Xopenex (levalbuterol HCI) 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 beta2-adrenergic receptor agonist (see CLINICAL PHARMACOLOGY). The chemical name for levalbuterol HCl is (R)-α1-[[(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 C₁₃H₂₁NO₃•HCI. 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 HCI is the USAN modified name for (R)-albuterol HCI in the United States.

Xopenex (levalbuterol HCI) 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 HCI) or 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCI) or 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCI), sodium chloride to adjust tonicity, and sulfuric acid to adjust the pH to 4.0 (3.3 to 4.5).

Xopenex (levalbuterol HCl) Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 yearsof age and older with reversible obstructive airway disease.

Children 6-11 years old: The recommended dosage of Xopenex (levalbuterol HCI) Inhalation Solution for patients 6-11 years old is 0.31 mg administered three times a day, by nebulization. Routine dosing should not exceed 0.63 mg three times a day.

Adults and Adolescents ≥ 12 years old: The recommended starting dosage of Xopenex (levalbuterol HCI) 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 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 expected relief, medical advice should be sought immediately, since this is often a sign of seriously worsening asthma that would require reassessment of therapy.

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-Neb® 2000 and Dura-Neb® 3000 compressors. The safety and efficacy of Xopenex Inhalation Solution when administered using other nebulizer systems have not been established.

Xopenex (levalbuterol HCl) 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 levalbuterolHCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 63402-511-24).

Xopenex (levalbuterol HCl) Inhalation Solution, 0.63 mg (foil pouch label color yellow) contains 0.63 mg of levalbuterol (as 0.73 mg of levalbuterolHCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 63402-512-24).

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 63402-513-24).

Xopenex (levalbuterol HCl) Inhalation Solution is also available as a concentrate in individually pouched 0.5 mL unit-dose vials containing 1.25 mg of levalbuterol (NDC 63402-515-30).

Caution

Federal law (U.S.) prohibits dispensing without prescription.

Store Xopenex (levalbuterol HCl) Inhalation Solution in the protective foil pouch at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. Protect fromlight 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 fromthe pouch, if not used immediately, should be protected from light and used within 1 week. Discard any vial if the solution is not colorless.

Manufactured for: Sepracor Inc. Marlborough, MA 01752 USA. For customer service, call 1-888-394-7377. To report adverse events, call 1-877-737-7226. For medical information, call 1-800-739-0565. August 2007. FDA Rev date: 9/7/2006

Adults and Adolescents ≥ 12 years old

Adverse events reported in ≥ 2% of patients receiving Xopenex Inhalation Solution or racemic albuterol and more frequently than in patients receiving placebo in a 4-week, controlled clinical trial are listed in Table 3.

Table 3: Adverse Events Reported in a 4-Week, Controlled Clinical Trial in Adults and Adolescents ≥ 12 years old

The incidence of certain systemic beta-adrenergic adverse effects (e.g., tremor, nervousness) was slightly less in the Xopenex 0.63 mg group compared with theother 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 clin-ically comparable in the Xopenex 1.25 mg and racemic albuterol 2.5 mg groups (see Table 4). Changes in heart rate and plasma glucose were slightly less inthe Xopenex 0.63 mg group compared with the other active treatment groups (see Table 4). The clinical significance of these small differences is unknown. After4 weeks, effects on heart rate, plasma glucose, and plasma potassium were generally diminished compared with day 1 in all active treatment groups.

Table 4: 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

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 events, 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, hypesthesia of the hand, insomnia, paresthesia, tremor
Special Senses: eye itch

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

Children 6-11 years old

Adverse events reported in ≥ 2% of patients in any treatment group and more frequently than in patients receiving placebo in a 3-week, controlled clinical trial arelisted in Table 5.

Table 5: Most Frequently Reported Adverse Events ( ≥ 2% in Any Treatment Group) and Those Reported More Frequently Than in Placebo during the Double-Blind Period (ITT Population, 6-11 Years Old)

Changes in heart rate, plasma glucose, and serum potassium are shown in Table 6. The clinical significance of these small differences is unknown.

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

Postmarketing Adverse Reactions

In addition to the adverse events reported in clinical trials, the following adverse events have been observed in postapproval use of Xopenex InhalationSolution. 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, dyspnea, nausea, nervousness, rash, tachycardia, tremor, urticaria. Because these events have been reported spontaneously from a population of unknown size,estimates of frequency cannot be made.

Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should be used with caution with levalbuterol. If additional adrenergic drugsare to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

1. Beta-blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists such as Xopenex (levalbuterol HCl)Inhalation Solution, but may also produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated withbeta-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 could be considered, although they should be administered with caution.
2. Diuretics: The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazidediuretics) 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.
3. Digoxin: Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemicalbuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructiveairway disease who are receiving levalbuterol HCI and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate theserum digoxin levels in patients who are currently receiving digoxin and Xopenex Inhalation Solution.
4. Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: Xopenex Inhalation Solution should be administered with extreme caution to patients beingtreated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of levalbuterolHCI on the vascular system may be potentiated.

1. Paradoxical Bronchospasm: Like other inhaled beta-adrenergic agonists, Xopenex Inhalation Solution can produce paradoxical bronchospasm, whichmay be life threatening. If paradoxical bronchospasm occurs, Xopenex Inhalation Solution should be discontinued immediately and alternative therapyinstituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of anew canister or vial.
2. Deterioration of Asthma: Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs moredoses of Xopenex Inhalation Solution than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatmentregimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
3. Use of Anti-Inflammatory Agents: The use of beta-adrenergic agonist bronchodilators 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.
4. Cardiovascular Effects: Xopenex Inhalation Solution, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effectin some patients, as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of XopenexInhalation Solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce 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. Do Not Exceed Recommended Dose: Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patientswith 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.
6. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of racemic albuterol, as demonstrated byrare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be consideredin the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving Xopenex Inhalation Solution.

General

Levalbuterol HCI, 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 unusuallyresponsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients andcould 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. As with other beta-adrenergicagonist medications, levalbuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential toproduce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

Information for Patients

See illustrated Patient's Instructions for Use.

The action of Xopenex (levalbuterol HCl) Inhalation Solution may last up to 8 hours. Xopenex Inhalation Solution should not be used more frequently thanrecommended. Do not increase the dose or frequency of dosing of Xopenex Inhalation Solution without consulting your physician. If you find that treatmentwith Xopenex Inhalation Solution becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product morefrequently than usual, you should seek medical attention immediately. While you are taking Xopenex Inhalation Solution, other inhaled drugs and asthmamedications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, headache, dizziness, and tremor or nervousness. If you are pregnant or nursing, contact your physician about the use of Xopenex Inhalation Solution.

Effective and safe use of Xopenex Inhalation Solution requires consideration of the following information in addition to that provided under Patient'sInstructions for Use:

Xopenex Inhalation Solution single-use low-density polyethylene (LDPE) vials should be protected from light and excessive heat. Store in the protective foilpouch between 20°C and 25°C (68°F and 77°F) [see USP Controlled Room Temperature]. Do not use after the expiration date stamped on the container.Unused vials should be stored in the protective foil pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials removed from thepouch, if not used immediately, should be protected from light and used within 1 week. Discard any vial if the solution is not colorless.

The drug compatibility (physical and chemical), efficacy, and safety of Xopenex Inhalation Solution when mixed with other drugs in a nebulizer have not beenestablished.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No carcinogenesis or impairment of fertility studies have been carried out with levalbuterol HCI alone. However, racemic albuterol sulfate has been evaluated for its carcinogenic potential and ability to impair fertility.

In a 2-year study in Sprague-Dawley rats, racemic albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of themesovarium at and above dietary doses of 2 mg/kg (approximately 2 times the maximum recommended daily inhalation dose of levalbuterol HCI for adultsand children on a mg/m² basis). In another study, this effect was blocked by the coadministration of propranolol, a nonselective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, racemic albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 260times the maximum recommended daily inhalation dose of levalbuterol HCI for adults and children on a mg/m² basis). In a 22-month study in the Goldenhamster, racemic albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 35 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m² basis).

Levalbuterol HCI was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Although levalbuterol HCI has not beentested for clastogenicity, racemic albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleusassay. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose of levalbuterol HCI for adults on a mg/m² basis).

