LEVALBUTEROL- levalbuterol solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LEVALBUTEROL HYDROCHLORIDE (UNII: WDQ1526QJM) (LEVALBUTEROL - UNII:EDN2NBH5SS)
Available from:
Mylan Pharmaceuticals Inc.
INN (International Name):
LEVALBUTEROL HYDROCHLORIDE
Composition:
LEVALBUTEROL 1.25 mg in 3 mL
Administration route:
RESPIRATORY (INHALATION)
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Levalbuterol inhalation solution 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 is contraindicated in patients with a history of hypersensitivity to levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema [see Warnings and Precautions (5.6)] . There are no adequate and well-controlled studies of levalbuterol inhalation solution in pregnant women. Because animal reproduction studies are not always predictive of human response, levalbuterol inhalation solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in newborns of women treated with racemic albuterol which contains the levalbuterol isomer
Product summary:
Levalbuterol Inhalation Solution, USP is supplied in 3 mL unit-dose, low-density polyethylene (LDPE) vials as a clear, colorless, sterile, preservative-free, aqueous solution, in three different strengths of levalbuterol (0.31 mg, 0.63 mg, 1.25 mg). Each strength of levalbuterol inhalation solution is available in a shelf-carton containing two foil pouches, each containing 12 unit-dose LDPE vials. Levalbuterol Inhalation Solution USP, 0.31 mg (foil pouch label color green ) contains 0.31 mg/3 mL (0.0103%) of levalbuterol (as 0.36 mg/3 mL of levalbuterol hydrochloride) and is available in cartons of 24 unit-dose LDPE vials (NDC 0378-9680-44). Levalbuterol Inhalation Solution USP, 0.63 mg (foil pouch label color yellow ) contains 0.63 mg/3 mL (0.021%) of levalbuterol (as 0.73 mg/3 mL of levalbuterol hydrochloride) and is available in cartons of 24 unit-dose LDPE vials (NDC 0378-9681-44). Levalbuterol Inhalation Solution USP, 1.25 mg (foil pouch label color red ) contains 1.25 mg/3 mL (0.042%) of levalbuterol (as 1.44 mg/3 mL of levalbuterol hydrochloride) and is available in cartons of 24 unit-dose LDPE vials (NDC 0378-9682-44). Store levalbuterol inhalation solution in the protective foil pouch at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light and excessive heat. Keep unopened vials in the foil pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials removed from the pouch, if not used immediately, should be protected from light and used within one week. Discard any vial if the solution is not colorless.
Authorization status:
Abbreviated New Drug Application
Authorization number:
0378-9680-44, 0378-9680-96, 0378-9681-44, 0378-9681-96, 0378-9682-44, 0378-9682-96

LEVALBUTEROL- levalbuterol solution

Mylan Pharmaceuticals Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LEVALBUTEROL INHALATION SOLUTION

safely and effectively. See full prescribing information for LEVALBUTEROL INHALATION SOLUTION.

LEVALBUTEROL inhalation solution, for inhalation use

Initial U.S. Approval: 1999

INDICATIONS AND USAGE

Levalbuterol inhalation solution is a beta -adrenergic agonist indicated for:

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

Inhalation Solution (unit-dose vial for nebulization): 0.31 mg/3 mL, 0.63 mg/3 mL and 1.25 mg/3 mL. (3)

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

Most common adverse reactions are: palpitations, chest pain, tachycardia, headache, dizziness, tremor and nervousness.

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-

4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with

reversible obstructive airway disease. (1)

FOR ORAL INHALATION ONLY (2)

Children 6 to 11 Years Old: 0.31 mg administered 3 times a day, by nebulization. Routine dosing should not exceed

0.63 mg 3 times a day. (2)

Adults and Adolescents 12 Years Old: 0.63 mg administered 3 times a day, every 6 to 8 hours, by nebulization. The

maximum recommended dose is 1.25 mg 3 times a day. (2)

For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor. (2)

Hypersensitivity to levalbuterol or racemic albuterol. (4)

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)

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)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 5/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Paradoxical Bronchospasm

5.2 Deterioration of Asthma

5.3 Use of Anti-Inflammatory Agents

5.4 Cardiovascular Effects

5.5 Do Not Exceed Recommended Dose

5.6 Immediate Hypersensitivity Reactions

5.7 Coexisting Conditions

5.8 Hypokalemia

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-marketing Experience

7 DRUG INTERACTIONS

7.1 Short-Acting Bronchodilators

7.2 Beta-blockers

7.3 Diuretics

7.4 Digoxin

7.5 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Levalbuterol inhalation solution 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.

2 DOSAGE AND ADMINISTRATION

Levalbuterol inhalation solution 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 to 11 Years Old: The recommended dosage of levalbuterol inhalation solution for patients 6

to 11 years old is 0.31 mg administered 3 times a day, by nebulization. Routine dosing should not exceed

0.63 mg 3 times a day.

Adults and Adolescents ≥ 12 Years Old: The recommended starting dosage of levalbuterol inhalation

solution for patients 12 years of age and older is 0.63 mg administered 3 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 may benefit from a dosage of 1.25 mg 3 times a

day.

Patients receiving the highest dose of levalbuterol inhalation solution 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 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

when mixed with other drugs in a nebulizer have not been established.

