Levalbuterol

LEVALBUTEROL- levalbuterol hydrochloride solution
REMEDYREPACK INC.

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 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 three times a day, by nebulization. Routine dosing should not exceed 0.63 mg three times a day.

Adults and Adolescents 12 years old: The recommended starting dosage of levalbuterol inhalation solution for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.

Patients 12 years of age and older with more severe asthma or patients who do not respond adequately to a dose of 0.63 mg of levalbuterol inhalation solution may benefit from a dosage of 1.25 mg three 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-Neb ® 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 is supplied in 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 USP is available in a shelf carton containing 6 foil pouches, each containing 5 unit-dose LDPE 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 agonists alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.

5.4 Cardiovascular Effects

Levalbuterol inhalation solution, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms. Although such effects are uncommon after administration of levalbuterol inhalation solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the t-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, levalbuterol inhalation solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.5 Do Not Exceed Recommended Dose

Do not exceed the recommended dose. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

5.6 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving levalbuterol inhalation solution.

5.7 Coexisting Conditions

Levalbuterol inhalation solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.

Changes in blood glucose may occur. Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.8 Hypokalemia

As with other beta-adrenergic agonist medications, levalbuterol inhalation solution may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

6 ADVERSE REACTIONS

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

  • Paradoxical bronchospasm [see Warnings and Precautions ( 5.1) ]
  • Cardiovascular effects [see Warnings and Precautions ( 5.4) ]
  • Immediate hypersensitivity reactions [see Warnings and Precautions ( 5.6) ]
  • Hypokalemia [see Warnings and Precautions ( 5.8) ]

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

Percent of Patients 1

Body System Preferred Term

Placebo (n = 75)

Levalbuterol 1.25 mg (n = 73)

Levalbuterol 0.63 mg (n = 72)

Racemic albuterol 2.5 mg (n = 74)

Body as a Whole

Allergic reaction

1.3

0

0

2.7

Flu syndrome

0

1.4

4.2

2.7

Accidental injury

0

2.7

0

0

Pain

1.3

1.4

2.8

2.7

Back pain

0

0

0

2.7

Cardiovascular System

Tachycardia

0

2.7

2.8

2.7

Migraine

0

2.7

0

0

Digestive System

Dyspepsia

1.3

2.7

1.4

1.4

Musculoskeletal System

Leg cramps

1.3

2.7

0

1.4

Central Nervous System

Dizziness

1.3

2.7

1.4

0

Hypertonia

0

0

0

2.7

Nervousness

0

9.6

2.8

8.1

Tremor

0

6.8

0

2.7

Anxiety

0

2.7

0

0

Respiratory System

Cough increased

2.7

4.1

1.4

2.7

Infection viral

9.3

12.3

6.9

12.2

Rhinitis

2.7

2.7

11.1

6.8

Sinusitis

2.7

1.4

4.2

2.7

Turbinate edema

0

1.4

2.8

0

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

The incidence of certain systemic beta-adrenergic adverse reactions (e.g., tremor, nervousness) was slightly less in the levalbuterol inhalation solution 0.63 mg group compared with the other active treatment groups. The clinical significance of these small differences is unknown.

Changes in heart rate 15 minutes after drug administration and in plasma glucose and potassium 1 hour after drug administration on day 1 and day 29 were clinically comparable in the levalbuterol inhalation solution 1.25 mg and racemic albuterol 2.5 mg groups (see Table 2). Changes in heart rate and plasma glucose were slightly less in the levalbuterol inhalation solution 0.63 mg group compared with the other active treatment groups (see Table 2). The clinical significance of these small differences is unknown. After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were generally diminished compared with day 1 in all active treatment groups.

Table 2: Mean Changes from Baseline Heart Rate at 15 Minutes and Glucose and Potassium at 1 Hour After First Dose (Day 1) in Adults and Adolescents ≥ 12 Years Old
Treatment Heart Rate (bpm) Glucose (mg/dL) Potassium (mEq/L)

Mean Changes (day 1)

Levalbuterol 0.63 mg, n = 72

2.4

4.6

-0.2

Levalbuterol 1.25 mg, n = 73

6.9

10.3

-0.3

Racemic albuterol 2.5 mg, n = 74

5.7

8.2

-0.3

Placebo, n = 75

-2.8

-0.2

-0.2

No other clinically relevant laboratory abnormalities related to administration of levalbuterol inhalation solution were observed in this study.

