Levalbuterol Inhalation 1.25Mg/3Ml

1 INDICATIONS AND USAGE Levalbuterol Inhalation Solution, USP 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, USP 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. ( 1 )

2 DOSAGE AND ADMINISTRATION 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. 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. FOR ORAL INHALATION ONLY ( 2 ) Children 6-11 years old: 0.31 mg administered three times a day, by nebulization. Routine dosing should not exceed 0.63 mg three times a day. ( 2 ) Adults and Adolescents ≥12 years old: 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization. The maximum recommended dose is 1.25 mg three times a day. ( 2 ) For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor. ( 2 )

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 Cipla Ltd., India at 1-866-604-3268 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 ­ a One treatment group, racemic albuterol 1.25 mg, with 68 subjects is omitted. ­ ­ Percent of Patients a ­ ­ Levalbuterol Levalbuterol Racemic albuterol Body System Placebo 1.25mg 0.63mg 2.5mg Preferred Term (n=75) (n=73) (n=72) (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 ­ Mean Changes (day 1) ­ Heart Rate (bpm) Glucose (mg/dL) Potassium (mEq/L) Treatment ­ ­ ­ Levalbuterol 0.63mg, n=72 2.4 4.6 -0.2 Levalbuterol 1.25mg, n=73 6.9 10.3 -0.3 Racemic albuterol 2.5mg, 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 1.25 mg compared with the other active treatment groups. The following adverse reactions, considered potentially related to Levalbuterol, occurred in less than 2% of the 292 subjects who received Levalbuterol 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, 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, 6-11 Years Old) ­ Percent of Patients ­ ­ ­ ­ Racemic Racemic ­ ­ Levalbuterol Levalbuterol albuterol albuterol Body System Placebo 0.31mg 0.63mg 1.25mg 2.5mg Preferred Term (n=59) (n=66) (n=67) (n=64) (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 6-11 Years Old ­ Mean Changes (day 1) ­ Heart Rate (bpm) Glucose (mg/dL) Potassium (mEq/L) Treatment ­ ­ ­ Levalbuterol 0.31mg, n=66 0.8 4.9 -0.31 Levalbuterol 0.63mg, n=67 6.7 5.2 -0.36 Racemic albuterol 1.25mg, n=64 6.4 8.0 -0.27 Racemic albuterol 2.5mg, n=60 10.9 10.8 -0.56 Placebo, n=59 -1.8 0.6 -0.05 ­ Mean Changes (day 21) ­ Heart Rate (bpm) Glucose (mg/dL) Potassium (mEq/L) Treatment ­ ­ ­ Levalbuterol 0.31mg, n=60 0 2.6 -0.32 Levalbuterol 0.63mg, n=66 3.8 5.8 -0.34 Racemic albuterol 1.25mg, n=62 5.8 1.7 -0.18 Racemic albuterol 2.5mg, 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, gastrooesophageal 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.

12.3 Pharmacokinetics Adults and Adolescents ≥ 12 Years Old The inhalation pharmacokinetics of Levalbuterol Inhalation Solution were investigated in a randomized cross-over study in 30 healthy adults following administration of a single dose of 1.25 mg and a cumulative dose of 5 mg of Levalbuterol Inhalation Solution and a single dose of 2.5 mg and a cumulative dose of 10 mg of racemic albuterol sulfate inhalation solution by nebulization using a PARI LC Jet™ nebulizer with a Dura-Neb ® 2000 compressor. Following administration of a single 1.25 mg dose of Levalbuterol Inhalation Solution, exposure to (R)-albuterol (AUC of 3.3 ng•hr/mL) was approximately 2-fold higher than following administration of a single 2.5 mg dose of racemic albuterol inhalation solution (AUC of 1.7 ng•hr/mL) (see Table 5). Following administration of a cumulative 5 mg dose of Levalbuterol Inhalation Solution (1.25 mg given every 30 minutes for a total of four doses) or a cumulative 10 mg dose of racemic albuterol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), C max and AUC of (R)-albuterol were comparable (see Table 5). Table 5: Mean (SD) Values for Pharmacokinetic Parameters in Healthy Adults ­ ­ Single Dose Cumulative Dose ­ Levalbuterol 1.25 mg Racemic albuterol sulfate 2.5 mg Levalbuterol 5 mg Racemic albuterol sulfate 10 mg C max (ng/mL) (R)-albuterol 1.1 (0.45) 0.8 (0.41)** 4.5 (2.20) 4.2 (1.51)** T max (h)γ (R)-albuterol 0.2 (0.17, 0.37) 0.2 (0.17, 1.50) 0.2 (-0.18*, 1.25) 0.2 (-0.28*, 1.00) AUC (ng . h/mL) (R)-albuterol 3.3 (1.58) 1.7 (0.99)** 17.4 (8.56) 16.0 (7.12)** T ½ (h) (R)-albuterol 3.3 (2.48) 1.5 (0.61) 4.0 (1.05) 4.1 (0.97) γ Median (Min, Max) reported for T max . * A negative T max indicates C max occurred between first and last nebulizations. ** Values reflect only (R)-albuterol and do not include (S)-albuterol. Children 6-11 Years Old The pharmacokinetic parameters of (R)-and (S)-albuterol in children with asthma were obtained using population pharmacokinetic analysis. These data are presented in Table 6. For comparison, adult data obtained by conventional pharmacokinetic analysis from a different study also are presented in Table 6. In children, AUC and C max of (R)-albuterol following administration of 0.63 mg Levalbuterol Inhalation Solution were comparable to those following administration of 1.25 mg racemic albuterol sulfate inhalation solution. When the same dose of 0.63 mg of Levalbuterol Inhalation Solution was given to children and adults, the predicted C max of (R)-albuterol in children was similar to that in adults (0.52 vs. 0.56 ng/mL), while predicted AUC in children (2.55 ng•hr/mL) was about 1.5-fold higher than that in adults (1.65 ng•hr/mL). These data support lower doses for children 6-11 years old compared with the adult doses [see Dosage and Administration ( 2 ) ]. Table 6: (R)-Albuterol Exposure in Adults and Pediatric Subjects (6-11 years) ­ Children 6-11 years Adults ≥12 years ­ ­ ­ Racemic Racemic ­ ­ ­ Levalbuterol Levalbuterol albuterol albuterol Levalbuterol Levalbuterol Treatment 0.31 mg 0.63 mg 1.25mg 2.5 mg 0.63 mg 1.25 mg AUC 0 - ∞ (ng•hr/mL) c 1.36 2.55 2.65 5.02 1.65 a 3.3 b C m a x (ng/mL) d 0.303 0.521 0.553 1.08 0.56 a 1.1 b a The values are predicted by assuming linear pharmacokinetics b The data obtained from Table 5 c Area under the plasma concentration curve from time 0 to infinity d Maximum plasma concentration Metabolism and Elimination Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol enantiomers in humans is SULT1A3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)-and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3. The primary route of elimination of albuterol enantiomers is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine. Special Populations Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Levalbuterol Inhalation Solution has not been evaluated. Renal Impairment The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in racemic albuterol clearance. Caution should be used when administering high doses of Levalbuterol Inhalation Solution to patients with renal impairment [see Use in Specific Populations ( 8.6 ) ].