The safety and efficacy of levalbuterol inhalation solution have been established in clinical trials when

administered using the PARI LC Jet™ and PARI LC Plus™ nebulizers, and the PARI Master

Dura-

2000 and Dura-Neb

3000 compressors. The safety and efficacy of levalbuterol inhalation

solution when administered using other nebulizer systems have not been established.

3 DOSAGE FORMS AND STRENGTHS

Levalbuterol Inhalation Solution, USP 3 mL unit-dose vials in three dosage strengths of levalbuterol;

0.31 mg, 0.63 mg, 1.25 mg. Each strength of levalbuterol inhalation solution is available in a shelf

carton containing two foil pouches, each containing 12 unit-dose vials.

4 CONTRAINDICATIONS

Levalbuterol inhalation solution is contraindicated in patients with a history of hypersensitivity to

levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm,

anaphylaxis, and oropharyngeal edema [see Warnings and Precautions (5.6)].

5 WARNINGS AND PRECAUTIONS

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:

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

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

Flu syndrome

Accidental injury

Pain

Back pain

Cardiovascular System

Tachycardia

Migraine

Digestive System

Dyspepsia

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)]

Musculoskeletal

System

Leg cramps

Central Nervous

System

Dizziness

Hypertonia

Nervousness

Tremor

Anxiety

Respiratory System

Cough increased

Infection viral

12.3

12.2

Rhinitis

11.1

Sinusitis

Turbinate edema

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 one 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

One Hour after First Dose (Day 1) in Adults and Adolescents ≥ 12 Years Old

Treatment

Mean Changes (Day 1)

Heart Rate

(bpm)

Glucos e

(mg/dL)

Potas s ium

(mEq/L)

Levalbuterol Inhalation

Solution 0.63 mg, n = 72

-0.2

Levalbuterol Inhalation

Solution 1.25 mg, n = 73

10.3

-0.3

Racemic Albuterol 2.5 mg, n =

-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,

One treatment group, racemic albuterol 1.25 mg, with 68 subjects is omitted.

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

Accidental injury

Asthenia

Fever

Headache

11.9

Pain

Viral infection

Digestive System

Diarrhea

Hemic and Lymphatic

Lymphadenopathy

Musculoskeletal

System

Myalgia

Respiratory System

Asthma

10.0

Pharyngitis

10.4

Rhinitis

10.4

Note: Subjects may have more than one adverse event per body system and preferred term.

Rhinitis

10.4

Skin and Appendages

Eczema

Rash

Urticaria

Special Senses

Otitis media

Table 4: Mean Changes from Baseline Heart Rate at 30 Minutes and Glucose and Potassium at

One 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)

Glucos e

(mg/dL)

Potas s ium

(mEq/L)

Levalbuterol Inhalation

Solution 0.31 mg, n = 66

-0.31

Levalbuterol Inhalation

Solution 0.63 mg, n = 67

-0.36

Racemic Albuterol 1.25 mg, n

= 64

-0.27

Racemic Albuterol 2.5 mg, n =

10.9

10.8

-0.56

Placebo, n = 59

-1.8

-0.05

Treatment

Mean Changes (Day 21)

Heart Rate

(bpm)

Glucos e

(mg/dL)

Potas s ium

(mEq/L)

Levalbuterol Inhalation

Solution 0.31 mg, n = 60

-0.32

Levalbuterol Inhalation

Solution 0.63 mg, n = 66

-0.34

Racemic Albuterol 1.25 mg, n

= 62

-0.18

Racemic Albuterol 2.5 mg, n =

11.8

-0.26

Placebo, n = 55

-1.7

-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

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

Teratogenic Effects. Pregnancy Category C

There are no adequate and well-controlled studies of levalbuterol inhalation solution in pregnant

women. Because animal reproduction studies are not always predictive of human response, levalbuterol

inhalation solution should be used during pregnancy only if the potential benefit justifies the potential

risk to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb

defects, have been reported in newborns of women treated with racemic albuterol which contains the

levalbuterol isomer (active drug substance of levalbuterol inhalation solution). However, since multiple

medications were taken during some of the pregnancies and there was no consistent pattern of

anomalies, it was not possible to establish a relationship between racemic albuterol use and the

occurrence of these congenital anomalies.

In animal studies, oral administration of levalbuterol hydrochloride to pregnant New Zealand White

rabbits found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 108 times the

maximum recommended daily inhalation [MRDI] dose of levalbuterol hydrochloride for adults on a

mg/m basis).

However, other studies demonstrated that racemic albuterol sulfate was teratogenic in mice and rabbits

at doses comparable to the human therapeutic range. Pregnant mice administered racemic albuterol

sulfate subcutaneously had a dose-related increased incidence of cleft palate in their fetuses (4.5% of

fetuses at 0.25 mg/kg/day or greater, corresponding to approximately 0.3 times the MRDI dose, 9.3% of

fetuses at 2.5 mg/kg/day, approximately 3 times the MRDI dose of levalbuterol hydrochloride for adults

on a mg/m basis). The drug did not induce cleft palate formation when administered subcutaneously at a

dose of 0.025 mg/kg/day (approximately 0.03 times the MRDI dose of levalbuterol hydrochloride for

adults on a mg/m basis). In addition, oral administration of racemic albuterol sulfate to pregnant rabbits

resulted in an increased incidence of cranioschisis in fetuses (approximately 215 times the MRDI dose

of levalbuterol hydrochloride for adults on a mg/m basis).

