysphonia, gastroenteritis (< 2%), gastroesophageal reflux disease (GERD), dry mouth (xerostomia), and nausea.
Metabolic acidosis has been reported in post-marketing experience with levalbuterol inhalation solution and aerosol. A causal relationship has not been established. Diabetic ketoacidosis has been reported after administration of large doses of intravenous albuterol; the potential for this adverse event after the use of other albuterol dosage forms is unknown.
Do not exceed the recommended dose of levalbuterol; fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown; however, cardiac arrest after an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.
Levalbuterol is contraindicated in patients with a known levalbuterol hypersensitivity or albuterol hypersensitivity, or hypersensitivity to any component of the specific dosage formulation. Immediate hypersensitivity reactions can occur after administration of racemic albuterol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.
Paradoxical bronchospasm can occur after treatment with levalbuterol and can be life-threatening. If this occurs, levalbuterol should be discontinued immediately and supportive care provided as necessary. In addition, increased levalbuterol use (> 2 days/week, not including exercise-induced bronchospasm) 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 appropriate evaluation of the patient and the treatment strategy is warranted, giving special consideration to corticosteroid therapy. Levalbuterol 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 levalbuterol therapy is instituted. Clinical trials of levalbuterol nebulized solution (n = 379; children < 6 years) and inhalation aerosol (n = 65; children < 4 years) failed to meet the primary efficacy endpoint and demonstrated an increased number of asthma-related adverse reactions with chronic treatment. Young patients should be carefully monitored for treatment-emergent asthma exacerbations or asthma-related adverse reactions.
Levalbuterol, like other sympathomimetic amines, should be used cautiously in patients with a history of seizures or seizure disorder, hyperthyroidism, pheochromocytoma, or unusual responsiveness to other sympathomimetic amines. Pheochromocytoma may increase the risk of prolonging the QT interval when using levalbuterol.
Levalbuterol should be used with caution in patients with cardiovascular disorders including ischemic cardiac disease (coronary artery disease), hypertension, cardiac arrhythmias, tachycardia, or QT prolongation. Beta-agonists should also be avoided in patients with suspected or known congenital long QT syndrome due to the risk for torsade de pointes and QT prolongation. Use levalbuterol with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Significant changes in systolic and diastolic blood pressures and heart rate could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. As with other beta-adrenergic agonist medications, levalbuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects including QT prolongation. The decrease is usually transient, not requiring supplementation. Correct pre-existing hypokalemia prior to beta-agonist administration. Monitor heart rate and blood pressure in patients receiving high doses of levalbuterol for acute asthma exacerbations; cardiovascular adverse effects are more likely to occur when aggressive doses are used.
Because albuterol clearance is decreased in patients with renal impairment, use caution when administering high doses of inhaled levalbuterol to patients with renal impairment or renal failure. The pharmacokinetics of albuterol were studied in a small number of adult subjects with creatinine clearances between 7 to 53 mL/minute in comparison to healthy volunteers. The half-life was unchanged; however albuterol clearance was decreased by 67% in those with renal impairment.
Levalbuterol should be used with caution in patients with diabetes mellitus. Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. In addition, patients with diabetic ketoacidosis (DKA) typically have severe electrolyte imbalance. Serum potassium concentrations must be closely monitored during the treatment of DKA and levalbuterol may contribute to changes in serum potassium concentrations.
Description: Levalbuterol is a moderately selective short-acting beta-2 receptor agonist (SABA). It is the R-enantiomer of racemic albuterol. Levalbuterol is primarily responsible for beta-2 adrenergic receptor-mediated bronchodilation, while the S-isomer of albuterol appears to be devoid of significant therapeutic actions. When given in equimolar doses of R-albuterol (i.e., 2.5 mg of racemic albuterol or 1.25 mg of levalbuterol), levalbuterol produces bronchodilation and clinical activity similar to the parent drug. Levalbuterol is indicated for the treatment or prevention of bronchospasm in patients with reversible obstructive airway disease (e.g., asthma). Orally inhaled SABAs are recommended for the management of asthma exacerbations in pediatric patients. SABAs should not be used alone to manage asthma, but continue to be an option for reliever therapy in pediatric patients with intermittent asthma and those with mild or moderate persistent asthma who are taking controller therapy such as inhaled corticosteroid (ICS) or ICS-long-acting beta-agonist (LABA) regimens. SABAs remain a key reliever therapy for infants and very young children (less than 4 years of age). However, guidelines now promote the use of "SMART" (single maintenance and reliever therapy) inhaler dosing strategies as preferred asthma management for selected older pediatric patients; such regimens usually combine an ICS with formoterol. SABAs also prevent exercise-induced bronchospasm (EIB), however, tolerance can develop with regular use and the incidence of EIB can usually be reduced with maintenance ICS therapy. Levalbuterol HFA inhalation aerosol (MDI) is FDA-approved in pediatric patients 4 years of age and older; the solution for nebulization is FDA-approved in pediatric patients 6 years of age and older.
