Levalbuterol Drug Information

• Levalbuterol inhalation solution (concentrate) is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease. Levalbuterol inhalation solution (concentrate) is a beta 2 -adrenergic agonist indicated for:
• Treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

• Levalbuterol inhalation solution (concentrate) is for oral inhalation only. Dilute with sterile normal saline before administration. Administer by nebulization using with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor. Do not exceed recommended dose. For dosages less than 1.25 mg, the non-concentrate (i.e., levalbuterol inhalation solution, 3 mL) formulation must be used. Routine dosing should not exceed 0.63 mg three times a day. Patients 12 years of age and older with more severe asthma or patients who do not respond adequately to a dose of 0.63 mg of levalbuterol inhalation solution may benefit from a dosage of 1.25 mg three times a day. Patients receiving the highest dose of levalbuterol inhalation solution should be monitored closely for adverse systemic effects, and the risks of such effects should be balanced against the potential for improved efficacy. The use of levalbuterol inhalation solution can be continued as medically indicated to help control recurring bouts of bronchospasm. During this time, most patients gain optimal benefit from regular use of the inhalation solution. If a previously effective dosage regimen fails to provide the usual response this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. 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. The safety and efficacy of levalbuterol inhalation solution have been established in clinical trials when administered using the PARI LC Jet™ and PARI LC Plus™ nebulizers, and the PARI Master ® Dura-Neb ® 2000 and Dura-Neb ® 3000 compressors. The safety and efficacy of levalbuterol inhalation solution when administered using other nebulizer systems have not been established.
• FOR ORAL INHALATION ONLY
• Dilute levalbuterol inhalation solution (concentrate) with sterile normal saline before administration by nebulization.
• Children 6 to 11 Years Old: 0.31 mg administered three times a day, by nebulization. The maximum recommended dose is 1.25 mg three times a day.
• For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of the drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults and Adolescents 12 Years of Age and Older Adverse reaction information concerning levalbuterol inhalation solution in adults and adolescents is derived from one 4-week, multicenter, randomized, double-blind, active-, and placebo-controlled trial in 362 patients with asthma 12 years of age and older. Adverse reactions reported in ≥ 2% of patients receiving levalbuterol inhalation solution or racemic albuterol and more frequently than in patients receiving placebo are listed in Table 1.

Table 1: Adverse Reactions Reported in a 4-Week, Controlled Clinical Trial in Adults and Adolescents ≥ 12 Years Old 0 The incidence of certain systemic beta-adrenergic adverse reactions (e.g., tremor, nervousness) was slightly less in the levalbuterol inhalation solution 0.63 mg group compared with the other active treatment groups. The clinical significance of these small differences is unknown. Changes in heart rate and plasma glucose were slightly less in the levalbuterol inhalation solution 0.63 mg group compared with the other active treatment groups (see Table 2).

After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were generally diminished compared with day 1 in all active treatment groups. Table 2: Mean Changes from Baseline Heart Rate at 15 Minutes and Glucose and Potassium at 1 Hour after First Dose (Day 1) in Adults and Adolescents ≥ 12 Years Old No other clinically relevant laboratory abnormalities related to administration of levalbuterol inhalation solution were observed in this study. In the clinical trials, a slightly greater number of serious adverse events, discontinuations due to adverse events, and clinically significant ECG changes were reported in patients who received levalbuterol inhalation solution 1.25 mg compared with the other active treatment groups.

The following adverse reactions, considered potentially related to levalbuterol inhalation solution, occurred in less than 2% of the 292 subjects who received levalbuterol inhalation solution and more frequently than in patients who received placebo in any clinical trial: The following reactions, considered potentially related to levalbuterol inhalation solution, occurred in less than 2% of the treated subjects but at a frequency less than in patients who received placebo: asthma exacerbation, cough increased, wheezing, sweating, and vomiting. Adverse reactions reported in ≥ 2% of patients in any treatment group and more frequently than in patients receiving placebo are listed in Table 3. Table 3: Most Frequently Reported Adverse Reactions (≥ 2% in Any Treatment Group) and Those Reported More Frequently Than in Placebo during the Double-Blind Period (ITT Population, 6 to 11 Years Old) Note: Subjects may have more than one adverse event per body system and preferred term.

Changes in heart rate, plasma glucose, and serum potassium are shown in Table 4. 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 their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), asthma, chest pain, cough increased, dysphonia, dyspnea, gastroesophageal reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, urticaria.

