XOPENEX - levalbuterol hydrochloride solution

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

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Active ingredient:
Levalbuterol Hydrochloride (UNII: WDQ1526QJM) (Levalbuterol - UNII:EDN2NBH5SS)
Available from:
Akorn, Inc.
INN (International Name):
Levalbuterol Hydrochloride
Composition:
Levalbuterol 0.31 mg in 3 mL
Administration route:
RESPIRATORY (INHALATION)
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
XOPENEX (levalbuterol HCl) 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. XOPENEX 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) ]. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medication, including XOPENEX, during pregnancy. To enroll in MotherToBaby Pregnancy Studies' Asthma & Pregnancy Study or for more information about the registry, call 1-877-311-8972 or visit www.mothertobaby.org/ongoing-study/asthma. Risk Summary There are no adequate and well-controlled studies of XOPENEX Inhalation Solution in pregnant women. There are clinical considerations with the use of XOPENEX In
Product summary:
XOPENEX Inhalation Solution 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 XOPENEX Inhalation Solution is available in a shelf-carton containing one or more foil pouches, each containing 12 unit-dose LDPE vials. XOPENEX (levalbuterol HCl) Inhalation Solution, 0.31 mg (foil pouch label color green) contains 0.31 mg of levalbuterol (as 0.36 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 17478-172-24). XOPENEX (levalbuterol HCl) Inhalation Solution, 0.63 mg (foil pouch label color yellow) contains 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 17478-173-24). XOPENEX (levalbuterol HCl) Inhalation Solution, 1.25 mg (foil pouch label color red) contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 17478-174-24). XOPENEX Inhalation Solution is also available as a concentrate in individually pouched 0.5 mL unit-dose vials containing 1.25 mg of levalbuterol (NDC 17478-171-30). Storage: Store XOPENEX 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 1 week. Discard any vial if the solution is not colorless.
Authorization status:
New Drug Application
Authorization number:
17478-172-12, 17478-172-24, 17478-173-12, 17478-173-24, 17478-174-12, 17478-174-24

XOPENEX - levalbuterol hydrochloride solution

Akorn, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use XOPENEX Inhalation Solution safely and

effectively. See full prescribing information for XOPENEX Inhalation Solution.

XOPENEX (levalbuterol hydrochloride) Inhalation Solution

Initial U.S. Approval: 1999

INDICATIONS AND USAGE

XOPENEX (levalbuterol hydrochloride) Inhalation Solution is a beta -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)

DOSAGE AND ADMINISTRATION

FOR ORAL INHALATION ONLY (2)

Children 6 to 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)

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

Hypersensitivity to levalbuterol or racemic albuterol. (4)

WARNINGS AND PRECAUTIONS

Life-threatening paradoxical bronchospasm may occur. Discontinue XOPENEX Inhalation Solution immediately and

treat with alternative therapy. (5.1)

Need for more doses of XOPENEX Inhalation Solution than usual may be a sign of deterioration of asthma and requires

reevaluation of treatment. (5.2)

XOPENEX Inhalation Solution is not a substitute for corticosteroids. (5.3)

Cardiovascular effects may occur. Consider discontinuation of XOPENEX 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 XOPENEX Inhalation Solution immediately. (5.6)

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

ADVERSE REACTIONS

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

To report SUSPECTED ADVERSE REACTIONS, contact Akorn, Inc. at 1-800-932-5676 or FDA at 1-800-FDA-

1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs: May potentiate effect. (7.1)

Beta-blockers: May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. Patients with

asthma should not normally be treated with beta-blockers. (7.2)

Diuretic: May worsen electrocardiographic changes or hypokalemia associated with diuretic may worsen. Consider

monitoring potassium levels. (7.3)

Digoxin: May decrease serum digoxin levels. Consider monitoring digoxin levels. (7.4)

Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants: May potentiate effect of albuterol on the

cardiovascular system. (7.5)

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

Revised: 12/2018

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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 Lactation

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

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

XOPENEX (levalbuterol HCl) 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

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

airway disease.

2 DOSAGE AND ADMINISTRATION

XOPENEX 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 XOPENEX Inhalation Solution for patients 6

to11 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 XOPENEX Inhalation

Solution 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 XOPENEX Inhalation Solution may benefit from a dosage of 1.25 mg three

times a day.

