Professional Information
Levalbuterol (Inhalation-Local)
VA CLASSIFICATION
Primary: RE120
Commonly used brand name(s): Xopenex.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Bronchodilator, adrenergic (inhalation-local)—
Indications
Accepted
Bronchospasm (treatment) or
Bronchospasm (prevention)—Levalbuterol is indicated for the treatment or prevention of bronchospasm due to reversible obstructive airway disease {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Description
Levalbuterol is an off-white, crystalline solid and is the (R)-enantiomer of the drug substance racemic albuterol {01}.
Melting Point
187 °C.
Molecular weight—
275.8 {01}
pH
4. (3.3 to 4.5) {01}.
Solubility
180 mg/ml in water {01}.
Mechanism of action/Effect:
Levalbuterol binds to beta 2-adrenergic receptors on airway smooth muscle. This leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3', 5'-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which inhibits {01} the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation of the smooth muscles of all airways. Levalbuterol relaxes the smooth muscle of the respiratory tree from the trachea to the terminal bronchioles. The increased cyclic AMP concentrations also inhibit the release of mediators from mast cells in the airway {01}.
Other actions/effects:
It should be noted that beta 2-adrenergic receptors comprise between 10% and 50% of cardiac beta-adrenergic receptors and therefore, in some patients, levalbuterol may have significant cardiovascular effects, such as changes in pulse rate, blood pressure, symptoms, and/or electrocardiographic (ECG) changes {01}.
Half-life:
3.3 hours (single 1.25-mg inhalation dose); 4.0 hours (cumulative 5 mg inhalation dose given as 1.25 mg every 30 minutes for 4 doses) {01}.
Onset of action:
The mean time to onset of a 15% increase in forced expiratory volume (FEV 1) over baseline was 10 to 17 minutes for 1.25-mg and 0.63-mg inhalation doses, respectively {01}.
Time to peak concentration:
0.2 hours following both a single 1.25-mg inhalation dose and a cumulative 5-mg inhalation dose (1.25 mg every 30 minutes for 4 doses) {01}.
Peak serum concentration:
1.1 nanograms per milliliter (ng/ml) following a 1.25-mg single inhalation dose; 4.5 ng/ml following a cumulative 5-mg dose (1.25 mg every 30 minutes for 4 doses) {01}.
Time to peak effect:
The mean time to peak effect for inhalation doses of 0.63 mg and 1.25 mg was approximately 1.5 hours after 4 weeks of treatment {01}.
Duration of action:
The mean duration of effect (measured by a >15% increase in FEV 1 from baseline) was 5 and 6 hours after 0.63-mg and 1.25-mg inhalation doses, respectively, after 4 weeks of treatment {01}. In some patients, the duration of effect was as long as 8 hours.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to racemic albuterol may be sensitive to levalbuterol. Immediate hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, oropharyngeal edema, skin rash, and urticaria, may occur after administration of racemic albuterol {01}.
Carcinogenicity
No carcinogenicity studies have been done with levalbuterol {01}.
Tumorigenicity
No tumorigenic studies have been done with levalbuterol; however, there are data available on the tumorigenic effects of racemic albuterol. In a 2 year study in Sprague-Dawley rats, racemic albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above doses of 2 milligram per kilogram of body weight (mg/kg) (approximately 2 times the maximum recommended daily [MRD] human adult inhalation dose) of levalbuterol-HCl, on a mg/m 2 basis. This effect has been blocked by the beta-adrenergic blocker, propranolol {01}, in another study.
Additional studies of racemic albuterol in CD-1 mice and golden hamsters have shown no tumorigenicity at doses equivalent to 270 and 35 times, respectively, the MRD human adult inhalation dose of levalbuterol HCl, on a mg/m 2 basis {01}.
Mutagenicity
Levalbuterol-HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay {01}. Levalbuterol-HCl has not been tested for clastogenicity, but racemic albuterol was not found to be clastogenic when tested in human and mouse assays {01}.
Pregnancy/Reproduction
Fertility—
No impairment of fertility studies have been done with levalbuterol-HCl; however, data are available from fertility studies with racemic albuterol. No evidence of impaired fertility was found in rats using oral doses of racemic albuterol up to 50 mg/kg (approximately 55 times the MRD human adult inhalation dose) of levalbuterol HCl, on a mg/m 2 basis {01}.
Pregnancy—
Levalbuterol crosses the placenta. Well-controlled studies in humans have not been done {01}.