Non-Teratogenic Effects

A study in which pregnant rats were dosed with radiolabeled racemic albuterol sulfate demonstrated that

drug-related material is transferred from the maternal circulation to the fetus.

8.2 Labor and 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 in 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 hydrochloride 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 -agonists, including racemic albuterol.

8.3 Nursing Mothers

Plasma concentrations of levalbuterol after inhalation of therapeutic doses are very low in humans. It is

not known whether levalbuterol is excreted in human milk.

Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack

of experience with the use of levalbuterol inhalation solution by nursing mothers, a decision should be

made whether to discontinue nursing or to discontinue the drug, taking into account the importance of

the drug to the mother. Caution should be exercised when levalbuterol inhalation solution is

administered to a nursing woman.

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, active and placebo-

controlled study (Study 1) in 211 pediatric patients between the ages of 2 and 5 years, of whom 119

received levalbuterol inhalation solution. 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

As thma

Exacerbations

n (%)

Treatment

Dis continuations

due to Asthma

n (%)

As thma-related

Advers e

Reactions

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

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 five

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

Asthma exacerbation defined as worsening of asthma symptoms or pulmonary function that required any of the

following: emergency department visit, hospitalization, therapeutic intervention with oral or parenteral steroids,

unscheduled clinic visit to treat acute asthma symptoms

Includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to

drug): asthma, cough, hypoxia, status asthmaticus, tachypnea

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.

10 OVERDOSAGE

The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation

and/or occurrence or exaggeration of any of the symptoms listed under Adverse Reactions (6), e.g.,

seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min., arrhythmias,

nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and

sleeplessness. Hypokalemia also may occur. As with all sympathomimetic medications, cardiac arrest

and even death may be associated with the abuse of levalbuterol inhalation solution. Treatment consists

of discontinuation of levalbuterol inhalation solution together with appropriate symptomatic therapy.

The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that

such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is

beneficial for overdosage of levalbuterol inhalation solution.

11 DESCRIPTION

Levalbuterol inhalation solution, USP is a sterile, clear, colorless, preservative-free solution of the

hydrochloride salt of levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol.

Levalbuterol hydrochloride is a relatively selective beta -adrenergic receptor agonist [see Clinical

Pharmacology (12)]. The chemical name for levalbuterol hydrochloride is (R)-α -[[(1,1-

dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established

chemical structure is as follows:

The molecular weight of levalbuterol hydrochloride is 275.8, and its molecular formula is

H NO HCl. It is a white to off-white, crystalline solid, with a melting point of approximately

187°C and solubility of approximately 180 mg/mL in water.

Levalbuterol hydrochloride is the USAN modified name for (R)-albuterol hydrochloride in the United

States.

Levalbuterol inhalation solution is supplied in sterile unit-dose vials and requires no dilution before

administration by nebulization. Each 3 mL unit-dose vial contains 0.31 mg/3 mL (0.0103%) of

levalbuterol (as 0.36 mg/3 mL of levalbuterol hydrochloride) or 0.63 mg/3 mL (0.021%) of

levalbuterol (as 0.73 mg/3 mL of levalbuterol hydrochloride) or 1.25 mg/3 mL (0.042%) of levalbuterol

(as 1.44 mg/3 mL of levalbuterol hydrochloride), sodium chloride to adjust tonicity, edetate disodium

(EDTA) as a stabilizer for the active pharmaceutical ingredient, and sulfuric acid to adjust the pH to 4.0

(3.3 to 4.5).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Activation of beta -adrenergic receptors on airway smooth muscle leads to the activation of adenylate

cyclase and to an increase in the intracellular concentration of cyclic-3′, 5′-adenosine monophosphate

(cyclic AMP). The increase in cyclic AMP is associated with the activation of protein kinase A, which

in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations,

resulting in muscle relaxation. Levalbuterol relaxes the smooth muscles of all airways, from the trachea

to the terminal bronchioles. Increased cyclic AMP concentrations are also associated with the inhibition

of release of mediators from mast cells in the airway. Levalbuterol acts as a functional antagonist to

relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor

challenges. While it is recognized that beta -adrenergic receptors are the predominant receptors on

bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of

which are beta -adrenergic receptors. The precise function of these receptors has not been established

[see Warnings and Precautions (5.4)]. However, all beta-adrenergic agonist drugs can produce a

significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms,

and/or electrocardiographic changes.

12.2 Pharmacodynamics

Adults and Adolescents ≥ 12 Years Old

In a randomized, double-blind, placebo-controlled, cross-over study, 20 adults with mild-to-moderate

asthma received single doses of levalbuterol inhalation solution (0.31 mg, 0.63 mg, and 1.25 mg) and

racemic albuterol sulfate inhalation solution (2.5 mg). All doses of active treatment produced a

significantly greater degree of bronchodilation (as measured by percent change from pre-dose mean

FEV ) than placebo, and there were no significant differences between any of the active treatment arms.

The bronchodilator responses to 1.25 mg of levalbuterol inhalation solution and 2.5 mg of racemic

albuterol sulfate inhalation solution were clinically comparable over the 6 hour evaluation period,

except for a slightly longer duration of action (> 15% increase in FEV from baseline) after

administration of 1.25 mg of levalbuterol inhalation solution. Systemic beta-adrenergic adverse effects

were observed with all active doses and were generally dose-related for (R)-albuterol. Levalbuterol

inhalation solution at a dose of 1.25 mg produced a slightly higher rate of systemic beta-adrenergic

adverse effects than the 2.5 mg dose of racemic albuterol sulfate inhalation solution.