Patients receiving the highest dose of XOPENEX 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 XOPENEX 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 XOPENEX Inhalation Solution

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

The safety and efficacy of XOPENEX 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 XOPENEX Inhalation

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

3 DOSAGE FORMS AND STRENGTHS

Inhalation Solution 3 mL unit-dose, vials in three dosage strengths of levalbuterol; 0.31 mg, 0.63 mg,

1.25 mg. Each strength of XOPENEX Inhalation Solution is available in a shelf carton containing one or

more foil pouches, each containing 12 unit-dose vials.

4 CONTRAINDICATIONS

XOPENEX 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

XOPENEX Inhalation Solution can produce paradoxical bronchospasm, which may be life-threatening.

If paradoxical bronchospasm occurs, XOPENEX 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 XOPENEX 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

XOPENEX 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

XOPENEX 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 XOPENEX 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, XOPENEX 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 XOPENEX Inhalation

Solution.

5.7 Coexisting Conditions

XOPENEX 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, XOPENEX Inhalation Solution may produce

significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential

to produce adverse cardiovascular effects. The decrease is usually transient, not requiring

supplementation.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

Paradoxical bronchospasm [see Warnings and Precautions (5.1)]

Cardiovascular effects [see Warnings and Precautions (5.4)]

Immediate hypersensitivity reactions [see Warnings and Precautions (5.6)]

Hypokalemia [see Warnings and Precautions (5.8)]

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 XOPENEX 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 XOPENEX 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

Percent of Patients

Body System

Preferred Term

Placebo

(n=75)

XOPENEX

1.25 mg

(n=73)

XOPENEX

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

Musculoskeletal System

Leg cramps

Central Nervous System

Dizziness

Hypertonia

Nervousness

Tremor

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

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 XOPENEX Inhalation Solution 0.63 mg group compared with the other active

treatment groups. The clinical significance of these small differences is unknown.

Changes in heart rate 15 minutes after drug administration and in plasma glucose and potassium 1 hour

after drug administration on day 1 and day 29 were clinically comparable in the XOPENEX 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 XOPENEX Inhalation Solution 0.63 mg group compared with the

other active treatment groups (see Table 2). The clinical significance of these small differences is

unknown. After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were generally

diminished compared with day 1 in all active treatment groups.

Table 2: Mean Changes from Baseline Heart Rate at 15 Minutes and Glucose and Potassium at

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

Mean Changes (day 1)

Treatment

Heart Rate

(bpm)

Glucose

(mg/dL)

Potassium

(mEq/L)

XOPENEX 0.63 mg, n=72

-0.2

XOPENEX 1.25 mg, n=73

10.3

-0.3

Racemic albuterol 2.5 mg, n=74

-0.3

Placebo, n=75

-2.8

-0.2

-0.2

No other clinically relevant laboratory abnormalities related to administration of XOPENEX 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

XOPENEX 1.25 mg compared with the other active treatment groups.

The following adverse reactions, considered potentially related to XOPENEX, occurred in less than

2% of the 292 subjects who received XOPENEX 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 XOPENEX, 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 XOPENEX 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)

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

Percent of Patients

Body System

Preferred Term

Placebo

(n=59)

XOPENEX

0.31 mg

(n=66)

XOPENEX

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

Skin and Appendages

Eczema

Rash

Urticaria

Special Senses

Otitis media

Changes in heart rate, plasma glucose, and serum potassium are shown in Table 4. The clinical

significance of these small differences is unknown.

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

1 Hour after First Dose (Day 1) and Last Dose (Day 21) in Children 6 to 11 Years Old

Mean Changes (Day 1)

Treatment

Heart Rate

(bpm)

Glucose

(mg/dL)

Potassium

(mEq/L)

XOPENEX 0.31 mg, n=66

-0.31

XOPENEX 0.63 mg, n=67

-0.36

Racemic albuterol 1.25 mg, n=64

-0.27

Racemic albuterol 2.5 mg, n=60

10.9

10.8

-0.56

Placebo, n=59

-1.8

-0.05

Mean Changes (Day 21)

Treatment

Heart Rate

(bpm)

Glucose

(mg/dL)

Potassium

(mEq/L)

XOPENEX 0.31 mg, n=60

-0.32

XOPENEX 0.63 mg, n=66

-0.34

Racemic albuterol 1.25 mg, n=62

-0.18

Racemic albuterol 2.5 mg, n=54

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 XOPENEX 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, XOPENEX 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 XOPENEX 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 XOPENEX 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 XOPENEX 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 XOPENEX Inhalation Solution.

