Xopenex Hfa

Description

The active component of XOPENEX HFA inhalation aerosol is levalbuterol tartrate, the (R)-enantiomer of albuterol, which acts as a relatively selective beta-2-adrenergic receptor agonist. Levalbuterol tartrate is chemically designated as (R)-α-[1,1-dimethylethyl)aminomethyl]-4-hydroxy-1,3-benzenedimethanol L-tartrate (2:1 salt), with a molecular weight of 628.71 and an empirical formula of (C13H21NO3)2·C4H6O6. This compound appears as a white to light-yellow solid, is freely soluble in water, and exhibits very slight solubility in ethanol.

XOPENEX HFA inhalation aerosol is delivered via a pressurized metered-dose inhaler (MDI) equipped with a dose indicator, designed to produce an aerosol for oral inhalation. The formulation includes a suspension of micronized levalbuterol tartrate, propellant HFA-134a (1,1,1,2-tetrafluoroethane), Dehydrated Alcohol USP, and Oleic Acid NF. After priming the inhaler with four actuations, each actuation releases 67.8 mcg of levalbuterol tartrate (equivalent to 51.6 mcg of levalbuterol free base) from the valve and 59 mcg of levalbuterol tartrate (equivalent to 45 mcg of levalbuterol free base) from the actuator mouthpiece. Each 15 g canister contains a total of 200 actuations.

Uses and Indications

XOPENEX HFA is a beta2-adrenergic agonist indicated for the treatment or prevention of bronchospasm in patients aged 4 years and older with reversible obstructive airway disease.

There are no teratogenic or nonteratogenic effects associated with the use of XOPENEX HFA.

Dosage and Administration

XOPENEX HFA is indicated for oral inhalation only. For adults and children aged 4 years and older, the recommended dosage is 2 inhalations every 4 to 6 hours as needed. In certain patients, 1 inhalation every 4 hours may be sufficient.

Prior to the initial use and if the inhaler has not been used for more than 3 days, it is essential to prime XOPENEX HFA. This is accomplished by releasing 4 sprays into the air away from the face.

To maintain proper function of the inhaler, the actuator should be washed with warm water at least once a week and allowed to air-dry completely.

Contraindications

Use of XOPENEX HFA Inhalation Aerosol is contraindicated in patients with a known hypersensitivity to levalbuterol, racemic albuterol, or any other component of the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Life-threatening paradoxical bronchospasm may occur in patients using XOPENEX HFA. In such instances, it is imperative to discontinue the medication immediately and initiate alternative therapy to manage the patient's condition effectively.

Healthcare professionals should be vigilant for signs indicating the need for increased doses of XOPENEX HFA, as this may signify a deterioration in asthma control. Such changes necessitate a thorough reevaluation of the patient's treatment regimen to ensure optimal management of their asthma.

It is important to note that XOPENEX HFA is not a substitute for corticosteroids. Patients should continue their prescribed corticosteroid therapy as directed, as it plays a critical role in managing inflammation associated with asthma.

Cardiovascular effects, including but not limited to increased heart rate and hypertension, may occur with the use of XOPENEX HFA. In patients with pre-existing cardiovascular disorders, caution is advised, and discontinuation of the medication should be considered if any cardiovascular effects manifest.

Excessive use of XOPENEX HFA can lead to severe and potentially fatal outcomes. Therefore, it is crucial that patients adhere strictly to the recommended dosing guidelines and not exceed the prescribed amount.

Immediate hypersensitivity reactions, including anaphylaxis, may occur in some patients. Should any signs of hypersensitivity arise, XOPENEX HFA must be discontinued without delay.

Additionally, healthcare providers should monitor patients for hypokalemia and fluctuations in blood glucose levels, as these adverse effects may occur during treatment with XOPENEX HFA. Regular laboratory tests may be warranted to assess these parameters, particularly in patients with a history of electrolyte imbalances or diabetes.

Side Effects

Patients using XOPENEX HFA may experience a range of adverse reactions, which can be categorized into common and serious side effects.

The most common adverse reactions reported include accidental injury, bronchitis, dizziness, pain, pharyngitis, rhinitis, and vomiting. These reactions were observed in clinical trials and may vary in frequency among patients.

Serious side effects associated with XOPENEX HFA include life-threatening paradoxical bronchospasm, which necessitates immediate discontinuation of the medication and the initiation of alternative therapy. An increased need for doses beyond the usual may indicate a deterioration of asthma, warranting a reevaluation of the patient's treatment plan. Cardiovascular effects have also been noted; therefore, caution is advised when prescribing XOPENEX HFA to patients with pre-existing cardiovascular disorders, and discontinuation should be considered if such effects arise.

Excessive use of XOPENEX HFA can be fatal, and patients are advised not to exceed the recommended dosage. Immediate hypersensitivity reactions may occur, requiring prompt discontinuation of the medication. Additionally, hypokalemia and alterations in blood glucose levels have been reported.