In a randomized, double-blind, placebo-controlled, cross-over study, 12 adults with mild-to-moderate

asthma were challenged with inhaled methacholine chloride 20 and 180 minutes following

administration of a single dose of 2.5 mg of racemic albuterol sulfate, 1.25 mg of levalbuterol inhalation

solution, 1.25 mg of (S)-albuterol, or placebo using a Pari LC Jet™ nebulizer. Racemic albuterol

sulfate, levalbuterol inhalation solution, and (S)-albuterol had a protective effect against methacholine-

induced bronchoconstriction 20 minutes after administration, although the effect of (S)-albuterol was

minimal. At 180 minutes after administration, the bronchoprotective effect of 1.25 mg of levalbuterol

inhalation solution was comparable to that of 2.5 mg of racemic albuterol sulfate. At 180 minutes after

administration, 1.25 mg of (S)-albuterol had no bronchoprotective effect.

In a clinical study in adults with mild-to-moderate asthma, comparable efficacy (as measured by change

from baseline FEV ) and safety (as measured by heart rate, blood pressure, ECG, serum potassium, and

tremor) were demonstrated after a cumulative dose of 5 mg of levalbuterol inhalation solution (four

consecutive doses of 1.25 mg administered every 30 minutes) and 10 mg of racemic albuterol sulfate

inhalation solution (four consecutive doses of 2.5 mg administered every 30 minutes).

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 nghr/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 nghr/mL) (see Table 6).

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

and AUC of (R)-albuterol were

comparable (see Table 6).

Table 6: Mean (SD) Values for Pharmacokinetic Parameters in Healthy Adults

Single Dose

Cumulative Dose

Levalbuterol

Inhalation

Solution

1.25 mg

Racemic

Albuterol

Sulfate

2.5 mg

Levalbuterol

Inhalation

Solution

5 mg

Racemic

Albuterol

Sulfate

10 mg

(ng/mL)

(R)-albuterol

1.1 (0.45)

0.8 (0.41)

4.5 (2.20)

4.2 (1.51)

(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 (ngh/mL)

(R)-albuterol

3.3 (1.58)

1.7 (0.99)

17.4 (8.56)

16.0 (7.12)

T (h)

(R)-albuterol

3.3 (2.48)

1.5 (0.61)

4.0 (1.05)

4.1 (0.97)

Children 6 to 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 7. For comparison, adult data

obtained by conventional pharmacokinetic analysis from a different study also are presented in Table 7.

In children, AUC and C

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

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 nghr/mL) was about 1.5-fold higher than that in adults (1.65 nghr/mL).

These data support lower doses for children 6 to 11 years old compared with the adult doses [see

Dosage and Administration (2)].

Table 7: (R)-Albuterol Exposure in Adults and Pediatric Subjects (6 to 11 Years)

Values reflect only (R)-albuterol and do not include (S)-albuterol.

Median (Min, Max) reported for T

A negative T

indicates C

occurred between first and last nebulizations.

Treatment

Children 6 to 11 Years

Adults ≥ 12 Years

Levalbuterol

Inhalation

Solution

0.31 mg

Levalbuterol

Inhalation

Solution

0.63 mg

Racemic

Albuterol

1.25 mg

Racemic

Albuterol

2.5 mg

Levalbuterol

Inhalation

Solution

0.63 mg

Levalbuterol

Inhalation

Solution

1.25 mg

(nghr/mL)

1.36

2.55

2.65

5.02

1.65

(ng/mL)

0.303

0.521

0.553

1.08

0.56

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 five

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)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Although there have been no carcinogenesis studies with levalbuterol hydrochloride, racemic albuterol

sulfate has been evaluated for its carcinogenic potential. In a 2-year study in Sprague-Dawley rats,

dietary administration of racemic albuterol sulfate resulted in a significant dose-related increase in the

incidence of benign leiomyomas of the mesovarium at doses of 2 mg/kg/day and greater (approximately

4 times the MRDI dose of levalbuterol hydrochloride for adults and approximately 5 times the MRDI

dose of levalbuterol hydrochloride for children on a mg/m basis). In an 18-month study in CD-1 mice

and a 22-month study in the golden hamster, dietary administration of racemic albuterol sulfate showed

Area under the plasma concentration curve from time 0 to infinity

The values are predicted by assuming linear pharmacokinetics

The data obtained from Table 6

Maximum plasma concentration

0-∞

no evidence of tumorigenicity. Dietary doses in CD-1 mice were up to 500 mg/kg/day (approximately

540 times the MRDI dose of levalbuterol hydrochloride for adults and approximately 630 times the

MRDI dose of levalbuterol hydrochloride for children on a mg/m basis) and doses in the golden

hamster study were up to 50 mg/kg/day (approximately 90 times the MRDI dose of levalbuterol

hydrochloride for adults on a mg/m basis and approximately 105 times the MRDI dose of levalbuterol

hydrochloride for children on a mg/m basis).

Levalbuterol hydrochloride was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward

Gene Mutation Assay. Levalbuterol hydrochloride was not clastogenic in the in vivo micronucleus test

in mouse bone marrow. Racemic albuterol sulfate was not clastogenic in an in vitro chromosomal

aberration assay in CHO cell cultures.