7.5 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

XOPENEX Inhalation Solution should be administered with extreme caution to patients being treated

with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of

such agents, because the action of levalbuterol on the vascular system may be potentiated. Consider

alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma

medication, including XOPENEX, during pregnancy. To enroll in MotherToBaby Pregnancy Studies'

Asthma & Pregnancy Study or for more information about the registry, call 1-877-311-8972 or visit

www.mothertobaby.org/ongoing-study/asthma.

Risk Summary

There are no adequate and well-controlled studies of XOPENEX Inhalation Solution in pregnant

women. There are clinical considerations with the use of XOPENEX Inhalation Solution in pregnant

women [see Clinical Considerations].

Following oral administration of levelbuterol HCl to pregnant rabbits, there was no evidence of

teratogenicity at doses up to 25 mg/kg/day [approximately 108 times the maximum recommended human

daily inhalation dose (MRHDID) of levalbuterol HCl for adults on a mg/m basis]; however, racemic

albuterol sulfate was teratogenic in mice (cleft palate) and rabbits (cramioschisis) at doses slightly

higher than the human therapeutic range (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations(s)

are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the

mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women

should be closely monitored and medication adjusted as necessary to maintain optimal control.

Labor or Delivery

Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of

XOPENEX Inhalation Solution for the treatment of bronchospasm during labor should be restricted to

those patients for whom the benefits clearly outweigh the risk.

XOPENEX Inhalation Solution has not been approved for the management of preterm labor. The

benefit-risk ratio when XOPENEX 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.

Data

Animal Data

The oral administration of levalbuterol HCl to pregnant New Zealand White rabbits during the period of

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

times the MRHDID of levalbuterol HCl for adults on a mg/m basis). In a rat developmental study,

racemic albuterol sulfate administered by inhalation did not produce any teratogenic effects at

exposures approximately 63 times the MRHDID (on a mg/m basis at a maternal dose of 10.5 mg/kg).

However, other developmental studies with the racemic albuterol sulfate, did result in teratogenic

effects in mice and rabbits at doses slightly higher than the human therapeutic range. In a rabbit

developmental study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses

(37%) at approximately 215 times the MRHDID for adults (on a mg/m basis at a maternal dose of 50

mg/kg). In a mouse developmental study, subcutaneously administered albuterol sulfate produced cleft

palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately 0.3 times the MRHDID for

adults (on a mg/m basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at

approximately 3 times the MRHDID (on a mg/m basis at a maternal dose of 2.5 mg/kg/day). Similar

effects were not observed at approximately 0.03 times the MRHDID for adults on a mg/m basis at a

maternal dose of 0.025 mg/kg/day (i.e., less than the therapeutic dose). Cleft palate also occurred in 22

of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).

8.2 Lactation

Risk Summary

There are no available data on the presence of levalbuterol in human milk, the effects on the breastfed

child, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's

clinical need for XOPENEX Inhalation Solution and any potential adverse effects on the breastfed child

from XOPENEX Inhalation Solution or from the underlying maternal condition.

8.4 Pediatric Use

Pediatric Patients 6 Years of Age and Older

The safety and efficacy of XOPENEX 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

XOPENEX Inhalation Solution is not indicated for pediatric patients less than 6 years of age.

Clinical trials with XOPENEX 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

XOPENEX treatment.

XOPENEX 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 XOPENEX 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 XOPENEX 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 XOPENEX Inhalation Solution 0.31 mg, XOPENEX 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 XOPENEX 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 XOPENEX Inhalation-treated subjects

compared to control (Table 5). Other adverse reactions were consistent with those observed in the

clinical trial population of patients 6 years of age and older [see Adverse Reactions (6.1)].

Table 5: Asthma-related Adverse Reactions in 3- and 4-Week Clinical Trials in Children Birth to

<6 Years of Age

* Asthma 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.