Teratogenic Effects - Pregnancy Category C

A reproduction study in New Zealand White rabbits demonstrated that levalbuterol HCI was not teratogenic when administered orally at doses up to 25 mg/kg(approximately 110 times the maximum recommended daily inhalation dose of levalbuterol HCI for adults on a mg/m² basis). However, racemic albuterolsulfate has been shown to be teratogenic in mice and rabbits. A study in CD-1 mice given racemic albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose of levalbuterol HCI for adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose of levalbuterol HCl for adultson a mg/m² basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose of levalbuterol HCI for adults on a mg/m² basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg of isoproterenol (positive control).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when racemic albuterol sulfate was administered orally at a doseof 50 mg/kg (approximately 110 times the maximum recommended daily inhalation dose of levalbuterol HCI for adults on a mg/m² basis).

A study in which pregnant rats were dosed with radiolabeled racemic albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.

There are no adequate and well-controlled studies of Xopenex Inhalation Solution in pregnant women. Because animal reproduction studies are not alwayspredictive of human response, Xopenex Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to thefetus.

During marketing experience of racemic albuterol, various congenital anomalies, including cleft palate and limb defects, have been rarely reported in the off-spring of patients being treated with racemic albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between racemic albuterol use and congenital anomalies has not been established.

Use in Labor and Delivery

Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of Xopenex Inhalation Solution for the treatment ofbronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Tocolysis

Levalbuterol HCI has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol HCI is administered for tocolysishas not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta₂-agonists, including racemic albuterol.

Nursing Mothers

Plasma levels of levalbuterol after inhalation of therapeutic doses are very low in humans, but it is not known whether levalbuterol is excreted in human milk.

Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack of experience with the use of Xopenex InhalationSolution by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importanceof the drug to the mother. Caution should be exercised when Xopenex Inhalation Solution is administered to a nursing woman.

Pediatrics

The safety and efficacy of Xopenex (levalbuterol HCI) Inhalation Solution have been established in pediatric patients 6 years of age and older in one ade-quate and well-controlled clinical trial (see CLINICAL PHARMACOLOGY; Pharmacokinetics and Clinical Trials). Use of Xopenex in children isalso supported by evidence from adequate and well-controlled studies of Xopenex in adults, considering that the pathophysiology and the drug's expo-sure level and effects in pediatric and adult patients are substantially similar. Safety and effectiveness of Xopenex in pediatric patients below the age of6 years have not been established.

Geriatrics

Data on the use of Xopenex in patients 65 years of age and older are very limited. A very small number of patients 65 years of age and older were treatedwith Xopenex Inhalation Solution in a 4-week clinical study (see CLINICAL PHARMACOLOGY; Clinical Trials) (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. There are insufficient data to determine if thesafety and efficacy of Xopenex Inhalation Solution are different in patients < 65 years of age and patients 65 years of age and older. In general, patients 65years of age and older should be started at a dose of 0.63 mg of Xopenex Inhalation Solution. If clinically warranted due to insufficient bronchodilatorresponse, the dose of Xopenex Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratorymonitoring, to the maximum recommended daily dose (see DOSAGE AND ADMINISTRATION).

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, 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 beconsidered, 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.

The intravenous median lethal dose of levalbuterol HCl in mice is approximately 66 mg/kg (approximately 70 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m² basis). The inhalation median lethal dose has not been determined in animals.

Xopenex (levalbuterol HCl) Inhalation Solution is contraindicated in patients with a history of hypersensitivity to levalbuterol HCl or racemic albuterol.

Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3', 5'-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which inhibits thephosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved,thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

While it is recognized that beta₂-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta₂-receptors in the human heart that comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors has not been established (see WARNINGS). However, all beta-adrenergic agonist drugs can produce a significant cardiovascular effect in somepatients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

Preclinical Studies

Results from an in vitro study of binding to human beta-adrenergic receptors demonstrated that levalbuterol has approximately 2-fold greater bindingaffinity than racemic albuterol and approximately 100-fold greater binding affinity than (S)-albuterol. In guinea pig airways, levalbuterol HCl and racemicalbuterol decreased the response to spasmogens (e.g., acetylcholine and histamine), whereas (S)-albuterol was ineffective. These results suggest thatthe bronchodilatory effects of racemic albuterol are attributable to the (R)-enantiomer.

Intravenous studies in rats with racemic albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands),albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologicevidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings isunknown.

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 followingadministration 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 ng•hr/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 ng•hr/mL) (see Table 1).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 cumu-lative 10 mg dose of racemic albuterol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), Cmax and AUC of (R)-albuterol werecomparable (see Table 1).