No fertility studies have been conducted with levalbuterol hydrochloride. Reproduction studies in rats

using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50

mg/kg/day (approximately 108 times the maximum recommended daily inhalation dose of levalbuterol

hydrochloride for adults on a mg/m basis).

14 CLINICAL STUDIES

Adults and Adolescents ≥ 12 Years Old: The safety and efficacy of levalbuterol inhalation solution were

evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study

in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean

baseline FEV 60% of predicted). Approximately half of the patients were also receiving inhaled

corticosteroids. Patients were randomized to receive levalbuterol inhalation solution 0.63 mg,

levalbuterol inhalation solution 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5

mg, or placebo 3 times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb

portable

compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered-dose inhaler (MDI)

was used on an as-needed basis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline FEV , was demonstrated for all active

treatment regimens compared with placebo on day 1 and day 29. On both day 1 (see Figure 1) and day 29

(see Figure 2), 1.25 mg of levalbuterol inhalation solution demonstrated the largest mean percent change

from baseline FEV compared with the other active treatments. A dose of 0.63 mg of levalbuterol

inhalation solution and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean

percent change from baseline FEV on both day 1 and day 29.

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

Years Old

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

Years Old

1

1

The mean time to onset of a 15% increase in FEV over baseline for levalbuterol at doses of 0.63 mg

and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect

for both doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration of effect, as

measured by a > 15% increase from baseline FEV , was approximately 5 hours after administration of

0.63 mg of levalbuterol and approximately 6 hours after administration of 1.25 mg of levalbuterol after

4 weeks of treatment. In some patients, the duration of effect was as long as 8 hours.

Children 6 to 11 Years Old: A multicenter, randomized, double-blind, placebo- and active-controlled

study was conducted in children with mild-to-moderate asthma (mean baseline FEV 73% of predicted)

(n = 316). Following a 1-week placebo run-in, subjects were randomized to levalbuterol inhalation

solution (0.31 mg or 0.63 mg), racemic albuterol (1.25 mg or 2.5 mg), or placebo, which were delivered

3 times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb

3000 compressor.

Efficacy, as measured by mean peak percent change from baseline FEV , was demonstrated for all

active treatment regimens compared with placebo on day 1 and day 21. Time profile FEV curves for

day 1 and day 21 are shown in Figure 3 and Figure 4, respectively. The onset of effect (time to a 15%

increase in FEV over test-day baseline) and duration of effect (maintenance of a > 15% increase in

FEV over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.

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

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

1

1

16 HOW SUPPLIED/STORAGE AND HANDLING

Levalbuterol Inhalation Solution, USP is supplied in 3 mL unit-dose, low-density polyethylene (LDPE)

vials as a clear, colorless, sterile, preservative-free, aqueous solution, in three different strengths of

levalbuterol (0.31 mg, 0.63 mg, 1.25 mg). Each strength of levalbuterol inhalation solution is available

in a shelf-carton containing two foil pouches, each containing 12 unit-dose LDPE vials.

Levalbuterol Inhalation Solution USP, 0.31 mg (foil pouch label color green) contains 0.31 mg/3 mL

(0.0103%) of levalbuterol (as 0.36 mg/3 mL of levalbuterol hydrochloride) and is available in cartons

of 24 unit-dose LDPE vials (NDC 0378-9680-44).

Levalbuterol Inhalation Solution USP, 0.63 mg (foil pouch label color yellow) contains 0.63 mg/3 mL

(0.021%) of levalbuterol (as 0.73 mg/3 mL of levalbuterol hydrochloride) and is available in cartons of

24 unit-dose LDPE vials (NDC 0378-9681-44).

Levalbuterol Inhalation Solution USP, 1.25 mg (foil pouch label color red) contains 1.25 mg/3 mL

(0.042%) of levalbuterol (as 1.44 mg/3 mL of levalbuterol hydrochloride) and is available in cartons of

24 unit-dose LDPE vials (NDC 0378-9682-44).

Store levalbuterol inhalation solution in the protective foil pouch at 20° to 25°C (68° to 77°F). [See

USP Controlled Room Temperature.]

Protect from light and excessive heat.

Keep unopened vials in the foil pouch. Once the foil pouch is opened, the vials should be used within 2

weeks. Vials removed from the pouch, if not used immediately, should be protected from light and used

within one week. Discard any vial if the solution is not colorless.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information Leaflet and Instructions for Using Levalbuterol

Inhalation Solution).

Patients should be given the following information:

Hypersensitivity: Query patients about previously experienced hypersensitivity to levalbuterol or

racemic albuterol and counsel patients to report any hypersensitivity reactions to their physician.

Frequency of Use: Inform patients not to increase the dose or use levalbuterol inhalation solution more

frequently than recommended without consulting their physician. If patients find that treatment with

levalbuterol inhalation solution becomes less effective for symptomatic relief, symptoms become

worse, or they need to use the product more frequently than usual, they should seek medical attention

immediately.

Paradoxical Bronchospasm: Inform patients that levalbuterol inhalation solution can produce

paradoxical bronchospasm. Instruct patients to discontinue levalbuterol inhalation solution if

paradoxical bronchospasm occurs.

Concomitant Drug Use: Inform patients using levalbuterol inhalation solution, that other inhaled drugs

and asthma medications should be taken only as directed by their physician.