Asthma

Exacerbations*

n (%)

Treatment

Discontinuations due to

Asthma

n (%)

Asthma-related Adverse

Reactions**

n (%)

Study 1

XOPENEX 0.31 mg, n=58

6 (10)

4 (7)

XOPENEX 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

XOPENEX 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 XOPENEX Inhalation Solution did not include sufficient numbers of subjects aged

65 years and older to determine whether they respond differently from younger subjects. Only 5 patients

65 years of age and older were treated with XOPENEX 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 XOPENEX

Inhalation Solution. If clinically warranted due to insufficient bronchodilator response, the dose of

XOPENEX 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 XOPENEX Inhalation Solution. Treatment consists

of discontinuation of XOPENEX 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 XOPENEX Inhalation Solution.

11 DESCRIPTION

XOPENEX Inhalation Solution is a sterile, clear, colorless, preservative-free solution of the

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

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

(12)]. The chemical name for levalbuterol HCl 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 HCl is 275.8, and its empirical formula is C

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 HCl is the USAN modified name for (R)-albuterol HCl in the United States.

XOPENEX Inhalation Solution is supplied in unit-dose vials and requires no dilution before

administration by nebulization. Each 3 mL unit-dose vial contains 0.31 mg of levalbuterol (as 0.36 mg of

levalbuterol HCl) or 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) or 1.25 mg of

levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, 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 XOPENEX 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 XOPENEX 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 XOPENEX Inhalation Solution. Systemic beta-adrenergic adverse effects

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

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 XOPENEX, 1.25 mg

of (S)-albuterol, or placebo using a Pari LC Jet™ nebulizer. Racemic albuterol sulfate, XOPENEX, 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 XOPENEX 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 XOPENEX 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 XOPENEX 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 XOPENEX 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 XOPENEX 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 5).

Following administration of a cumulative 5 mg dose of XOPENEX 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

Median (Min, Max) reported for T

* A negative T

indicates C

occurred between first and last nebulizations.

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

Single Dose

Cumulative Dose

XOPENEX

1.25 mg

Racemic

albuterol sulfate

2.5 mg

XOPENEX

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

(0.17, 0.37)

(0.17, 1.50)

(–0.18*, 1.25)

(–0.28*, 1.00)

AUC (nghr/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 XOPENEX 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 XOPENEX 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)

The values are predicted by assuming linear pharmacokinetics

The data obtained from Table 6

Area under the plasma concentration curve from time 0 to infinity

Maximum plasma concentration

Children 6 to 11 years

Adults ≥12 years

Treatment

XOPENEX

0.31 mg

XOPENEX

0.63 mg

Racemic

albuterol

1.25 mg

Racemic

albuterol

2.5 mg

XOPENEX

0.63 mg

XOPENEX

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

0-∞

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 XOPENEX Inhalation Solution has not

been evaluated.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects

with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy

volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in racemic

albuterol clearance. Caution should be used when administering high doses of XOPENEX 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 HCl, 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 MRHDID of levalbuterol HCl for adults and

approximately 5 times the MRHDID of levalbuterol HCl 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 no evidence of tumorigenicity. Dietary doses in CD-1 mice were up to

500 mg/kg/day (approximately 540 times the MRHDID of levalbuterol HCl for adults and approximately

630 times the MRHDID of levalbuterol HCl 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 MRHDID of levalbuterol HCl for

adults on a mg/m basis and approximately 105 times the MRHDID of levalbuterol HCl for children on a

mg/m basis).

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

Mutation Assay. Levalbuterol HCl 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

HCl for adults on a mg/m basis).

14 CLINICAL STUDIES

Adults and Adolescents ≥12 Years Old

The safety and efficacy of XOPENEX 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 XOPENEX 0.63 mg, XOPENEX 1.25 mg, racemic albuterol sulfate 1.25 mg,

racemic albuterol sulfate 2.5 mg, or placebo three 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 XOPENEX demonstrated the largest mean percent change from baseline

FEV compared with the other active treatments. A dose of 0.63 mg of XOPENEX 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.

Fig ure 1: Mean Percent Chang e from Baseline FEV on Day 1, Adults and Adolescents ≥12 years old

Fig ure 2: Mean Percent Chang e from Baseline FEV on Day 29, Adults and Adolescents ≥12 years old

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

1

1

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 XOPENEX (0.31 or 0.63 mg), racemic albuterol

(1.25 or 2.5 mg), or placebo, which were delivered three 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.

