FDA label 57ecedff-83bf-6ecd-e053-2991aa0acc6e

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 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.

<table> <caption>Table 1: Adverse Reactions Reported in a 4-Week, Controlled Clinical Trial in Adults and Adolescents &#x2265;12 Years Old</caption> <tfoot> <tr> <td>&#xAD; ^a One treatment group, racemic albuterol 1.25 mg, with 68 subjects is omitted. &#xAD; </td> </tr> </tfoot> <tbody align="center"> <tr> <td> &#xAD;</td> <td>Percent of Patients ^a </td> </tr> <tr> <td> &#xAD;</td> <td> &#xAD;</td> <td>Levalbuterol </td> <td>Levalbuterol </td> <td>Racemic albuterol </td> </tr> <tr> <td align="left">Body System </td> <td>Placebo </td> <td>1.25mg </td> <td>0.63mg </td> <td>2.5mg </td> </tr> <tr> <td align="left">Preferred Term </td> <td>(n=75) </td> <td>(n=73) </td> <td>(n=72) </td> <td>(n=74) </td> </tr> <tr> <td align="left">Body as a Whole </td> <td> &#xAD;</td> <td> &#xFFFD;</td> <td> &#xAD;</td> <td> &#xAD;</td> </tr> <tr> <td align="left">Allergic reaction </td> <td>1.3 </td> <td>0 </td> <td>0 </td> <td>2.7 </td> </tr> <tr> <td align="left">Flu syndrome </td> <td>0 </td> <td>1.4 </td> <td>4.2 </td> <td>2.7 </td> </tr> <tr> <td align="left">Accidental injury </td> <td>0 </td> <td>2.7 </td> <td>0 </td> <td>0 </td> </tr> <tr> <td align="left">Pain </td> <td>1.3 </td> <td>1.4 </td> <td>2.8 </td> <td>2.7 </td> </tr> <tr> <td align="left">Back pain </td> <td>0 </td> <td>0 </td> <td>0 </td> <td>2.7 </td> </tr> <tr> <td align="left">Cardiovascular System </td> </tr> <tr> <td align="left">Tachycardia </td> <td>0 </td> <td>2.7 </td> <td>2.8 </td> <td>2.7 </td> </tr> <tr> <td align="left">Migraine </td> <td>0 </td> <td>2.7 </td> <td>0 </td> <td>0 </td> </tr> <tr> <td align="left">Digestive System </td> </tr> <tr> <td align="left">Dyspepsia </td> <td>1.3 </td> <td>2.7 </td> <td>1.4 </td> <td>1.4 </td> </tr> <tr> <td align="left">Musculoskeletal System </td> </tr> <tr> <td align="left">Leg cramps </td> <td>1.3 </td> <td>2.7 </td> <td>0 </td> <td>1.4 </td> </tr> <tr> <td align="left">Central Nervous System </td> </tr> <tr> <td align="left">Dizziness </td> <td>1.3 </td> <td>2.7 </td> <td>1.4 </td> <td>0 </td> </tr> <tr> <td align="left">Hypertonia </td> <td>0 </td> <td>0 </td> <td>0 </td> <td>2.7 </td> </tr> <tr> <td align="left">Nervousness </td> <td>0 </td> <td>9.6 </td> <td>2.8 </td> <td>8.1 </td> </tr> <tr align="left"> <td>Tremor </td> <td align="center">0 </td> <td align="center">6.8 </td> <td align="center">0 </td> <td align="center">2.7 </td> </tr> <tr align="left"> <td>Anxiety </td> <td align="center">0 </td> <td align="center">2.7 </td> <td align="center">0 </td> <td align="center">0 </td> </tr> <tr> <td align="left">Respiratory System </td> </tr> <tr> <td align="left">Cough increased </td> <td>2.7 </td> <td>4.1 </td> <td>1.4 </td> <td>2.7 </td> </tr> <tr> <td align="left">Infection viral </td> <td>9.3 </td> <td>12.3 </td> <td>6.9 </td> <td>12.2 </td> </tr> <tr> <td align="left">Rhinitis </td> <td>2.7 </td> <td>2.7 </td> <td>11.1 </td> <td>6.8 </td> </tr> <tr> <td align="left">Sinusitis </td> <td>2.7 </td> <td>1.4 </td> <td>4.2 </td> <td>2.7 </td> </tr> <tr> <td align="left">Turbinate edema </td> <td>0 </td> <td>1.4 </td> <td>2.8 </td> <td>0</td> </tr> </tbody> </table>

