Levalbuterol Tartrate

XOPENEX HFA is a beta 2 -adrenergic agonist indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. ( 1.1 )

1.1 Bronchospasm XOPENEX HFA is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 4 years of age and older with reversible obstructive airway disease.

Inhalation aerosol: XOPENEX HFA is a pressurized, metered dose aerosol. Each XOPENEX HFA 15 gram canister contains 200 metered actuations (or inhalations). Each canister is fitted with a dose indicator and is supplied with a blue plastic actuator mouthpiece and a red mouthpiece cap. After priming, each actuation of the inhaler delivers 59 mcg of levalbuterol tartrate (equivalent to 45 mcg of levalbuterol free base) from the actuator mouthpiece. Inhalation Aerosol: Each actuation delivers 59 mcg of levalbuterol tartrate (equivalent to 45 mcg of levalbuterol free base) from the actuator mouthpiece. 15 g pressurized canister containing 200 actuations ( 3)

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

Life-threatening paradoxical bronchospasm may occur. Discontinue XOPENEX HFA immediately and treat with alternative therapy. ( 5.1 ) Need for more doses of XOPENEX HFA than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. ( 5.2 ) XOPENEX HFA is not a substitute for corticosteroids. ( 5.3 ) Cardiovascular effects may occur. Consider discontinuation of XOPENEX HFA 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 HFA immediately. ( 5.6 ) Hypokalemia and changes in blood glucose may occur. ( 5.7 , 5.8 )

5.1 Paradoxical Bronchospasm XOPENEX HFA can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, XOPENEX HFA 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 canister.

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 HFA 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 The use of a 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 HFA, 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 HFA 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 HFA, 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 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 racemic albuterol, as demonstrated by rare cases of 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 HFA.

5.7 Coexisting Conditions XOPENEX HFA, 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. 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 HFA 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.

Use of XOPENEX HFA may be associated with the following: Paradoxical bronchospasm [see Warnings and Precautions (5.1 )] Cardiovascular effects [see Warnings and Precautions (5.4 )] Immediate hypersensitivity reactions [see Warnings and Precautions (5.6 )] Hypokalemia [see Warnings and Precautions (5.8) ] Most common adverse reactions (≥ 2% and > placebo) are accidental injury, bronchitis, dizziness, pain, pharyngitis, rhinitis, and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 HFA in adults and adolescents is derived from two 8-week, multicenter, randomized, double-blind, active- and placebo-controlled trials in 748 adult and adolescent patients with asthma that compared XOPENEX HFA, a marketed albuterol HFA inhaler, and an HFA-134a placebo inhaler. Table 1 lists the incidence of all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of 2% or greater in the group treated with XOPENEX HFA and more frequently than in the HFA-134a placebo inhaler group. Table 1: Adverse Reaction Incidence (% of Patients) in Two 8-Week Clinical Trials in Adults and Adolescents ≥ 12 Years of Age* * This table includes all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of 2% or greater in the group treated with XOPENEX HFA and more frequently than in the HFA-134a placebo inhaler group. Body System Preferred Term XOPENEX HFA 90 mcg (n=403) Racemic Albuterol HFA 180 mcg (n=179) Placebo (n=166) Respiratory System Asthma 9% 7% 6% Pharyngitis 8% 2% 2% Rhinitis 7% 2% 3% Body as a Whole Pain 4% 3% 4% Central Nervous System Dizziness 3% 1% 2% Adverse reactions reported by less than 2% and at least 2 or more of the adolescent and adult patients receiving XOPENEX HFA and by a greater proportion than receiving HFA-134a placebo inhaler include cyst, flu syndrome, viral infection, constipation, gastroenteritis, myalgia, hypertension, epistaxis, lung disorder, acne, herpes simplex, conjunctivitis, ear pain, dysmenorrhea, hematuria, and vaginal moniliasis. There were no significant laboratory abnormalities observed in these studies. Pediatric Patients 4 to 11 Years of Age Adverse reaction information concerning XOPENEX HFA in children is derived from a 4-week, randomized, double-blind trial of XOPENEX HFA, a marketed albuterol HFA inhaler, and an HFA-134a placebo inhaler in 150 children aged 4 to 11 years with asthma. Table 2 lists the adverse reactions reported for XOPENEX HFA in children at a rate of 2% or greater and more frequently than for placebo. Table 2: Adverse Reaction Incidence (% of Patients) in a 4-Week Clinical Trial in Children 4-11 Years of Age* * This table includes all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from the trial that occurred at a rate of 2% or greater in the group treated with XOPENEX HFA and more frequently than in the HFA-134a placebo inhaler group. Body System Preferred Term XOPENEX HFA 90 mcg (n=76) Racemic Albuterol HFA 180 mcg (n=39) Placebo (n=35) Digestive System Vomiting 11% 8% 6% Body as a Whole Accidental injury 9% 10% 6% Respiratory System Pharyngitis 7% 13% 6% Bronchitis 3% 0% 0% The incidence of systemic beta-adrenergic adverse reactions (e.g., tremor, nervousness) was low and comparable across all treatment groups, including placebo.