For asthma exacerbation (e.g., primary care or acute care management):
Nebulized Inhalation dosage (solution for nebulization; various concentrations):
Infants* and Children* 5 years and younger: 1.25 mg via nebulizer every 20 minutes for the first hour for acute exacerbation, with reassessment after that (further dosing not specified).
Children 6 to 11 years: 1.25 mg via nebulizer every 20 minutes for the first hour for acute exacerbation, with reassessment after that (further dosing not specified). Typical dose range: 0.31 mg to 0.63 mg via nebulizer 3 times daily, every 6 to 8 hours.
Children and Adolescents 12 to 17 years: 1.25 mg via nebulizer every 20 minutes for the first hour for mild to moderate exacerbation. After the first hour, 1.25 mg every 3 to 4 hours and up to 1.25 mg every 1 to 2 hours, or more often. Typical dose range: 0.63 mg to 1.25 mg via nebulizer 3 times daily, every 6 to 8 hours.
For transient increase in bronchospasm (e.g., episodic wheezing) as asthma reliever therapy:
Oral Inhalation dosage (inhalation aerosol, e.g., Xopenex HFA):
Children and Adolescents 4 to 17 years: 90 mcg (2 actuations of 45 mcg/actuation) every 4 to 6 hours as needed for bronchospasm; for some patients, 45 mcg (1 actuation) every 4 hours may be sufficient. Max: 12 actuations/day (540 mcg/day).
Nebulized Inhalation dosage (solution for nebulization; various concentrations):
Children 6 to 11 years: 0.31 to 0.63 mg via nebulizer 3 times daily as needed. Max: 3 doses/day (1.89 mg/day).
Children and Adolescents 12 to 17 years: 0.63 to 1.25 mg via nebulizer 3 times daily (every 6 to 8 hours) as needed. Max: 3 doses/day (3.75 mg/day).
For exercise-induced bronchospasm prophylaxis*:
Oral Inhalation dosage (inhalation aerosol; e.g., Xopenex HFA):
Children and Adolescents 4 to 17 years: 90 mcg (2 actuations of 45 mcg/actuation) via oral inhalation, administered 15 minutes (range, 5 to 20 minutes) before exercise. A controller agent (e.g., daily inhaled corticosteroid) is recommended to be used along with as-needed and pre-exercise SABAs like levalbuterol.
Maximum Dosage Limits:
Safety and efficacy have not been established.
Safety and efficacy have not been established.
< 4 years: Safety and efficacy have not been established.
4-5 years: 2 puffs (MDI) every 4 hours PRN for treatment/prevention of bronchospasm; higher doses may be required acutely during severe asthma exacerbations. Safety and efficacy of the nebulized oral solution has not been established; however, doses up to 0.15 mg/kg/dose (Max: 5 mg/dose) have been used off-label for acute exacerbations.
6-11 years: 2 puffs (MDI) every 4 hours PRN for treatment/prevention of bronchospasm; higher doses may be required acutely during severe asthma exacerbations. For nebulized solution, 0.63 mg/dose given 3 times/day for treatment/prevention of bronchospasm; doses up to 0.15 mg/kg/dose (Max: 5 mg/dose) have been used off-label for acute exacerbations.
12 years: 2 puffs (MDI) every 4 hours PRN for treatment/prevention of bronchospasm; higher doses may be required acutely during severe asthma exacerbations. For nebulized solution, 1.25 mg/dose given 3 times/day for treatment/prevention of bronchospasm; doses up to 5 mg/dose have been used off-label for acute exacerbations.
2 puffs (MDI) every 4 hours PRN for treatment/prevention of bronchospasm; higher doses may be required acutely during severe asthma exacerbations. For nebulized solution, 1.25 mg/dose given 3 times/day for treatment/prevention of bronchospasm; doses up to 5 mg/dose have been used off-label for acute exacerbations.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. Although no specific dosage adjustments are recommended, caution may be warranted during the administration of high doses in patients with renal impairment, as renal clearance is reduced.
