LEVALBUTEROL: 1,445 Adverse Event Reports & Safety Profile

The active component of Levalbuterol tartrate HFA inhalation aerosol is levalbuterol tartrate, the (R)-enantiomer of albuterol. Levalbuterol tartrate is a relatively selective beta 2 -adrenergic receptor agonist [see Clinical Pharmacology (12) ]. Levalbuterol tartrate has the chemical name (R)-α 1 -[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol L-tartrate (2:1 salt), and it has the following chemical structure: The molecular weight of levalbuterol tartrate is 628.71, and its empirical formula is (C 13 H 21 NO 3 ) 2 · C 4 H 6 O 6 . It is a white to light-yellow solid, freely soluble in water and very slightly soluble in ethanol. Levalbuterol tartrate is the generic name for (R)-albuterol tartrate in the United States. Levalbuterol tartrate HFA inhalation aerosol is a pressurized metered-dose aerosol inhaler (MDI) fitted with a dose indicator, which produces an aerosol for oral inhalation. It contains a suspension of micronized levalbuterol tartrate, propellant HFA-134a (1,1,1,2-tetrafluoroethane), Dehydrated Alcohol USP, and Oleic Acid NF. After priming with 4 actuations, each actuation of the inhaler delivers 67.8 mcg of levalbuterol tartrate (equivalent to 51.6 mcg of levalbuterol free base) from the valve and 59 mcg of levalbuterol tartrate (equivalent to 45 mcg of levalbuterol free base) from the actuator mouthpiece.

Each

15 g canister provides 200 actuations (or inhalations). The following chemical structure Levalbuterol tartrate is a relatively selective beta2-adrenergic receptor agonist [see Clinical Pharmacology (12)]. Levalbuterol tartrate has the chemical name (R)-α1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol L-tartrate (2:1 salt).

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

• Treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease. ( 1 )

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. 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 )

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.

Recent Major

Changes to the Dosage and Administration Section 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...") 2. Dosage and Administration Updated February 2020

Levalbuterol tartrate HFA inhalation aerosol is contraindicated in patients with a history of hypersensitivity to levalbuterol, racemic albuterol, or any other component of Levalbuterol tartrate HFA inhalation aerosol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. Hypersensitivity to levalbuterol, racemic albuterol or any other component of Levalbuterol tartrate HFA inhalation aerosol. ( 4 )

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, USP 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, USP 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 Percent of Patients One treatment group, racemic albuterol 1.25 mg, with 68 subjects is omitted.

Body System Preferred Term

Placebo (n =75)

Levalbuterol Inhalation

Solution, USP 1.25 mg (n = 73)

Levalbuterol Inhalation

Solution, USP 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, USP 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, USP 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, USP 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, USP 0.63 mg, n = 72 2.4 4.6 -0.2 Levalbuterol Inhalation Solution, USP 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, USP 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, USP 1.25 mg compared with the other active treatment groups. The following adverse reactions, considered potentially related to Levalbuterol Inhalation Solution, USP, occurred in less than 2% of the 292 subjects who received Levalbuterol Inhalation Solution, USP 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, USP, 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, USP 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)

Body System Preferred Term

Percent of Patients Placebo (n = 59)

Levalbuterol Inhalation

Solution, USP 0.31 mg (n = 66)

Levalbuterol Inhalation

Solution, USP 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 6-11 Years Old 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 Treatment Mean Changes (Day 1)

Heart

Rate (bpm) Glucose (mg/dL) Potassium (mEq/L)

Levalbuterol Inhalation

Solution, USP 0.31 mg, n = 66 0.8 4.9 -0.31 Levalbuterol Inhalation Solution, USP 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, USP 0.31 mg, n = 60 0 2.6 -0.32 Levalbuterol Inhalation Solution, USP 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, 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.

AND PRECAUTIONS

• Life-threatening paradoxical bronchospasm may occur.

Discontinue Levalbuterol Inhalation

Solution, USP immediately and treat with alternative therapy. ( 5.1 )

• Need for more doses of Levalbuterol Inhalation Solution, USP than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. ( 5.2 )
• Levalbuterol Inhalation Solution, USP is not a substitute for corticosteroids. ( 5.3 )
• Cardiovascular effects may occur. Consider discontinuation of Levalbuterol Inhalation Solution, USP 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, USP immediately. ( 5.6 )

• Hypokalemia and changes in blood glucose may occur. ( 5.7 , 5.8 )

5.1 Paradoxical Bronchospasm 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.

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, 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.

5.3 Use of Anti-Inflammatory Agents 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.

5.4 Cardiovascular Effects 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.

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, USP.

5.7 Coexisting Conditions 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.

5.8 Hypokalemia 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.

INTERACTIONS Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with Levalbuterol tartrate HFA inhalation aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs : May potentiate effect. ( 7 ) Beta-blockers : May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. Patients with asthma should not normally be treated with beta-blockers. ( 7.1 ) Diuretics : May worsen electrocardiographic changes or hypokalemia associated with diuretics may worsen. Consider monitoring potassium levels. ( 7.2 ) Digoxin : May decrease serum digoxin levels. Consider monitoring digoxin levels. ( 7.3 ) Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants : May potentiate effect of albuterol on the cardiovascular system. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants. ( 7.4 )

7.1 Beta-blockers Beta-blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists, such as Levalbuterol tartrate HFA inhalation aerosol, 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., as 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.

7.2 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.

7.3 Digoxin Mean decreases of 16% to 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 tartrate HFA inhalation aerosol 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 tartrate HFA inhalation aerosol.

7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants Levalbuterol tartrate HFA inhalation aerosol 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 albuterol on the vascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.