Studies in New Zealand white rabbits receiving doses up to 25 mg/kg (approximately 110 times the MRD human adult inhalation dose) of levalbuterol-HCl, on a mg/m 2 basis, showed no teratogenicity. Racemic albuterol has been shown to cause cleft palate formation in 4.5 to 9.3% of mice and rabbits receiving subcutaneous doses slightly less than and equivalent to the MRD human adult inhalation dose of levalbuterol-HCl, on a mg/m 2 basis. Cleft palate did not result when a subcutaneous dose of 0.025 mg/kg (less than the MRD human adult inhalation dose) of levalbuterol-HCl, on a mg/m 2 basis, was administered. Cranioschisis occurred in 37% of Stride Dutch rabbits receiving racemic albuterol at a dose of 50 mg/kg (equivalent to 110 times the MRD human adult inhalation dose) of levalbuterol-HCl, on a mg/m 2 basis {01}. A study of pregnant rats receiving radiolabeled racemic albuterol demonstrated that drug-related material is transferred from the maternal circulation to the fetus {01}.
FDA Pregnancy Category C.
Labor—
Beta-adrenergic agonists, such as levalbuterol, have the potential to interfere with uterine contractility. Therefore, its use for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Levalbuterol-HCl has not been approved for the management of tocolysis (preterm labor). Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2-agonists, including racemic albuterol {01}.
Breast-feeding
It is not known whether levalbuterol is distributed into human breast milk. Because of the potential for tumorigenicity for racemic albuterol observed in animal studies, caution should be exercised when administering levalbuterol to a nursing woman.
Pediatrics
Appropriate studies on the relationship of age to the effects of levalbuterol have not been performed in children up to 12 years of age. Safety and efficacy have not been established {01}.
Geriatrics
Studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of levalbuterol in the elderly, but these data are insufficient to determine its safety and efficacy in patients 65 years of age and older as compared to patients younger than 65 years of age. In general, patients 65 years of age and older should be started at an inhalation dose of 0.63 mg levalbuterol solution and increased as tolerated, in conjunction with frequent clinical and laboratory monitoring {01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
» Beta-adrenergic blocking agents, systemic (concurrent use, especally propranolol, with adrenergic bronchodilators may result in mutual inhibition of therapeutic effects; beta-adrenergic blockage may antagonize the bronchodilating effect of levalbuterol; cardioselective beta-blockers could be considered, but caution is recommended with these agents as well)
» Digoxin (concurrent use with levalbuterol may reduce serum digoxin levels, as in the case with racemic albuterol. Serum digoxin levels should be carefully evaluated in patients receving digoxin and levalbuterol {01})
» Diuretics, non–potassium-sparing (concurrent use of levalbuterol with non–potassium-sparing diuretics may worsen hypokalemia)
» Monoamine oxidase (MAO) inhibitors or
» Tricyclic antidepressants (concurrent use, or within 2 weeks of discontinuation of MAO inhibitors or tricyclic antidepressants, with levalbuterol may potentiate the action of levalbuterol on the vascular system)
» Methylxanthines (cardiac arrhythmia and sudden death have been reported in animals from concurrent use with levalbuterol)
» Short-acting sympathomimetic aerosol bronchodilators (concurrent use may potentiate cardiac effects)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Electrocardiogram (ECG) (flattened T waves, ST segment depression, and prolongation of the QT c interval are reported rarely with adrenergic bronchodilators {01})
Potassium, serum (concentration may decrease, resulting in hypokalemia {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cardiovascular disorders, such as coronary insufficiency (decreased blood flow through the heart) or cardiac arrhythmias (irregular heartbeat) or
» Convulsive disorders (seizures) (concurrent use may worsen these conditions)
» Hypertension (clinically significant changes in systolic and diastolic blood pressure have been reported after the use of any beta-adrenergic bronchodilators {01})
» Sensitivity to adrenergic bronchodilators or other sympathomimetic amines{01}
Risk-benefit should be considered when the following medical problems exist
Diabetes mellitus (Use of levalbuterol may worsen blood glucose control and diabetic ketoacidosis)
Hyperthyroidism
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Tachycardia (fast heartbeat)
Incidence less frequent or rare
Allergic reaction, bronchospasm, or exacerbation of asthma (chest tightness; hives; shortness of breath; troubled breathing; wheezing)
cardiovascular effects, specifically abnormal ECG changes, hypertension, hypotension,, or syncope (high or low blood pressure; dizziness; light-headedness; feeling “faint”)
chest pain
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Anxiety
dizziness
dyspepsia (stomach pain or burning)
hypertonia (muscle tightness)
increased cough
influenza-like symptoms (fever; general aches and pains; headache; loss of appetite; weakness)
leg cramps
migraines or other headaches
nervousness
rhinitis (runny nose)
sinusitis (runny or stuffy nose)
tremor
viral infection (chills; cough or hoarseness; fever)
Incidence less frequent or rare
Dry mouth or throat
eye itch
gastrointestinal effects (diarrhea; vomiting)
hypesthesia of the hand (numbness or decreased sensitivity)
insomnia (sleeplessness)
lymphadenopathy (fever; night sweats; weight loss)
myalgia (muscle pain)
nausea
paresthesia (tingling sensation in extremities)
Overdose
Although uncommon, fatalities have been reported in association with excessive use of inhaled sympathomimetics {01}.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
The expected symptoms are those of excessive beta-adrenergic receptor stimulation; specifically:
Angina or cardiac arrest (chest pain)
arrhythmia or palpitations (irregular heartbeat)
dizziness
dry mouth
fatigue
headache
hypertension
hypokalemia (low potassium levels in the blood; irregular heartbeat)
hypotension (impaired consciousness; light-headedness; sweating)
insomnia (sleeplessness)
malaise (general feeling of discomfort or illness)
nausea
nervousness
seizures
sudden death
tachycardia (fast heartbeat)
tremor
Treatment of overdose
To enhance elimination—There is insufficient evidence to determine if dialysis is beneficial {01}.