Table 1: Mean (SD) Values for Pharmacokinetic Parameters in Healthy Adults

Pharmacokinetics (Children 6-11 years old)

The pharmacokinetic parameters of (R)-and (S)-albuterol in children with asthma were obtained using population pharmacokinetic analysis. These data arepresented in Table 2. For comparison, adult data obtained by conventional pharmacokinetic analysis from a different study also are presented in Table 2. In children, AUC and Cmax of (R)-albuterol following administration of 0.63 mg Xopenex Inhalation Solution were comparable to those following admin-istration of 1.25 mg racemic albuterol sulfate inhalation solution.

When the same dose of 0.63 mg of Xopenex was given to children and adults, the predicted Cmax 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 ng•hr/mL) was about 1.5-fold higher than that in adults (1.65 ng•hr/mL). These data sup-port lower doses for children 6-11 years old compared with the adult doses (see DOSAGE AND ADMINISTRATION).

Table 2: (R)-Albuterol Exposure in Adults and Pediatric Subjects (6-11 years)

Metabolism and Elimination

Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol enantiomers in humans isSULT1A3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there wasa 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 primarymetabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% ofthe (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 clearanceof 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 renalimpairment.

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 XopenexInhalation Solution (0.31, 0.63, 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 FEV₁) 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 racemicalbuterol sulfate inhalation solution were clinically comparable over the 6-hour evaluation period, except for a slightly longer duration of action ( > 15%increase in FEV₁ from baseline) after administration of 1.25 mg of Xopenex Inhalation Solution. Systemic beta-adrenergic adverse effects were observedwith 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 rateof 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 FEV₁) and safety (as measuredby 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 dosesof 2.5 mg administered every 30 minutes).

Clinical Trials (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 FEV₁ 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 aDura-Neb® portable compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered dose inhaler (MDI) was used on an as-neededbasis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline FEV₁, was demonstrated for all active treatment regimens compared with placebo onday 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 frombaseline FEV₁ compared with the other active treatments. A dose of 0.63 mg of Xopenex and 2.5 mg of racemic albuterol sulfate produced a clinicallycomparable mean percent change from baseline FEV₁ on both day 1 and day 29.

Figure 1: Mean Percent Change from Baseline FEV₁ on Day 1, Adults and Adolescents ≥ 12 years old

Figure 2: Mean Percent Change from Baseline FEV₁ on Day 29, Adults and Adolescents ≥ 12 years old

The mean time to onset of a 15% increase in FEV₁ over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and10 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 ofeffect, as measured by a > 15% increase from baseline FEV₁, was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately6 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.

Clinical Trials (Children 6-11 years old)

A multi-center, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV₁ 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 FEV₁, was demonstrated for all active treatment regimens compared with placebo onday 1 and day 21. Time profile FEV₁ 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 FEV₁ over test-day baseline) and duration of effect (maintenance of a > 15% increase in FEV₁ over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.

Figure 3: Mean Percent Change from Baseline FEV₁ on Day 1, Children 6-11 Years of Age

Figure 4: Mean Percent Change from Baseline FEV₁ on Day 21, Children 6-11 Years of Age

Xopenex®
(levalbuterol HCl) Inhalation Solution; 0.31 mg*, 0.63 mg*, 1.25 mg*; 3 mL Unit-Dose Vials

*Potency expressed as levalbuterol

Read complete instructions carefully before using.

1. Open the foil pouch by tearing on the serrated edge along the seam of the pouch. Remove one unit-dose vial for immediate use. Keep the rest of the unused unit-dose vials in the foil pouch to protect them from light.
2. Carefully twist open the top of the unit-dose vial (Figure 1) and squeeze the entire contents into the nebulizer reservoir.
3. Connect the nebulizer reservoir to the mouthpiece or face mask (Figure 2).
4. Connect the nebulizer to the compressor.
5. Sit in a comfortable, upright position. Place the mouthpiece in your mouth (Figure 3) (or put on the face mask) and turn on the compressor.
6. Breathe as calmly, deeply, and evenly as possible until no more mist is formed in the nebulizer reservoir (about 5 to 15 minutes). At this point, the treatment is finished.
7. Clean the nebulizer (see manufacturer's instructions).