Fig ure 3: Mean Percent Chang e from Baseline FEV on Day 1, Children 6 to 11 Years of Ag e

Fig ure 4 : Mean Percent Chang e from Baseline FEV on Day 21, Children 6 to 11 Years of Ag e

16 HOW SUPPLIED/STORAGE AND HANDLING

XOPENEX Inhalation Solution 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

1

1

levalbuterol (0.31 mg, 0.63 mg, 1.25 mg). Each strength of XOPENEX Inhalation Solution is available

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

XOPENEX (levalbuterol HCl) Inhalation Solution, 0.31 mg (foil pouch label color green) contains

0.31 mg of levalbuterol (as 0.36 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose

LDPE vials (NDC 17478-172-24).

XOPENEX (levalbuterol HCl) Inhalation Solution, 0.63 mg (foil pouch label color yellow) contains

0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose

LDPE vials (NDC 17478-173-24).

XOPENEX (levalbuterol HCl) Inhalation Solution, 1.25 mg (foil pouch label color red) contains

1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose

LDPE vials (NDC 17478-174-24).

XOPENEX Inhalation Solution is also available as a concentrate in individually pouched 0.5 mL unit-

dose vials containing 1.25 mg of levalbuterol (NDC 17478-171-30).

Storage: Store XOPENEX 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 1

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

17 PATIENT COUNSELING INFORMATION

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

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 XOPENEX Inhalation Solution more frequently than

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

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 XOPENEX Inhalation Solution can produce paradoxical bronchospasm. Instruct

patients to discontinue XOPENEX Inhalation Solution if paradoxical bronchospasm occurs.

Concomitant Drug Use

Inform patients using XOPENEX 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 XOPENEX Inhalation Solution

including 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 XOPENEX

Inhalation Solution.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma

medication, including XOPENEX, during pregnancy. To enroll in the Asthma & Pregnancy Study or for

more information about the registry, call 1-877-311-8972 or visit www.mothertobaby.org/ongoing-

study/asthma [see Use in Specific Populations (8.1)].

General Information on Storage and Use

Advise patients to store XOPENEX Inhalation Solution in the foil pouch between 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

1 week. Discard any vial if the solution is not colorless.

Advise patients not to mix XOPENEX Inhalation Solution with other drugs in a nebulizer.

AKORN

Distributed by: Akorn, Inc.

Lake Forest, IL 60045

Manufactured for: Oak Pharmaceuticals, Inc.

For customer service, call 1-800-932-5676.

To report adverse events, call 1-800-932-5676.

For medical information, call 1-800-932-5676.

Xopenex is a registered trademark of Sunovion Pharmaceuticals Inc. and is used under license.

XP00N December 2018

AKNX024-642R01

PATIENT INFORMATION

XOPENEX (pronounced zō-pen-eks)

(levalbuterol hydrochloride)

Inhalation Solution

0.31 mg, 0.63 mg, 1.25 mg

3 mL Unit-Dose Vials

For Oral Inhalation Only

XOPENEX Inhalation Solution is only for use with a nebulizer.

Read this Patient Information before you start to use XOPENEX 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 XOPENEX Inhalation Solution?

XOPENEX Inhalation Solution is an inhaled prescription medicine used for the treatment or prevention

of bronchospasm in people 6 years of age and older.

XOPENEX Inhalation Solution has not been shown to be safe and effective in children younger than

6 years of age.

XOPENEX Inhalation Solution is supplied in 3 mL unit-dose vials in three different strengths of

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

Who should not use XOPENEX Inhalation Solution?

Do not use XOPENEX Inhalation Solution if you are allergic to levalbuterol, racemic albuterol, or

any of the ingredients in XOPENEX. See the end of this leaflet for a complete list of ingredients in

®

XOPENEX Inhalation Solution.

What should I tell my doctor before using XOPENEX Inhalation Solution?

Before you use XOPENEX Inhalation Solution, tell your doctor if you have:

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 XOPENEX 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 XOPENEX Inhalation Solution passes into

your breast milk. You and your doctor should decide if you will use XOPENEX Inhalation Solution

or breastfeed. You should not do both.

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

medicines, vitamins, and herbal supplements. XOPENEX Inhalation Solution may affect the way other

medicines work, and other medicines may affect how XOPENEX Inhalation Solution works.