Supportive care—Treatment consists of discontinuation of levalbuterol together with symptomatic therapy. The use of a cardioselective beta-adrenergic receptor blocker may be considered, bearing in mind that this may induce bronchospasm {01}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Levalbuterol— (Inhalation-Local) .
In providing consultation, consider emphasizing the following» selected information ( = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to sympathomimetics
Pregnancy—May have the potential to affect uterine contractility when used in labor
Other medications, especially beta-adrenergic blocking– agents (systemic), digoxin, diuretics (nonpotassium-sparing), methylxanthines, MAO inhibitors, short-acting sympathomimetic aerosol bronchodilators, and tricyclic antidepressants
Other medical problems, especially cardiovascular disorders (coronary insufficiency and cardiac arrhythmia), convulsive disorders (seizures), and hypertension {01}
Proper use of this medication
» Reading patient instructions carefully before using
» Importance of not using more medication than the amount prescribed, because of the potential for enhanced absorption and increased severity of side effects
Proper administration technique for use in nebulizer, administered over a period of 5 to 15 minutes
Not using solution if discolored or cloudy
Not mixing with another inhalation solution unless directed by physician
» Proper dosing
Missed dose: Using as soon as possible; skipping missed dose if almost time for next dose; not doubling doses
» Proper storage
Precautions while using this medication
Regular visits to physician to check progress during therapy
» Checking with physician immediately if difficulty in breathing persists after use of this medication, if condition worsens, or if using more often than prescribed
» Checking with physician before adding or stopping other inhaled drugs or asthma medications {01}
Side/adverse effects
Signs of potential side effects, especially allergic reaction, bronchospasm, or exacerbation of asthma, cardiovascular effects, specifically abnormal ECG changes, hypertension, hypotension, or syncope, chest pain, and tachycardia
Inhaled Dosage Forms
LEVALBUTEROL INHALATION SOLUTION
Usual adult and adolescent dose
Bronchodilator
Inhaled, by nebulization, 0.63 mg to 1.25 mg administered three times a day, every six to eight hours.
Usual adult and adolescent prescribing limits
Up to 1.25 mg three times a day. If a previous effective dose fails to provide the expected relief, medical advice should be sought immediately, as this may be a sign of worsening asthma {01}.
Usual pediatric dose
Bronchodilator
Children up to 12 years of age: Safety and efficacy have not been established {01}.
Children 12 years of age and older: See Usual adult and adolescent dose .
Usual geriatric dose
Bronchodilator
Inhaled, by nebulization, 0.63 mg three times daily, every six to eight hours, may increase as tolerated {01}.
Usual geriatric prescribing limits
Dose increases in this population should only be made in conjunction with frequent clinical and laboratory monitoring {01}. See Usual adult and adolescent prescribing limits .
Strength(s) usually available
U.S.—
0.63 mg (0.73 mg as the HCl salt) (Rx) [Xopenex (sodium chloride)]
1.25 mg (1.44 mg as the HCl salt) (Rx) [Xopenex (sodium chloride)]
Packaging and storage:
Store, in the protective foil pouch, below 40 °C (104 °F), preferably between 15 and 25 °C (59 and 77 °F), unless otherwise specified by manufacturer.
Protect from light and excessive heat.
Unopened vials should be kept in the pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials should be discarded if the solution is not colorless. {01}
Preparation of dosage form:
Levalbuterol inhalation solution is administered by nebulization. Nebulizer systems with established safety and efficacy when used with levalbuterol inhalation solution include the PARI LC Jet™ and the PARI LC Plus™ nebulizers and the PARI Master® and DURA-Neb® 2000 compressors. No diluent is necessary {01}.
Incompatibilities:
The drug compatibility (physical and chemical), efficacy, and safety of levalbuterol inhalation solution when mixed with other drugs in a nebulizer have not been established {01}.
Auxiliary labeling:
• For inhalation only; do not inject or use orally {01}.
• Protect from light and excessive heat {01}.
Revised: 06/14/1999
References
- Xopenex package insert draft (Sepracor—US), Approved 3/29/99, Available from: http://www.fda.gov/cder/approval/index.htm
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