Get your patient on Levalbuterol - Levalbuterol Hydrochloride solution (Levalbuterol Hydrochloride)

Children 6-11 years old: The recommended dosage of Levalbuterol Inhalation Solution, USP for patients 6-11 years old is 0.31 mg administered three times a day, by nebulization. Routine dosing should not exceed 0.63 mg three times a day.

Adults and Adolescents ≥ 12 years old: The recommended starting dosage of Levalbuterol Inhalation Solution, USP for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.

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, USP may benefit from a dosage of 1.25 mg three times a day.

Patients receiving the highest dose of Levalbuterol Inhalation Solution, USP 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, USP 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, USP when mixed with other drugs in a nebulizer have not been established.

The safety and efficacy of Levalbuterol Inhalation Solution, USP 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, USP when administered using other nebulizer systems have not been established.

Levalbuterol Inhalation Solution, USP is for oral inhalation only. 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.

(Added the word "with" to read "Administer by nebulization using with a standard jet nebulizer...")

Risk Summary

There are no available data on the presence of levalbuterol in human milk, the effects on the breastfed child, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Levalbuterol Inhalation Solution, USP and any potential adverse effects on the breastfed child from Levalbuterol Inhalation Solution, USP or from the underlying maternal condition.

Pediatric Patients 6 Years of Age and Older

The safety and efficacy of Levalbuterol Inhalation Solution, USP have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial [see Adverse Reactions (6) and Clinical Studies (14) ].

Pediatric Patients less than 6 Years of Age

Levalbuterol Inhalation Solution, USP is not indicated for pediatric patients less than 6 years of age.

Clinical trials with Levalbuterol Inhalation Solution, USP 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, USP treatment.

Levalbuterol Inhalation Solution, USP was studied in 379 pediatric patients less than 6 years of age with asthma or reactive airway disease - (291 patients 2 to 5 years of age, and 88 patients from birth to less than 2 years of age). Efficacy and safety data for Levalbuterol Inhalation Solution, USP in this age group are primarily available from one 3-week, multicenter, randomized, double-blind, active and placebo-controlled study (Study 1) in 211 pediatric patients between the ages of 2 and 5 years, of whom 119 received Levalbuterol Inhalation Solution, USP. 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, USP 0.31 mg, Levalbuterol Inhalation Solution, USP 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, USP. 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-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 [see Adverse Reactions (6.1) ].

• Asthma exacerbation defined as worsening of asthma symptoms or pulmonary function that required any of the following: emergency department visit, hospitalization, therapeutic intervention with oral or parenteral steroids, unscheduled clinic visit to treat acute asthma symptoms

•• Includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnea.

Clinical studies of Levalbuterol Inhalation Solution, USP did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Only 5 patients 65 years of age and older were treated with Levalbuterol Inhalation Solution, USP in a 4-week clinical study [see Clinical Pharmacology (12) and Clinical Studies (14) ] (n = 2 for 0.63 mg and n = 3 for 1.25 mg). In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of Levalbuterol Inhalation Solution, USP. If clinically warranted due to insufficient bronchodilator response, the dose of Levalbuterol Inhalation Solution, USP may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose [see Dosage and Administration (2) ].

Albuterol is 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.

Levalbuterol Inhalation Solution, USP can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, Levalbuterol Inhalation Solution, USP should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new vial.

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of Levalbuterol Inhalation Solution, USP than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

Levalbuterol Inhalation Solution, USP is not a substitute for corticosteroids. The use of beta-adrenergic agonist 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.

Levalbuterol Inhalation Solution, USP, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms. Although such effects are uncommon after administration of Levalbuterol Inhalation Solution, USP at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the t-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, Levalbuterol Inhalation Solution, USP, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Do not exceed the recommended dose. 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 following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

Immediate hypersensitivity reactions may occur after administration of levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving Levalbuterol Inhalation Solution, USP.

Levalbuterol Inhalation Solution, USP, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.

Changes in blood glucose may occur. Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

As with other beta-adrenergic agonist medications, Levalbuterol Inhalation Solution, USP 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.

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.

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been observed in postapproval use of Levalbuterol Inhalation Solution, USP. 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, USP, 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.