<table> <caption>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 &#x2265;12 Years Old</caption> <tbody align="center"> <tr> <td>&#xAD;</td> <td>Mean Changes (day 1)</td> </tr> <tr> <td>&#xAD;</td> <td>Heart Rate (bpm)</td> <td>Glucose (mg/dL)</td> <td>Potassium (mEq/L)</td> </tr> <tr> <td align="left">Treatment</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> </tr> <tr> <td align="left">Levalbuterol 0.63mg, n=72</td> <td>2.4</td> <td>4.6</td> <td>-0.2</td> </tr> <tr> <td align="left">Levalbuterol 1.25mg, n=73</td> <td>6.9</td> <td>10.3</td> <td>-0.3</td> </tr> <tr> <td align="left">Racemic albuterol 2.5mg, n=74</td> <td>5.7</td> <td>8.2</td> <td>-0.3</td> </tr> <tr> <td align="left">Placebo, n=75</td> <td>-2.8</td> <td>-0.2</td> <td>-0.2</td> </tr> </tbody> </table>

<table> <caption>Table 3: Most Frequently Reported Adverse Reactions (&#x2265;2% in Any Treatment Group) and Those Reported More Frequently Than in Placebo during the Double-Blind Period (ITT Population, 6-11 Years Old)</caption> <tbody align="center"> <tr> <td>&#xAD;</td> <td>Percent of Patients</td> </tr> <tr> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>Racemic</td> <td>Racemic</td> </tr> <tr> <td>&#xAD;</td> <td>&#xAD;</td> <td>Levalbuterol</td> <td>Levalbuterol</td> <td>albuterol</td> <td>albuterol</td> </tr> <tr> <td align="left">Body System</td> <td>Placebo</td> <td>0.31mg</td> <td>0.63mg</td> <td>1.25mg</td> <td>2.5mg</td> </tr> <tr> <td align="left">Preferred Term</td> <td>(n=59)</td> <td>(n=66)</td> <td>(n=67)</td> <td>(n=64)</td> <td>(n=60)</td> </tr> <tr> <td align="left">Body as a Whole</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> </tr> <tr> <td align="left">Abdominal pain</td> <td>3.4</td> <td>0</td> <td>1.5</td> <td>3.1</td> <td>6.7</td> </tr> <tr> <td align="left">Accidental injury</td> <td>3.4</td> <td>6.1</td> <td>4.5</td> <td>3.1</td> <td>5.0</td> </tr> <tr> <td align="left">Asthenia</td> <td>0</td> <td>3.0</td> <td>3.0</td> <td>1.6</td> <td>1.7</td> </tr> <tr> <td align="left">Fever</td> <td>5.1</td> <td>9.1</td> <td>3.0</td> <td>1.6</td> <td>6.7</td> </tr> <tr> <td align="left">Headache</td> <td>8.5</td> <td>7.6</td> <td>11.9</td> <td>9.4</td> <td>3.3</td> </tr> <tr> <td align="left">Pain</td> <td>3.4</td> <td>3.0</td> <td>1.5</td> <td>4.7</td> <td>6.7</td> </tr> <tr> <td align="left">Viral infection</td> <td>5.1</td> <td>7.6</td> <td>9.0</td> <td>4.7</td> <td>8.3</td> </tr> <tr> <td align="left">Digestive System</td> </tr> <tr> <td align="left">Diarrhea</td> <td>0</td> <td>1.5</td> <td>6.0</td> <td>1.6</td> <td>0</td> </tr> <tr> <td align="left">Hemic and Lymphatic</td> </tr> <tr> <td align="left">Lymphadenopathy</td> <td>0</td> <td>3.0</td> <td>0</td> <td>1.6</td> <td>0</td> </tr> <tr> <td align="left">Musculoskeletal System</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> </tr> <tr> <td align="left">Myalgia</td> <td>0</td> <td>0</td> <td>1.5</td> <td>1.6</td> <td>3.3</td> </tr> <tr> <td align="left">Respiratory System</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> </tr> <tr> <td align="left">Asthma</td> <td>5.1</td> <td>9.1</td> <td>9.0</td> <td>6.3</td> <td>10.0</td> </tr> <tr> <td align="left">Pharyngitis</td> <td>6.8</td> <td>3.0</td> <td>10.4</td> <td>0</td> <td>6.7</td> </tr> <tr> <td align="left">Rhinitis</td> <td>1.7</td> <td>6.1</td> <td>10.4</td> <td>3.1</td> <td>5.0</td> </tr> <tr> <td align="left">Skin and Appendages</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> </tr> <tr> <td align="left">Eczema</td> <td>0</td> <td>0</td> <td>0</td> <td>0</td> <td>3.3</td> </tr> <tr> <td align="left">Rash</td> <td>0</td> <td>0</td> <td>7.5</td> <td>1.6</td> <td>0</td> </tr> <tr> <td align="left">Urticaria</td> <td>0</td> <td>0</td> <td>3.0</td> <td>0</td> <td>0</td> </tr> <tr> <td align="left">Special Senses</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> <td>&#xAD;</td> </tr> <tr> <td align="left">Otitis media</td> <td>1.7</td> <td>0</td> <td>0</td> <td>0</td> <td>3.3</td> </tr> <tr> <td/> </tr> </tbody> </table>