Levalbuterol

5 WARNINGS AND PRECAUTIONS • Life-threatening paradoxical bronchospasm may occur. Discontinue levalbuterol inhalation solution immediately and treat with alternative therapy. ( 5.1 ) • Need for more doses of levalbuterol inhalation solution than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. ( 5.2 ) • Levalbuterol inhalation solution is not a substitute for corticosteroids. ( 5.3 ) • Cardiovascular effects may occur. Consider discontinuation of levalbuterol inhalation solution if these effects occur. Use with caution in patients with underlying cardiovascular disorders. ( 5.4 ) • Excessive use may be fatal. Do not exceed recommended dose. ( 5.5 ) • Immediate hypersensitivity reactions may occur. Discontinue levalbuterol inhalation solution immediately. ( 5.6 ) • Hypokalemia and changes in blood glucose may occur. ( 5.7 , 5.8 ) 5.1 Paradoxical Bronchospasm Levalbuterol inhalation solution can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, levalbuterol inhalation solution 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. 5.2 Deterioration of Asthma 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 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. 5.3 Use of Anti-Inflammatory Agents Levalbuterol inhalation solution 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. 5.4 Cardiovascular Effects Levalbuterol inhalation solution, 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 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, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.5 Do Not Exceed Recommended Dose 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. 5.6 Immediate Hypersensitivity Reactions 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. 5.7 Coexisting Conditions Levalbuterol inhalation solution, 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. 5.8 Hypokalemia As with other beta-adrenergic agonist medications, levalbuterol inhalation solution 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Paradoxical bronchospasm [see Warnings and Precautions (5.1) ] • Cardiovascular effects [see Warnings and Precautions (5.4) ] • Immediate hypersensitivity reactions [see Warnings and Precautions (5.6) ] • Hypokalemia [see Warnings and Precautions (5.8) ] Most common adverse reactions are: palpitations, chest pain, tachycardia, headache, dizziness, tremor and nervousness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Body System Preferred Term Percent of Patients One treatment group, racemic albuterol 1.25 mg, with 68 subjects is omitted. Placebo (n = 75) Levalbuterol Inhalation Solution 1.25 mg (n = 73) Levalbuterol Inhalation Solution 0.63 mg (n = 72) Racemic Albuterol 2.5 mg (n = 74) Body as a Whole Allergic reaction 1.3 0 0 2.7 Flu syndrome 0 1.4 4.2 2.7 Accidental injury 0 2.7 0 0 Pain 1.3 1.4 2.8 2.7 Back pain 0 0 0 2.7 Cardiovascular System Tachycardia 0 2.7 2.8 2.7 Migraine 0 2.7 0 0 Digestive System Dyspepsia 1.3 2.7 1.4 1.4 Musculoskeletal System Leg cramps 1.3 2.7 0 1.4 Central Nervous System Dizziness 1.3 2.7 1.4 0 Hypertonia 0 0 0 2.7 Nervousness 0 9.6 2.8 8.1 Tremor 0 6.8 0 2.7 Anxiety 0 2.7 0 0 Respiratory System Cough increased 2.7 4.1 1.4 2.7 Infection viral 9.3 12.3 6.9 12.2 Rhinitis 2.7 2.7 11.1 6.8 Sinusitis 2.7 1.4 4.2 2.7 Turbinate edema 0 1.4 2.8 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 15 minutes after drug administration and in plasma glucose and potassium 1 hour after drug administration on day 1 and day 29 were clinically comparable in the levalbuterol inhalation solution 1.25 mg and racemic albuterol 2.5 mg groups (see Table 2). 