Note: Xopenex (levalbuterol HCl) Inhalation Solution should be used in a nebulizer only under the direction of a physician. More frequent administration or higher doses are not recommended without first discussing with your doctor. This solution should not be injected or administered orally. Protect from light and excessive heat. Store in the protective foil pouch at 20-25°C (68-77°F)[see USP Controlled Room Temperature]. 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.

The safety and effectiveness of Xopenex Inhalation Solution have not been determined when one or more drugs are mixed with it in a nebulizer. Check with your doctor before mixing any medications in your nebulizer.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

LEVALBUTEROL - INHALATION SOLUTION

(lev-al-BYOU-ter-ohl)

COMMON BRAND NAME(S): Xopenex

USES: Levalbuterol is used to treat wheezing and shortness of breath that commonly occur with lung problems (e.g., asthma, chronic obstructive pulmonary disease). Controlling these symptoms can decrease time lost from work or school. Levalbuterol is a bronchodilator (beta-2 receptor agonist) that works by opening breathing passages to make breathing easier.

HOW TO USE: Read the Patient Information Leaflet available from your pharmacist. This product is used with special breathing equipment (nebulizer). Consult your doctor, pharmacist, or respiratory therapist on how to inhale this medication properly with this equipment. Make sure you understand how to operate the machine and how to properly clean it to prevent infections. If a child is using this equipment, a parent or other responsible adult should supervise the child. Ask your doctor or pharmacist if you have any questions.

Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Do not mix this medication with other solutions or products in the nebulizer. This product does not require any mixing before use unless your doctor instructs you otherwise.

This medication is inhaled into the lungs using a nebulizer, usually 3 times a day. Dosage is based on your medical condition, age, and response to therapy.

Use this medication as directed. Do not increase your dose or use this more frequently than directed or the medication may not work as well over time, and you will be at greater risk of side effects. Do not stop using this medication without first consulting your doctor.

If you take other asthma drugs by mouth or with inhaling devices, ask your doctor about how to correctly use this medication with your other asthma medicines.

If you notice less effect than usual from this medication, if your symptoms get worse, or you feel you need to take any of your asthma medications more often than recommended, seek immediate medical attention.

SIDE EFFECTS: Headache, nervousness, shaking (tremor), dizziness, trouble sleeping, dry mouth, nausea, stomach upset, diarrhea, cough, sore throat, or runny nose may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: anxiety, fast/pounding/irregular heartbeat, leg/muscle cramps, weakness.

Seek immediate medical attention if this unlikely but serious side effect occurs: chest pain.

Rarely, this medication has caused severe (rarely fatal), sudden worsening of breathing problems/asthma (paradoxical bronchospasm). If you experience sudden wheezing, seek immediate medical attention.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking levalbuterol, tell your doctor or pharmacist if you are allergic to it; or to similar bronchodilators (e.g., albuterol, metaproterenol, salmeterol); or to sympathomimetic drugs (e.g., epinephrine, pseudoephedrine); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart disease (e.g., high blood pressure, abnormal heart rhythm, coronary insufficiency), seizures, overactive thyroid (hyperthyroidism), diabetes, kidney disease, low blood potassium level (hypokalemia).

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

The elderly may be at greater risk for the effects on the heart while using this drug.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Avoid taking MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) within 2 weeks before, during, and after treatment with this medication. In some cases a serious, possibly fatal drug interaction may occur.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other asthma drugs (e.g., albuterol), beta blockers (e.g., atenolol, propranolol), digoxin, inhaled anesthetics (e.g., halothane, isoflurane), other sympathomimetic drugs (e.g., ephedrine, epinephrine), tricyclic antidepressants (e.g., amitriptyline, nortriptyline), certain "water pills" (diuretics that cause potassium loss such as furosemide, hydrochlorothiazide).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: chest pain, fast/pounding/irregular heartbeat, headache, shaking (tremors), nervousness, weakness, severe dizziness, seizures.

NOTES: Do not share this medication with others.

Avoid allergens, irritants, smoking and other factors that make asthma worse.

Laboratory and/or medical tests (e.g., blood pressure, heart rate, EKG) may be performed from time to time to monitor your progress or check for side effects. Consult your doctor for more details.

Learn to use a peak flow meter, use it daily, and promptly report worsening asthma (such as readings in the yellow/red range or increased use of quick-relief inhalers).

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store vials in the foil pouch at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Once the foil pouch is opened, use the vials within 2 weeks. Once vials are removed from the foil pouch, use immediately, or protect from light and use within 1 week. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.