In the clinical trials, a slightly greater number of serious adverse events, discontinuations due to adverse events, and clinically significant ECG changes were reported in patients who received levalbuterol 1.25 mg compared with the other active treatment groups.

The following adverse reactions, considered potentially related to levalbuterol, occurred in less than 2% of the 292 subjects who received levalbuterol and more frequently than in patients who received placebo in any clinical trial:

Body as a Whole:

chills, pain, chest pain

Cardiovascular System:

ECG abnormal, ECG change, hypertension, hypotension, syncope

Digestive System:

diarrhea, dry mouth, dry throat, dyspepsia, gastroenteritis, nausea

Hemic and Lymphatic System:

lymphadenopathy

Musculoskeletal System:

leg cramps, myalgia

Nervous System:

anxiety, hyperesthesia of the hand, insomnia, paresthesia, tremor

Special Senses:

eye itch

The following reactions, considered potentially related to levalbuterol, occurred in less than 2% of the treated subjects but at a frequency less than in patients who received placebo: asthma exacerbation, cough increased, wheezing, sweating, and vomiting.

Pediatric Patients 6 to 11 Years of Age

Adverse reaction information concerning levalbuterol inhalation solution in pediatric patients is derived from one 3 week, multicenter, randomized, double-blind, active-, and placebo-controlled trial in 316 pediatric patients 6 to 11 years of age. Adverse reactions reported in ≥ 2% of patients in any treatment group and more frequently than in patients receiving placebo are listed in Table 3.

Table 3: Most Frequently Reported Adverse Reactions (≥ 2% in Any Treatment Group) and Those Reported More Frequently Than in Placebo During the Double-Blind Period (ITT Population, 6 to 11 Years Old)
Body System Preferred Term Placebo (n = 59) Levalbuterol 0.31 mg (n = 66) Levalbuterol 0.63 mg (n = 67) Racemic albuterol 1.25 mg (n = 64) Racemic albuterol 2.5 mg (n = 60)

Percent of Patients

Body as a Whole

Abdominal pain

3.4

0

1.5

3.1

6.7

Accidental injury

3.4

6.1

4.5

3.1

5.0

Asthenia

0

3.0

3.0

1.6

1.7

Fever

5.1

9.1

3.0

1.6

6.7

Headache

8.5

7.6

11.9

9.4

3.3

Pain

3.4

3.0

1.5

4.7

6.7

Viral infection

5.1

7.6

9.0

4.7

8.3

Digestive System

Diarrhea

0

1.5

6.0

1.6

0

Hemic and Lymphatic

Lymphadenopathy

0

3.0

0

1.6

0

Musculoskeletal System

Myalgia

0

0

1.5

1.6

3.3

Respiratory System

Asthma

5.1

9.1

9.0

6.3

10.0

Pharyngitis

6.8

3.0

10.4

0

6.7

Rhinitis

1.7

6.1

10.4

3.1

5.0

Skin and Appendages

Eczema

0

0

0

0

3.3

Rash

0

0

7.5

1.6

0

Urticaria

0

0

3.0

0

0

Special Senses

Otitis media

1.7

0

0

0

3.3

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

Changes in heart rate, plasma glucose, and serum potassium are shown in Table 4. The clinical significance of these small differences is unknown.

Table 4: Mean Changes from Baseline Heart Rate at 30 Minutes and Glucose and Potassium at 1 Hour after First Dose (Day 1) and Last Dose (Day 21) in Children 6 to 11 Years Old

Mean Changes (Day 1)

Treatment

Heart Rate (bpm)

Glucose (mg/dL)

Potassium (mEq/L)

Levalbuterol 0.31 mg, n = 66

0.8

4.9

-0.31

Levalbuterol 0.63 mg, n = 67

6.7

5.2

-0.36

Racemic albuterol 1.25 mg, n = 64

6.4

8.0

-0.27

Racemic albuterol 2.5 mg, n = 60

10.9

10.8

-0.56

Placebo, n = 59

-1.8

0.6

-0.05

Mean Changes (Day 21)

Treatment

Heart Rate (bpm)

Glucose (mg/dL)

Potassium (mEq/L)

Levalbuterol 0.31 mg, n = 60

0

2.6

-0.32

Levalbuterol 0.63 mg, n = 66

3.8

5.8

-0.34

Racemic albuterol 1.25 mg, n = 62

5.8

1.7

-0.18

Racemic albuterol 2.5 mg, n = 54

5.7

11.8

-0.26

Placebo, n = 55

-1.7

1.1

-0.04

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