Common Adverse Reactions: Advise patients of the common adverse reactions of treatment with

levalbuterol inhalation solution include palpitations, chest pain, fast heart rate, headache, dizziness,

tremor and nervousness.

Pregnancy: Advise patients who are pregnant or nursing to contact their physician about the use of

levalbuterol inhalation solution.

General Information on Storage and Use: Advise patients to store levalbuterol inhalation solution in the

foil pouch at 20° to 25°C (68° to 77°F) protected from light and excessive heat. Do not use after the

expiration date stamped on the container. Store unused vials in the protective foil pouch. Once the foil

pouch is opened, use the vials within 2 weeks. Use vials removed from the pouch, immediately, or

protect from light and use within one week. Discard any vial if the solution is not colorless.

Advise patients not to mix levalbuterol inhalation solution with other drugs in a nebulizer.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

Manufactured for:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203 U.S.A.

REVISED MAY 2016

MS:LVIS:R4

PHARMACIST — DETACH HERE AND GIVE LEAFLET TO PATIENT

PATIENT INFORMATION LEAFLET

LEVALBUTEROL INHALATION SOLUTION, USP

(lev″ al bue′ ter ol)

0.31 mg, 0.63 mg, 1.25 mg

3 mL Unit-Dose Vials

For Oral Inhalation Only

Levalbuterol Inhalation Solution is only for use with a nebulizer.

Read this Patient Information Leaflet before you start to use levalbuterol inhalation solution and each

time you get a refill. There may be new information. This information does not take the place of talking

with your doctor about your medical condition or your treatment.

What is levalbuterol inhalation solution?

Levalbuterol inhalation solution is an inhaled prescription medicine used for the treatment or prevention

of bronchospasm in people 6 years of age and older.

Levalbuterol inhalation solution has not been shown to be safe and effective in children younger than 6

years of age.

Levalbuterol inhalation solution is supplied in 3 mL unit-dose vials in three different strengths of

levalbuterol (0.31 mg, 0.63 mg, 1.25 mg). The vials do not require dilution before use.

Who should not use levalbuterol inhalation solution?

Do not use levalbuterol inhalation solution if you are allergic to levalbuterol, racemic albuterol, or

any of the ingredients in levalbuterol inhalation solution. See the end of this leaflet for a complete list

of ingredients in levalbuterol inhalation solution.

What should I tell my doctor before using levalbuterol inhalation solution?

Before you use levalbuterol inhalation solution, tell your doctor if you have:

Tell your doctor about all the medicines you take including prescription and over-the-counter

medicines, vitamins, and herbal supplements. Levalbuterol inhalation solution may affect the way other

medicines work, and other medicines may affect how levalbuterol inhalation solution works.

Especially tell your doctor if you take:

Ask your doctor if you are not sure if any of your medicines are the kinds listed above.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you

get a new medicine.

How should I use levalbuterol inhalation solution?

had an allergic reaction to levalbuterol or racemic albuterol

heart problems

high blood pressure

seizures

diabetes

thyroid problems

any other medical conditions

are pregnant or planning to become pregnant. It is not known if levalbuterol inhalation solution will

harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.

are breastfeeding or plan to breastfeed. It is not known if levalbuterol passes into your breast milk.

You and your doctor should decide if you will use levalbuterol inhalation solution or breastfeed.

You should not do both.

other asthma medicines

heart medicines

medicines that increase urination (diuretics)

antidepressants

medicine to treat chronic obstructive pulmonary disease (COPD)

Read the step-by-step Instructions for Using Levalbuterol Inhalation Solution at the end of this

leaflet.

Use levalbuterol inhalation solution exactly as your doctor tells you to. Do not change your dose

without talking to your doctor first.

Your doctor will tell you how many times and when to use your levalbuterol inhalation solution.

An adult should help a child use levalbuterol inhalation solution.

Do not use your levalbuterol inhalation solution more often than your doctor tells you to.

Get medical help right away if levalbuterol inhalation solution:

does not work as well for your asthma symptoms or

What are the possible side effects of levalbuterol inhalation solution?

Levalbuterol inhalation solution can cause serious side effects including:

Call your doctor or go to the nearest hospital emergency room right away if you have any of the

serious side effects listed above or if you have worsening lung symptoms.

The most common side effects of levalbuterol inhalation solution include:

Tell your doctor if you have any side effects that bother you or that do not go away.

These are not all the possible side effects of levalbuterol inhalation solution. For more information, ask

your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-

800-FDA-1088.

How should I store levalbuterol inhalation solution?

your asthma symptoms get worse or

you need to use your levalbuterol inhalation solution more often than usual

If you also use another medicine by inhalation, you should ask your doctor for instructions on

when to use it while you are also using levalbuterol inhalation solution.

Do not mix levalbuterol inhalation solution with other medicines in your nebulizer.

Only use levalbuterol inhalation solution if it is colorless. Throw away the levalbuterol

inhalation solution vial if the liquid medicine is not colorless.

Do not use levalbuterol inhalation solution after the expiration date on the vial.

sudden shortness of breath (bronchospasm). Sudden shortness of breath can happen right

away after using levalbuterol inhalation solution.

worsening asthma

heart problems

death. If you use too much levalbuterol inhalation solution you can have heart or lung problems

that can lead to death.

serious allergic reactions. Call your doctor and stop using levalbuterol inhalation solution right

away if you have any symptoms of an allergic reaction such as:

swelling of the face, throat or tongue

hives

rash

breathing problems

low potassium levels in your blood

palpitations

chest pain

fast heart rate

headache

dizziness

tremor

nervousness

Keep levalbuterol inhalation solution and all medicines out of the reach of children.