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). The clinical significance of these small differences is unknown. 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 Treatment Mean Changes (Day 1) Heart Rate (bpm) Glucose (mg/dL) Potassium (mEq/L) Levalbuterol Inhalation Solution 0.63 mg, n = 72 2.4 4.6 -0.2 Levalbuterol Inhalation Solution 1.25 mg, n = 73 6.9 10.3 -0.3 Racemic Albuterol 2.5 mg, n = 74 5.7 8.2 -0.3 Placebo, n = 75 -2.8 -0.2 -0.2 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: Body as a Whole: chills, pain, chest pain Cardiovascular System: ECG abnormal, ECG change, hypertension, hypotension, syncope Digestive System: diarrhea, dry mouth, dry throat, dyspepsia, gastroenteritis, nausea Hemic and Lymphatic System: lymphadenopathy Musculoskeletal System: leg cramps, myalgia Nervous System: anxiety, hyperesthesia of the hand, insomnia, paresthesia, tremor Special Senses: eye itch 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. Pediatric Patients 6 to 11 Years of Age Adverse reaction information concerning levalbuterol inhalation solution in pediatric patients is derived from one 3-week, multicenter, randomized, double-blind, active-, and placebo-controlled trial in 316 pediatric patients 6 to 11 years of age. 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) Body System Preferred Term Percent of Patients Placebo (n = 59) Levalbuterol Inhalation Solution 0.31 mg (n = 66) Levalbuterol Inhalation Solution 0.63 mg (n = 67) Racemic Albuterol 1.25 mg (n = 64) Racemic Albuterol 2.5 mg (n = 60) Body as a Whole Abdominal pain 3.4 0 1.5 3.1 6.7 Accidental injury 3.4 6.1 4.5 3.1 5.0 Asthenia 0 3.0 3.0 1.6 1.7 Fever 5.1 9.1 3.0 1.6 6.7 Headache 8.5 7.6 11.9 9.4 3.3 Pain 3.4 3.0 1.5 4.7 6.7 Viral infection 5.1 7.6 9.0 4.7 8.3 Digestive System Diarrhea 0 1.5 6.0 1.6 0 Hemic and Lymphatic Lymphadenopathy 0 3.0 0 1.6 0 Musculoskeletal System Myalgia 0 0 1.5 1.6 3.3 Respiratory System Asthma 5.1 9.1 9.0 6.3 10.0 Pharyngitis 6.8 3.0 10.4 0 6.7 Rhinitis 1.7 6.1 10.4 3.1 5.0 Skin and Appendages Eczema 0 0 0 0 3.3 Rash 0 0 7.5 1.6 0 Urticaria 0 0 3.0 0 0 Special Senses Otitis media 1.7 0 0 0 3.3 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. The clinical significance of these small differences is unknown. Table 4: Mean Changes from Baseline Heart Rate at 30 Minutes and Glucose and Potassium at 1 Hour after First Dose (Day 1) and Last Dose (Day 21) in Children 6 to 11 Years Old Treatment Mean Changes (Day 1) Heart Rate (bpm) Glucose (mg/dL) Potassium (mEq/L) Levalbuterol Inhalation Solution 0.31 mg, n = 66 0.8 4.9 -0.31 Levalbuterol Inhalation Solution 0.63 mg, n = 67 6.7 5.2 -0.36 Racemic Albuterol 1.25 mg, n = 64 6.4 8.0 -0.27 Racemic Albuterol 2.5 mg, n = 60 10.9 10.8 -0.56 Placebo, n = 59 -1.8 0.6 -0.05 Treatment Mean Changes (Day 21) Heart Rate (bpm) Glucose (mg/dL) Potassium (mEq/L) Levalbuterol Inhalation Solution 0.31 mg, n = 60 0 2.6 -0.32 Levalbuterol Inhalation Solution 0.63 mg, n = 66 3.8 5.8 -0.34 Racemic Albuterol 1.25 mg, n = 62 5.8 1.7 -0.18 Racemic Albuterol 2.5 mg, n = 54 5.7 11.8 -0.26 Placebo, n = 55 -1.7 1.1 -0.04 6.2 Post-marketing Experience In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been observed in postapproval use of levalbuterol inhalation solution. 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.