In addition, levalbuterol inhalation solution, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, headache, and drying or irritation of the oropharynx.

Short-Acting Bronchodilators

Avoid concomitant use of other short-acting sympathomimetic bronchodilators or epinephrine in patients being treated with levalbuterol inhalation solution. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

Beta-blockers

Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists such as levalbuterol inhalation solution, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma.

In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

Diuretics The ECG changes or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop and 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 beta-agonists with non-potassium-sparing diuretics. Consider monitoring potassium levels.

Digoxin

Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving levalbuterol inhalation solution 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 levalbuterol inhalation solution.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

Levalbuterol inhalation solution 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 levalbuterol on the vascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medication, including levalbuterol inhalation solution during pregnancy. To enroll in MotherToBaby Pregnancy Studies’ Asthma & Pregnancy Study or for more information about the registry, call 1-877- 311-8972 or visit www.mothertobaby.org/ongoing-study/asthma. Risk Summary There are no adequate and well-controlled studies of levalbuterol inhalation solution (concentrate) in pregnant women.

There are clinical considerations with the use of levalbuterol inhalation solution (concentrate) in pregnant women. Following oral administration of levalbuterol HCl to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day; however, racemic albuterol sulfate was teratogenic in mice (cleft palate) and rabbits (cranioschisis) at doses slightly higher than the human therapeutic range ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations(s) are unknown.

In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, 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.

Labor or Delivery Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of levalbuterol inhalation solution for the treatment of bronchospasm during labor should be restricted to those patients for whom the benefits clearly outweigh the risk. Levalbuterol inhalation solution has not been approved for the management of preterm labor. The benefit-risk ratio when levalbuterol inhalation solution is administered for tocolysis has not been established.

Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including racemic albuterol. Data Animal Data The oral administration of levalbuterol HCl to pregnant New Zealand White rabbits during the period of organogenesis found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 108 times the MRHDID of levalbuterol HCl for adults on a mg/m 2 basis). In a rat development study, racemic albuterol sulfate administered by inhalation did not produce any teratogenic effects at exposure approximately 63 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg).

However, other developmental studies with the racemic albuterol sulfate, did result in teratogenic effects in mice and rabbits at doses slightly higher than the human therapeutic range. Similar effects were not observed at approximately 0.03 times the MRHDID for adults on a mg/m 2 basis at maternal dose of 0.025 mg/kg/day (i.e., less than the therapeutic dose). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).

Pediatric Use Pediatric Patients 6 Years of Age and Older The safety and efficacy of levalbuterol inhalation solution have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial. Pediatric Patients Less Than 6 Years of Age Levalbuterol inhalation solution is not indicated for pediatric patients less than 6 years of age. Clinical trials with levalbuterol inhalation solution in this age group failed to meet the primary efficacy endpoint and demonstrated an increased number of asthma-related adverse reactions following chronic levalbuterol inhalation solution treatment.

Efficacy and safety data for levalbuterol inhalation solution in this age group are primarily available from one 3-week, multicenter, randomized, double-blind, placebo-controlled study (Study 1) in 211 pediatric patients between the ages of 2 and 5 years, of whom 119 received levalbuterol inhalation solution. Over the 3 week treatment period, there were no significant treatment differences in the Pediatric Asthma Questionnaire (PAQ) total score between groups receiving levalbuterol inhalation solution 0.31 mg, levalbuterol inhalation solution 0.63 mg, racemic albuterol, and placebo. Additional safety data following chronic dosing is available from a 4-week, multicenter, randomized, modified-blind, placebo-controlled study (Study 2) of 196 patients between the ages of birth and 3 years, of whom 63 received open-label levalbuterol inhalation solution.

In these two studies, treatment-emergent asthma exacerbations or asthma-related adverse reactions and treatment discontinuations due to asthma occurred at a higher frequency in levalbuterol inhalation solution-treated subjects compared to control (Table 5). Other adverse reactions were consistent with those observed in the clinical trial population of patients 6 years of age and older.

• Levalbuterol inhalation solution is contraindicated in patients with a history of hypersensitivity to levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.
• Hypersensitivity to levalbuterol or racemic albuterol.

The expected symptoms with overdosage are those of excessive beta-adrenergic receptor 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/min., arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of levalbuterol inhalation solution.

Treatment consists of discontinuation of levalbuterol inhalation solution together with appropriate symptomatic therapy. The judicious use of a cardio selective 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 levalbuterol inhalation solution.