Especially tell your doctor if you take:

other asthma medicines

heart medicines

medicines that increase urination (diuretics)

antidepressants

medicine to treat chronic obstructive pulmonary disease (COPD)

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 XOPENEX Inhalation Solution?

Read the step-by-step Instructions for Using XOPENEX Inhalation Solution at the end of this leaflet.

Use XOPENEX 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 XOPENEX Inhalation Solution.

An adult should help a child use XOPENEX Inhalation Solution.

Do not use your XOPENEX Inhalation Solution more often than your doctor tells you to.

Get medical help right away if XOPENEX Inhalation Solution:

does not work as well for your asthma symptoms or

your asthma symptoms get worse or

you need to use your XOPENEX 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 XOPENEX Inhalation Solution.

Do not mix XOPENEX Inhalation Solution with other medicines in your nebulizer.

Only use XOPENEX Inhalation Solution if it is colorless. Throw away the XOPENEX Inhalation

Solution vial if the liquid medicine is not colorless.

Do not use XOPENEX Inhalation Solution after the expiration date on the vial.

What are the possible side effects of XOPENEX Inhalation Solution?

XOPENEX Inhalation Solution can cause serious side effects including:

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

after using XOPENEX Inhalation Solution.

worsening asthma

heart problems

death. If you use too much XOPENEX Inhalation Solution you can have heart or lung problems that

can lead to death.

serious allergic reactions. Call your doctor and stop using XOPENEX 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

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 XOPENEX Inhalation Solution include:

palpitations

chest pain

fast heart rate

headache

dizziness

tremor

nervousness

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 XOPENEX 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 XOPENEX Inhalation Solution?

Store unopened XOPENEX Inhalation Solution vials in the protective foil pouch they come in

between 68°F to 77°F (20°C to 25°C).

Keep XOPENEX Inhalation Solution away from light and heat.

When a XOPENEX Inhalation Solution foil pouch is opened, use the vials within 2 weeks.

When XOPENEX Inhalation Solution vials are removed from the foil pouch, use them right away or

within 1 week.

Keep XOPENEX Inhalation Solution and all medicines out of the reach of children.

General information about the safe and effective use of XOPENEX Inhalation Solution.

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

Do not use XOPENEX Inhalation Solution for a condition for which it was not prescribed. Do not give

XOPENEX 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 XOPENEX Inhalation

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

doctor for information about XOPENEX Inhalation Solution that is written for health professionals.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma

medication, including XOPENEX, during pregnancy. To enroll in the Asthma & Pregnancy Study or for

more information about the registry, call 1-877-311-8972 or visit www.mothertobaby.org/ongoing-

study/asthma.

For customer service, call 1-800-932-5676.

To report adverse events, call 1-800-932-5676.

For medical information, call 1-800-932-5676.

What are the ingredients in XOPENEX Inhalation Solution?

Active ingredient: levalbuterol hydrochloride

Inactive ingredients: sodium chloride, sulfuric acid, water and nitrogen

Instructions for Using XOPENEX Inhalation Solution

XOPENEX Inhalation Solution vial (see Figure A):

Fig ure A

Using your XOPENEX Inhalation Solution:

Read the following Steps before using your XOPENEX 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 1 vial to be used right away. Keep the rest of the unused vials in the foil pouch to protect them

from light and heat.

Fig ure B

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).

Fig ure 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).

Fig ure D

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

E.2).

Figure E.1

Figure E.2

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

Fig ure 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.

Figure G.1

Figure G.2

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 and Instructions for Use have been approved by the U.S. Food and Drug

Administration.

AKORN

Distributed by: Akorn, Inc.

Lake Forest, IL 60045

Manufactured for: Oak Pharmaceuticals, Inc.

For customer service, call 1-800-932-5676.

To report adverse events, call 1-800-932-5676.

For medical information, call 1-800-932-5676.

Xopenex is a registered trademark of Sunovion Pharmaceuticals Inc. and is used under license.