Monograph content under development
Mechanism of Action: Levalbuterol is the R-isomer of albuterol. It is a moderately selective beta2-adrenergic agonist that stimulates receptors of the smooth muscle in the lungs, uterus, and vasculature supplying skeletal muscle. Results from an in vitro study of binding to human beta-adrenergic receptors demonstrated that levalbuterol has approximately 2-fold greater binding affinity than racemic albuterol and approximately 100-fold greater binding affinity than (S)-albuterol.
Relief of Bronchoconstriction
The R-isomer of albuterol, levalbuterol, is primarily responsible for bronchodilation, while the S-isomer lacks significant bronchodilator effects. Although not confirmed during clinical trials in humans, the S-isomer of albuterol has been shown to increase airway reactivity in animal models. The net result of beta2-receptor agonism in the lungs is relaxation of bronchial and tracheal smooth muscles, which in turn relieves bronchospasm, reduces airway resistance, facilitates mucous drainage, and increases vital capacity. Stimulation of beta2-receptors on peripheral vascular smooth muscle can cause vasodilation and a modest decrease in diastolic blood pressure. Intracellularly, the actions of levalbuterol are mediated by cyclic-3',5'-adenosine monophosphate (cAMP), the production of which is augmented by beta2-stimulation. Levalbuterol is believed to work by activating adenyl cyclase, the enzyme responsible for generating cAMP, an intracellular mediator. Increased cAMP leads to activation of protein kinase A, which inhibits phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in bronchial smooth muscle relaxation. Increased cAMP also inhibits the release of histamine, leukotriene, and prostaglandin D2, and tumor necrosis factor alpha from mast cells. Inhibition of mediator release is believed to inhibit bronchoconstriction secondary to exercise and cold dry air.
Treatment of Hyperkalemia
Albuterol is an effective adjunctive treatment for hyperkalemia; beta2-adrenergic stimulation results in intracellular accumulation of serum potassium due to stimulation of the sodium-potassium adenosine triphosphatase (Na/K ATPase) pump, leading to moderate degrees of hypokalemia. When compared to albuterol, levalbuterol is equivalent to albuterol in lowering serum potassium and may have a faster onset of action.
Pharmacokinetics: Levalbuterol is administered by inhalation, either by nebulization or inhaler. Levalbuterol is the pharmacologically active R-isomer of albuterol. Intravenous studies in animals have shown that racemic albuterol crosses the blood-brain barrier. Levalbuterol appears to be preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3 (sulfotransferase); however, levalbuterol is not administered enterally in clinical practice. The primary route of elimination of albuterol enantiomers is through renal excretion (80-100%), with 25-46% of the levalbuterol portion being excreted as unchanged drug in the urine. Less than 20% of the drug is excreted in the feces. The half-life is 3.3-4 hours in patients >= 12 years.
Affected cytochrome P450 isoenzymes: none
Although some of the inhaled dose is swallowed, systemic bioavailability via the GI tract is minimal. Plasma concentrations of levalbuterol after oral inhalation of therapeutic doses are very low. Peak serum concentrations of levalbuterol occur approximately 12 minutes after administration.
-Oral inhalation solution: In adolescents and adults (>= 12 years of age), the mean onset time (15% increase in FEV1) for nebulized doses of 0.63 mg and 1.25 mg levalbuterol is approximately 17 and 10 minutes, respectively. The mean time to peak effect is approximately 1.5 hours. The mean duration (>15% increase in FEV1) after administration of 0.63 and 1.25 mg doses of levalbuterol is 5 and 6 hours, respectively. In some patients, the duration of effect was as long as 8 hours.
-Oral inhalation aerosol: In patients 4-81 years of age, the mean onset time (15% increase in FEV1) for aerosolized doses of 90 mcg of levalbuterol (2 inhalations) ranges from 5.5-10.2 minutes. The median time to peak effect is 76-78 minutes. The median duration (> 15% increase in FEV1) after administration of 90 mcg of levalbuterol is 3-4 hours, with a duration of effect as long as 6 hours in some patients.
The pharmacokinetics of albuterol were studied in a small number of subjects with creatinine clearances between 7-53 ml/minute in comparison to healthy volunteers. The half-life was unchanged; however, albuterol clearance was decreased by 67% in those with renal impairment. Caution should be used when administering high doses of inhaled albuterol (or levalbuterol) to patients with renal impairment.