In cases of overdosage, symptoms may reflect excessive beta-adrenergic receptor stimulation, which can include seizures, angina, hypertension or hypotension, tachycardia (with rates up to 200 beats per minute), arrhythmias, nervousness, headache, tremor, dry mouth, palpitations, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia may also be present. As with all sympathomimetic medications, there is a risk of cardiac arrest and even death associated with the abuse of XOPENEX HFA.

Drug Interactions

The use of this medication may result in significant drug interactions that warrant careful consideration and monitoring.

Sympathomimetic Agents Co-administration with other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs may enhance the therapeutic effects of this medication. Caution is advised when using these agents concurrently.

Beta-Blockers The concomitant use of beta-blockers may inhibit the bronchodilatory effects of beta-agonists, potentially leading to severe bronchospasm. It is generally recommended that patients with asthma avoid treatment with beta-blockers.

Diuretics The use of diuretics may exacerbate electrocardiographic changes or hypokalemia. It is advisable to monitor potassium levels in patients receiving both this medication and diuretics to mitigate the risk of complications.

Digoxin This medication may reduce serum digoxin levels. Monitoring of digoxin levels is recommended to ensure therapeutic efficacy and prevent potential toxicity.

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants The concurrent use of monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants may amplify the cardiovascular effects of this medication. Alternative therapies should be considered for patients currently taking MAO inhibitors or tricyclic antidepressants to avoid adverse effects.

Packaging & NDC

The table below lists all NDC Code configurations of Xopenex Hfa (levalbuterol tartrate), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Pediatric patients 4 years of age and older have demonstrated safety and efficacy with XOPENEX HFA, as established in an adequate and well-controlled clinical trial. In contrast, XOPENEX HFA is not indicated for pediatric patients less than 4 years of age. A clinical trial involving 196 pediatric patients with asthma or reactive airway disease, including 68 patients aged birth to <2 years and 128 patients aged 2 to <4 years, showed no statistically significant difference in the primary efficacy endpoint between treatment groups.

The primary efficacy endpoint was the mean change in the Pediatric Asthma Caregiver Assessment (PACA) total score from baseline over a 4-week treatment period. Results indicated no statistical difference in PACA total score changes between XOPENEX HFA and placebo.

Safety data revealed an increased incidence of asthma-related adverse reactions in patients under 4 years treated with XOPENEX HFA compared to placebo, with 8 subjects reporting such reactions versus 3 in the placebo group. Additionally, one subject in the XOPENEX HFA group discontinued treatment due to asthma, while no subjects in the placebo group did. Other adverse reactions observed were consistent with those reported in the clinical trial population of patients aged 4 years and older.

Geriatric Use

Clinical studies of XOPENEX HFA did not include a sufficient number of subjects aged 65 and older to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly patients and their younger counterparts.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Careful monitoring of these patients is recommended to ensure safety and efficacy.

Pregnancy

There are no adequate and well-controlled studies of XOPENEX HFA in pregnant women. Clinical considerations should be taken into account when using XOPENEX HFA in this population. Following oral administration of levalbuterol HCl to pregnant rabbits, no evidence of teratogenicity was observed at doses up to 25 mg/kg/day, which is approximately 750 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol tartrate for adults on a mg/m² basis. However, racemic albuterol sulfate has demonstrated teratogenic effects in mice and rabbits at doses slightly higher than the human therapeutic range.

The estimated background risk of major birth defects and miscarriage for the indicated populations is 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. Women with poorly or moderately controlled asthma may face an increased risk of preeclampsia, as well as prematurity, low birth weight, and small for gestational age neonates. Therefore, pregnant women should be closely monitored, and medication should be adjusted as necessary to maintain optimal control.

Due to 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 limited to those patients in whom the benefits clearly outweigh the risks. XOPENEX HFA has not been approved for the management of preterm labor, and the benefit:risk ratio for levalbuterol tartrate when 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 beta2-agonists, including racemic albuterol.

In developmental studies, the oral administration of levalbuterol HCl to pregnant New Zealand White rabbits during the period of organogenesis showed no evidence of teratogenicity at doses up to 25 mg/kg/day. In a rat developmental study, a racemic albuterol sulfate formulation administered by inhalation did not produce teratogenic effects at exposures approximately 160 times the MRHDID. However, other studies with racemic albuterol sulfate indicated teratogenic effects in mice and rabbits at doses slightly higher than the human therapeutic range. Specifically, in a rabbit study, orally administered albuterol sulfate induced cranioschisis in 37% of fetuses at approximately 1500 times the MRHDID, while in a mouse study, cleft palate formation occurred in 4.5% to 9.3% of fetuses at exposures ranging from approximately 2 to 20 times the MRHDID. Similar teratogenic effects were not observed at approximately 0.2 times the MRHDID of levalbuterol tartrate for adults.