XP00N December 2018

AKNX024-642R01

Principal Display Panel Text for Pouch Label:

Xopenex® NDC 17478-172-12

(levalbuterol HCl)

Inhalation Solution 0.31 mg/3 mL* *Potency expressed as levalbuterol

Principal Display Panel Text for Carton Label:

NDC 17478-172-24

0.31 mg/3 mL

Xopenex®

(levalbuterol HCl) *Potency expressed as levalbuterol

Inhalation Solution For Oral Inhalation Only. Sterile Unit-Dose Vial

0.31 mg/3 mL* 24 x 3 mL Sterile Unit-Dose Vials

Rx only

Akorn Logo

Principal Display Panel Text for Pouch Label:

Xopenex® NDC 17478-173-12

(levalbuterol HCl)

Inhalation Solution 0.63 mg/3 mL* *Potency expressed as levalbuterol

Principal Display Panel Text for Carton Label:

NDC 17478-173-24

0.63 mg/3 mL

Xopenex®

(levalbuterol HCl) *Potency expressed as levalbuterol

Inhalation Solution For Oral Inhalation Only. Sterile Unit-Dose Vial

0.63 mg/3 mL* 24 x 3 mL Sterile Unit-Dose Vials

Rx only

Akorn Logo

Principal Display Panel Text for Pouch Label:

Xopenex® NDC 17478-174-12

(levalbuterol HCl)

Inhalation Solution 1.25 mg/3 mL* *Potency expressed as levalbuterol

Principal Display Panel Text for Carton Label:

NDC 17478-174-24

1.25 mg/3 mL

Xopenex®

(levalbuterol HCl) *Potency expressed as levalbuterol

Inhalation Solution For Oral Inhalation Only. Sterile Unit-Dose Vial

1.25 mg/3 mL* 24 x 3 mL Sterile Unit-Dose Vials

Rx only

Akorn Logo

XOPENEX

levalbuterol hydrochloride solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:17478 -172

Route of Administration

RESPIRATORY (INHALATION)

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Leva lbutero l Hydro chlo ride (UNII: WDQ1526 QJM) (Levalbutero l - UNII:EDN2NBH5SS)

Le va lbute ro l

0 .31 mg in 3 mL

Inactive Ingredients

Ingredient Name

Stre ng th

So dium Chlo ride (UNII: 451W47IQ8 X)

Sulfuric Acid (UNII: O40 UQP6 WCF)

Wa ter (UNII: 0 59 QF0 KO0 R)

Nitro g en (UNII: N76 29 21K75)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:17478 -172-

2 in 1 CARTON

0 2/27/20 15

1

NDC:17478 -172-

12 in 1 POUCH

1

3 mL in 1 VIAL, SINGLE-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 8 37

0 2/27/20 15

XOPENEX

levalbuterol hydrochloride solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:17478 -173

Route of Administration

RESPIRATORY (INHALATION)

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Leva lbutero l Hydro chlo ride (UNII: WDQ1526 QJM) (Levalbutero l - UNII:EDN2NBH5SS)

Le va lbute ro l

0 .6 3 mg in 3 mL

Inactive Ingredients

Ingredient Name

Stre ng th

So dium Chlo ride (UNII: 451W47IQ8 X)

Sulfuric Acid (UNII: O40 UQP6 WCF)

Wa ter (UNII: 0 59 QF0 KO0 R)

Nitro g en (UNII: N76 29 21K75)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:17478 -173-

2 in 1 CARTON

0 2/27/20 15

1

NDC:17478 -173-

12 in 1 POUCH

1

3 mL in 1 VIAL, SINGLE-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 8 37

0 2/27/20 15

XOPENEX

levalbuterol hydrochloride solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:17478 -174

Route of Administration

RESPIRATORY (INHALATION)

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Leva lbutero l Hydro chlo ride (UNII: WDQ1526 QJM) (Levalbutero l - UNII:EDN2NBH5SS)

Le va lbute ro l

1.25 mg in 3 mL

Inactive Ingredients

Ingredient Name

Stre ng th

So dium Chlo ride (UNII: 451W47IQ8 X)

Sulfuric Acid (UNII: O40 UQP6 WCF)

Wa ter (UNII: 0 59 QF0 KO0 R)

Nitro g en (UNII: N76 29 21K75)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:17478 -174-

2 in 1 CARTON

0 2/27/20 15

1

NDC:17478 -174-

12 in 1 POUCH

1

3 mL in 1 VIAL, SINGLE-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Akorn, Inc.

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 8 37

0 2/27/20 15

Labeler -

Akorn, Inc. (062649876)

Revised: 12/2018

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