6.2 Post-marketing Experience In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been observed in post-approval use of levalbuterol inhalation solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), asthma, chest pain, cough increased, dysphonia, dyspnea, gastrooesophageal reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, urticaria. In addition, XOPENEX HFA, 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.

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

7.1 Beta-blockers Beta-blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists, such as XOPENEX HFA, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

7.2 Diuretics The ECG changes or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop and thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium-sparing diuretics. Consider monitoring potassium levels.

7.3 Digoxin Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving XOPENEX HFA 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 HFA.

7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants XOPENEX HFA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

8.1 PREGNANCY Risk Summary There are no adequate and well-controlled studies of XOPENEX HFA in pregnant women. There are clinical considerations with the use of XOPENEX HFA in pregnant women [see Clinical Considerations]. Following oral administration of levalbuterol HCl to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day [approximately 750 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol tartrate for adults on a mg/m 2 basis]; however, racemic albuterol sulfate was teratogenic in mice (cleft palate) and rabbits (cranioschisis) at doses slightly higher than the human therapeutic range ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population(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 HFA for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. XOPENEX HFA has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol tartrate 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 2 -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 750 times the MRHDID of levalbuterol tartrate for adults on a mg/m 2 basis). In a rat developmental study, a racemic albuterol sulfate (comprising approximately 50% levalbuterol)/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 160 times the MRHDID (on a mg/m 2 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 development study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 1500 times the MRHDID (on a mg/m 2 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 2 times MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 20 times MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg/day). Similar effects were not observed at approximately 0.2 times MRHDID of levalbuterol tartrate for adults on a mg/m 2 basis (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 HFA and any potential adverse effects on the breastfed child from XOPENEX HFA or from the underlying maternal condition. 8.4 PEDIATRIC USE Pediatric Patients 4 Years of Age and Older The safety and efficacy of XOPENEX HFA have been established in pediatric patients 4 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 4 Years of Age XOPENEX HFA is not indicated for pediatric patients less than 4 years of age. A clinical trial in pediatric patients below the age of 4 years showed no statistical significant difference between treatment groups in the primary efficacy endpoint. There was an increased incidence of asthma-related adverse reactions reported in pediatric patients below the age of 4 years treated with XOPENEX HFA compared to placebo. XOPENEX HFA was evaluated in one 4-week, multicenter, randomized, modified-blind, placebo-controlled, parallel group trial of 196 pediatric patients ages birth to <4 years of age with asthma or reactive airway disease (68 patients birth to <2 years of age and 128 patients 2 to <4 years of age). XOPENEX HFA 45 mcg (N=23), XOPENEX HFA 90 mcg (N=42), levalbuterol inhalation solution 0.31 mg (N=63), and placebo HFA (N=68) were administered three times daily. XOPENEX HFA or placebo HFA was delivered with the Monaghan AeroChamber MAX™ Valved Holding Chamber with mask. The primary efficacy endpoint was the mean change in Pediatric Asthma Caregiver Assessment (PACA) total score from baseline over the 4 week treatment period. There was no statistical difference in the change in PACA total score between XOPENEX HFA and placebo. Regarding safety, an increased number of treatment-emergent asthma-related adverse reactions were reported in XOPENEX HFA-treated patients. Eight subjects reported asthma-related adverse reactions for XOPENEX HFA compared to 3 subjects for placebo. There was one subject that discontinued treatment due to asthma in the XOPENEX HFA group compared to zero subjects in the placebo group (Table 3). Other adverse reactions were consistent with those observed in the clinical trial population of patients 4 years of age and older [see Adverse Reactions (6.1)]. Table 3: Asthma-related Adverse Reactions in a 4-Week Clinical Trial in Children Birth to <4 Years of Age * * This table includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnea XOPENEX HFA 45-90 mcg (n=65) Levalbuterol inhalation solution 0.31 mg (n=63) Placebo (n=68) Asthma-related adverse reactions*, n (%) 8 (12%) 6 (10%) 3 (4%) Treatment discontinuations due to asthma, n (%) 1 (2%) 2 (3%) 0 8.5 GERIATRIC USE Clinical studies of XOPENEX HFA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

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.

Activation of beta 2 -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 the release of mediators from mast cells in the airways. 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 2 -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 2 -adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions (5) ]. 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.