7 DRUG INTERACTIONS • Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs: May potentiate effect. ( 7.1 ) • Beta-blockers: May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. Patients with asthma should not normally be treated with beta-blockers. ( 7.2 ) • Diuretic: May worsen electrocardiographic changes or hypokalemia associated with diuretic may worsen. Consider monitoring potassium levels. ( 7.3 ) • Digoxin: May decrease serum digoxin levels. Consider monitoring digoxin levels. ( 7.4 ) • Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants: May potentiate effect of albuterol on the cardiovascular system. ( 7.5 ) 7.1 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. 7.2 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. 7.3 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. 7.4 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. 7.5 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.

8 USE IN SPECIFIC POPULATIONS 8.1 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 [see Clinical Considerations]. Following oral administration of levalbuterol HCl to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day [approximately 108 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol HCl for adults on a mg/m 2 basis]; 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 2 to 4% and 15 to 20% 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. In a rabbit developmental study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 215 times the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a mouse developmental study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately 0.3 times the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 3 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg/day). 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). 8.2 Lactation 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 development and health benefits of breastfeeding should be considered along with the mother’s clinical need for levalbuterol inhalation solution and any potential adverse effects on the breastfed child from levalbuterol inhalation solution or from the underlying maternal condition. 8.4 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 [see Adverse Reactions (6) and Clinical Studies (14) ] . 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. Levalbuterol inhalation solution 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 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 [see Adverse Reactions (6.1) ] . Table 5: Asthma-related Adverse Reactions in 3- and 4-Week Clinical Trials in Children Birth to < 6 Years of Age Asthma Exacerbations 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 n (%) Treatment Discontinuations due to Asthma n (%) Asthma-related Adverse Reactions Includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnea n (%) Study 1 Levalbuterol Inhalation Solution 0.31 mg, n = 58 6 (10) 4 (7) — Levalbuterol Inhalation Solution 0.63 mg, n = 51 7 (14) 6 (12) — Racemic Albuterol, n = 52 3 (6) 2 (4) — Placebo, n = 50 2 (4) 2 (4) — Study 2 Levalbuterol Inhalation Solution 0.31 mg, n = 63 — 2 (3) 6 (10) Levalbuterol HFA Inhalation Aerosol, n = 65 — 1 (2) 8 (12) Placebo, n = 68 — 0 3 (4) 8.5 Geriatric Use Clinical studies of levalbuterol inhalation solution 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 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. If clinically warranted due to insufficient bronchodilator response, the dose of levalbuterol inhalation solution 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) ] . 8.6 Renal Impairment 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.

8.1 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 [see Clinical Considerations]. Following oral administration of levalbuterol HCl to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day [approximately 108 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol HCl for adults on a mg/m 2 basis]; 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 2 to 4% and 15 to 20% 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. In a rabbit developmental study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 215 times the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a mouse developmental study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately 0.3 times the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 3 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg/day). 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).

8.4 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 [see Adverse Reactions (6) and Clinical Studies (14) ] . 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. Levalbuterol inhalation solution 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 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 [see Adverse Reactions (6.1) ] . Table 5: Asthma-related Adverse Reactions in 3- and 4-Week Clinical Trials in Children Birth to < 6 Years of Age Asthma Exacerbations 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 n (%) Treatment Discontinuations due to Asthma n (%) Asthma-related Adverse Reactions Includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnea n (%) Study 1 Levalbuterol Inhalation Solution 0.31 mg, n = 58 6 (10) 4 (7) — Levalbuterol Inhalation Solution 0.63 mg, n = 51 7 (14) 6 (12) — Racemic Albuterol, n = 52 3 (6) 2 (4) — Placebo, n = 50 2 (4) 2 (4) — Study 2 Levalbuterol Inhalation Solution 0.31 mg, n = 63 — 2 (3) 6 (10) Levalbuterol HFA Inhalation Aerosol, n = 65 — 1 (2) 8 (12) Placebo, n = 68 — 0 3 (4)