General information about the safe and effective use of levalbuterol inhalation solution.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information

Leaflet. Do not use levalbuterol inhalation solution for a condition for which it was not prescribed. Do

not give levalbuterol inhalation solution to other people, even if they have the same symptoms that you

have. It may harm them.

This Patient Information Leaflet summarizes the most important information about levalbuterol inhalation

solution. If you would like more information, talk with your doctor. You can ask your pharmacist or

doctor for information about levalbuterol inhalation solution that is written for health professionals.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in levalbuterol inhalation solution?

Active ingredient: levalbuterol hydrochloride

Inactive ingredients: sodium chloride, edetate disodium and sulfuric acid

Instructions for Using Levalbuterol Inhalation Solution

Levalbuterol Inhalation Solution vial (see Figure A):

Using your Levalbuterol Inhalation Solution:

Read the following steps before using your levalbuterol inhalation solution. If you have any questions,

ask your doctor or pharmacist.

Step 1. Open the foil pouch by tearing the notched edge along the seam of the pouch (see Figure B).

Remove one vial to be used right away. Keep the rest of the unused vials in the foil pouch to protect

them from light and heat.

Store unopened levalbuterol inhalation solution vials in the protective foil pouch they come in at

20° to 25°C (68° to 77°F).

Keep levalbuterol inhalation solution away from light and heat.

When a levalbuterol inhalation solution foil pouch is opened, use the vials within 2 weeks.

When levalbuterol inhalation solution vials are removed from the foil pouch, use them right away

or within one week.

Step 2. Hold the vial in your hands. Make sure your thumb and finger cover the twist-off tabs below the

X-top (see Figure C).

Step 3. While holding the top firmly between your thumb and finger, twist the body of the vial to open

the vial (see Figure C).

Step 4. Throw away the top of the vial and squeeze the entire contents of the vial into the nebulizer

reservoir (see Figure D).

Step 5. Connect the nebulizer reservoir to the mouthpiece (see Figure E.1) or face mask (see Figure

E.2).

Step 6. Connect the nebulizer to the compressor (see Figure F).

Step 7. Sit in a comfortable, upright position. Place the mouthpiece in your mouth (see Figure G.1) or

put on your face mask (see Figure G.2). Turn on the compressor.

Step 8. Breathe as calmly, deeply, and evenly as possible until no more mist is seen in the nebulizer

reservoir. Your treatment will take about 5 to 15 minutes. When you do not see any mist in the nebulizer

reservoir, your treatment is finished.

Step 9. Clean and store your nebulizer. See the manufacturer’s instructions that come with your

nebulizer for how to clean and store your nebulizer.

This Patient Information Leaflet and Instructions for Use have been approved by the U.S. Food and Drug

Administration.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

Manufactured for:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Morgantown, WV 26505 U.S.A.

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203 U.S.A.

REVISED JULY 2015

MS:PIL:LVIS:R3

PRINCIPAL DISPLAY PANEL – 0.31 mg/3 mL (0.0103%)

NDC 0378-9680-44

Levalbuterol

Inhalation Solution, USP

0.31 mg (0.0103%)

0.31 mg / 3 mL*

* POTENCY EXPRESSED AS LEVALBUTEROL

24 Vials (2 Pouches of 12 – 3 mL Sterile Unit-Dose Vials)

For Oral Inhalation Only

Each 3 mL unit-dose vial contains 0.31 mg (0.0103%) of levalbuterol provided as the hydrochloride

salt in an aqueous

solution containing sodium chloride, edetate disodium and sulfuric acid to adjust the pH of the solution

to 4.0.

Contains no preservatives.

ATTENTION PHARMACIST: Detach “Patient Information Leaflet” from package insert and dispense

it with product.

Use only as directed by your physician. Do not exceed recommended dosage.

Protect from light. Avoid excessive heat. Store at 20˚-25˚C (68˚-77˚F) [See USP Controlled Room

Temperature].

Keep out of reach of children.

Unit-dose vials should remain stored in the protective foil pouch at all times. Once the foil pouch is

opened, the vials

should be used within two weeks. Once removed from the foil pouch, the individual vials should be

used within one

week. Discard if the solution is not colorless.

Rx only

Manufactured for:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

MS:9680:24C:R3

PRINCIPAL DISPLAY PANEL – 0.63 mg/3 mL (0.021%)

NDC 0378-9681-44

Levalbuterol

Inhalation Solution, USP

0.63 mg (0.021%)

0.63 mg / 3 mL*

* POTENCY EXPRESSED AS LEVALBUTEROL

24 Vials (2 Pouches of 12 – 3 mL Sterile Unit-Dose Vials)

For Oral Inhalation Only

Each 3 mL unit-dose vial contains 0.63 mg (0.021%) of levalbuterol provided as the hydrochloride salt

in an aqueous

solution containing sodium chloride, edetate disodium and sulfuric acid to adjust the pH of the solution

to 4.0.

Contains no preservatives.

ATTENTION PHARMACIST: Detach “Patient Information Leaflet” from package insert and dispense

it with product.

Use only as directed by your physician. Do not exceed recommended dosage.