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

Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists such as Levalbuterol Inhalation Solution, USP, 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.

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.

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, USP 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, USP.

Levalbuterol Inhalation Solution, USP 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.

Activation of beta ₂ -adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3′, 5′-adenosine monophosphate (cyclic AMP). The increase in 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. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. While it is recognized that beta ₂ -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 beta ₂ -adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions (5.4) ]. However, all 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.

Although there have been no carcinogenesis studies with levalbuterol HCl, racemic albuterol sulfate has been evaluated for its carcinogenic potential.

In a 2-year study in Sprague-Dawley rats, dietary administration of racemic albuterol sulfate resulted in a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at doses of 2 mg/kg/day and greater (approximately 4 times the MRHDID of levalbuterol HCl for adults and approximately 5 times the MRHDID of levalbuterol HCl for children on a mg/m ² basis). In an 18-month study in CD-1 mice and a 22-month study in the golden hamster, dietary administration of racemic albuterol sulfate showed no evidence of tumorigenicity. Dietary doses in CD-1 mice were up to 500 mg/kg/day (approximately 540 times the MRHDID of levalbuterol HCl for adults and approximately 630 times the MRHDID of levalbuterol HCl for children on a mg/m ² basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 90 times the MRHDID of levalbuterol HCl for adults on a mg/m ² basis and approximately 105 times the MRHDID of levalbuterol HCl for children on a mg/m ² basis).

Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Levalbuterol HCl was not clastogenic in the in vivo micronucleus test in mouse bone marrow. Racemic albuterol sulfate was not clastogenic in an in vitro chromosomal aberration assay in CHO cell cultures.

No fertility studies have been conducted with levalbuterol hydrochloride. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 108 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m ² basis).

Adults and Adolescents ≥ 12 Years Old

The safety and efficacy of Levalbuterol Inhalation Solution, USP were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV ₁ 60% of predicted). Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive Levalbuterol Inhalation Solution, USP 0.63 mg, Levalbuterol Inhalation Solution, USP 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb ^® portable compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) was used on an as-needed basis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline FEV ₁ , was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29. On both day 1 (see Figure 1 ) and day 29 (see Figure 2 ), 1.25 mg of Levalbuterol Inhalation Solution, USP demonstrated the largest mean percent change from baseline FEV ₁ compared with the other active treatments. A dose of 0.63 mg of Levalbuterol Inhalation Solution, USP and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV ₁ on both day 1 and day 29.

Figure 1: Mean Percent Change from Baseline FEV 1 on Day 1, Adults and Adolescents ≥ 12 years old

Figure 2: Mean Percent Change from Baseline FEV 1 on Day 29, Adults and Adolescents ≥ 12 years old

The mean time to onset of a 15% increase in FEV ₁ over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration of effect, as measured by a > 15% increase from baseline FEV ₁ , was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately 6 hours after administration of 1.25 mg of levalbuterol after 4 weeks of treatment. In some patients, the duration of effect was as long as 8 hours.

Children 6-11 Years Old

A multicenter, randomized, double-blind, placebo-and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV ₁ 73% of predicted) (n = 316). Following a 1-week placebo run-in, subjects were randomized to Levalbuterol Inhalation Solution, USP (0.31 mg or 0.63 mg), racemic albuterol (1.25 mg or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb ^® 3000 compressor.

Efficacy, as measured by mean peak percent change from baseline FEV ₁ , was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21. Time profile FEV ₁ curves for day 1 and day 21 are shown in Figure 3 and Figure 4, respectively. The onset of effect (time to a 15% increase in FEV ₁ over test-day baseline) and duration of effect (maintenance of a > 15% increase in FEV ₁ over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.

Figure 3: Mean Percent Change from Baseline FEV 1 on Day 1, Children 6-11 Years of Age

Figure 4: Mean Percent Change from Baseline FEV 1 on Day 21, Children 6-11 Years of Age

Store Levalbuterol Inhalation Solution, USP in the protective foil pouch at 20°- 25°C (68°- 77°F) [see USP Controlled Room Temperature]. Protect from light and excessive heat. Keep unopened vials in the foil pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials removed from the pouch, if not used immediately, should be protected from light and used within 1 week. Discard any vial if the solution is not colorless.

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