Protect from light. Avoid excessive heat. Store at 20˚-25˚C (68˚-77˚F) [See USP Controlled Room

Temperature].

Keep out of reach of children.

Unit-dose vials should remain stored in the protective foil pouch at all times. Once the foil pouch is

opened, the vials

should be used within two weeks. Once removed from the foil pouch, the individual vials should be

used within one

week. Discard if the solution is not colorless.

Rx only

Manufactured for:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

MS:9681:24C:R3

PRINCIPAL DISPLAY PANEL – 1.25 mg/3 mL (0.042%)

NDC 0378-9682-44

Levalbuterol

Inhalation Solution, USP

1.25 mg (0.042%)

1.25 mg / 3 mL*

* POTENCY EXPRESSED AS LEVALBUTEROL

24 Vials (2 Pouches of 12 – 3 mL Sterile Unit-Dose Vials)

For Oral Inhalation Only

Each 3 mL unit-dose vial contains 1.25 mg (0.042%) of levalbuterol provided as the hydrochloride salt

in an aqueous

solution containing sodium chloride, edetate disodium and sulfuric acid to adjust the pH of the solution

to 4.0.

Contains no preservatives.

ATTENTION PHARMACIST: Detach “Patient Information Leaflet” from package insert and dispense

it with product.

Use only as directed by your physician. Do not exceed recommended dosage.

Protect from light. Avoid excessive heat. Store at 20˚-25˚C (68˚-77˚F) [See USP Controlled Room

Temperature].

Keep out of reach of children.

Unit-dose vials should remain stored in the protective foil pouch at all times. Once the foil pouch is

opened, the vials

should be used within two weeks. Once removed from the foil pouch, the individual vials should be

used within one

week. Discard if the solution is not colorless.

Rx only

Manufactured for:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

Manufactured by:

The Ritedose Corporation

Columbia, SC 29203

MS:9682:24C:R3

LEVALBUTEROL

levalbuterol solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -9 6 8 2

Route of Administration

RESPIRATORY (INHALATION)

Active Ingredient/Active Moiety

Ingredient Name

Basis of

Stre ng th

Stre ng th

LEVALBUTERO L HYDRO CHLO RIDE (UNII: WDQ1526 QJM) (LEVALBUTEROL -

UNII:EDN2NBH5SS)

LEVALBUTEROL

1.25 mg

in 3 mL

Inactive Ingredients

Ingredient Name

Stre ng th

SO DIUM CHLO RIDE (UNII: 451W47IQ8 X)

EDETATE DISO DIUM (UNII: 7FLD9 1C8 6 K)

SULFURIC ACID (UNII: O40 UQP6 WCF)

WATER (UNII: 0 59 QF0 KO0 R)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 378 -9 6 8 2-44

2 in 1 CARTON

0 3/15/20 13

0 8 /31/20 19

1

NDC:0 378 -9 6 8 2-9 6

12 in 1 POUCH

1

3 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 778 0 0

0 3/15/20 13

0 8 /31/20 19

LEVALBUTEROL

levalbuterol solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -9 6 8 1

Route of Administration

RESPIRATORY (INHALATION)

Active Ingredient/Active Moiety

Ingredient Name

Basis of

Stre ng th

Stre ng th

LEVALBUTERO L HYDRO CHLO RIDE (UNII: WDQ1526 QJM) (LEVALBUTEROL -

UNII:EDN2NBH5SS)

LEVALBUTEROL

0 .6 3 mg

in 3 mL

Inactive Ingredients

Ingredient Name

Stre ng th

SO DIUM CHLO RIDE (UNII: 451W47IQ8 X)

EDETATE DISO DIUM (UNII: 7FLD9 1C8 6 K)

SULFURIC ACID (UNII: O40 UQP6 WCF)

WATER (UNII: 0 59 QF0 KO0 R)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 378 -9 6 8 1-44

2 in 1 CARTON

0 3/15/20 13

0 8 /31/20 19

1

NDC:0 378 -9 6 8 1-9 6

12 in 1 POUCH

1

3 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 778 0 0

0 3/15/20 13

0 8 /31/20 19

LEVALBUTEROL

levalbuterol solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 378 -9 6 8 0

Route of Administration

RESPIRATORY (INHALATION)

Active Ingredient/Active Moiety

Ingredient Name

Basis of

Stre ng th

Stre ng th

LEVALBUTERO L HYDRO CHLO RIDE (UNII: WDQ1526 QJM) (LEVALBUTEROL -

UNII:EDN2NBH5SS)

LEVALBUTEROL

0 .31 mg

in 3 mL

Inactive Ingredients

Ingredient Name

Stre ng th

SO DIUM CHLO RIDE (UNII: 451W47IQ8 X)

EDETATE DISO DIUM (UNII: 7FLD9 1C8 6 K)

SULFURIC ACID (UNII: O40 UQP6 WCF)

WATER (UNII: 0 59 QF0 KO0 R)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 378 -9 6 8 0 -44

2 in 1 CARTON

0 3/15/20 13

0 8 /31/20 19

1

NDC:0 378 -9 6 8 0 -9 6

12 in 1 POUCH

1

3 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Mylan Pharmaceuticals Inc.

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 778 0 0

0 3/15/20 13

0 8 /31/20 19

Labeler -

Mylan Pharmaceuticals Inc. (059295980)

Revised: 5/2016

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