Lactation

There are no adequate and well-controlled studies of XOPENEX HFA in nursing mothers. The potential for excretion of XOPENEX HFA in breast milk is unknown. Caution should be exercised when administering XOPENEX HFA to a nursing mother.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of overdosage, the expected symptoms primarily reflect excessive stimulation of beta-adrenergic receptors. Healthcare professionals should be vigilant for the occurrence or exacerbation of symptoms typically associated with adverse reactions. These may include seizures, angina, hypertension or hypotension, tachycardia with rates potentially reaching up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitations, nausea, dizziness, fatigue, malaise, and sleeplessness. Additionally, hypokalemia may also be observed.

It is critical to note that, similar to other sympathomimetic agents, the abuse of XOPENEX HFA can lead to severe outcomes, including cardiac arrest and even death.

Management of overdosage involves the immediate discontinuation of XOPENEX HFA, accompanied by appropriate symptomatic therapy tailored to the patient's clinical presentation. In certain cases, the judicious use of a cardioselective beta-receptor blocker may be considered; however, caution is warranted as such medications can induce bronchospasm.

Currently, there is insufficient evidence to ascertain the efficacy of dialysis in the management of XOPENEX HFA overdosage. Therefore, healthcare professionals should focus on supportive care and monitoring of the patient’s vital signs and symptoms.

Nonclinical Toxicology

Although there have been no carcinogenesis studies specifically conducted with levalbuterol tartrate, the carcinogenic potential of racemic albuterol sulfate has been evaluated. In a 2-year study involving 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. This dosage is approximately 30 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol tartrate for adults and approximately 15 times the MRHDID for children on a mg/m² basis.

In contrast, an 18-month study in CD-1 mice and a 22-month study in golden hamsters demonstrated no evidence of tumorigenicity following dietary administration of racemic albuterol sulfate. The doses administered in the CD-1 mice study reached up to 500 mg/kg/day, which is approximately 3800 times the MRHDID of levalbuterol tartrate for adults and approximately 1800 times for children on a mg/m² basis. In the golden hamster study, doses were administered up to 50 mg/kg/day, equating to approximately 500 times the MRHDID for adults and approximately 240 times for children on a mg/m² basis.

Levalbuterol HCl has been shown to be non-mutagenic in the Ames test and the CHO/HPRT Mammalian Forward Gene Mutation Assay. Additionally, it was not found to be clastogenic in the in vivo micronucleus test conducted in mouse bone marrow. Racemic albuterol sulfate also did not exhibit clastogenic effects in an in vitro chromosomal aberration assay using CHO cell cultures. No fertility studies have been conducted with levalbuterol tartrate; however, reproduction studies in rats using racemic albuterol sulfate indicated no evidence of impaired fertility at oral doses up to 50 mg/kg/day, which is approximately 750 times the MRHDID of levalbuterol tartrate for adults on a mg/m² basis.

In terms of animal pharmacology and toxicology, the propellant HFA-134a has been found to be rapidly absorbed and eliminated in both animals and humans, with an elimination half-life ranging from 3 to 27 minutes in animals and 5 to 7 minutes in humans. The time to maximum plasma concentration (tmax) and mean residence time are both extremely short, resulting in a transient presence of HFA-134a in the bloodstream without evidence of accumulation. Based on animal studies, HFA-134a exhibited no detectable toxicological activity at exposure levels less than 380 times the maximum human exposure, as determined by comparisons of area under the curve (AUC) values. Toxicological effects observed at very high doses included ataxia, tremors, dyspnea, and salivation, which are similar to effects produced by structurally-related chlorofluorocarbons (CFCs) previously used in metered-dose inhalers.

Postmarketing Experience

Postmarketing experience has identified several common adverse effects associated with the use of inhaled beta-agonists. Reports indicate that patients may experience palpitations, chest pain, rapid heart rate, tremor, and nervousness. These events have been documented through voluntary reporting and surveillance programs.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling, which includes the Patient Information and Instructions for Use, to ensure proper understanding of the medication. It is important to inform patients that the action of XOPENEX HFA is expected to last for 4 to 6 hours, and they should not use the medication more frequently than recommended.

Healthcare providers should instruct patients not to increase the dose or frequency of doses of XOPENEX HFA without consulting their physician. Patients must be made aware that if they find that treatment with XOPENEX HFA becomes less effective for symptomatic relief, if their symptoms worsen, or if they need to use the product more frequently than usual, they should seek medical attention immediately.

Priming the inhaler is essential to ensure appropriate levalbuterol content in each actuation. Patients should be instructed to shake the inhaler well before use and to prime XOPENEX HFA before using it for the first time and if the inhaler has not been used for more than 3 days. This can be done by releasing 4 test sprays into the air, away from the face.

To ensure proper dosing and prevent blockage of the actuator orifice, patients should be advised to wash the actuator in warm water and air-dry it thoroughly at least once a week. Detailed cleaning instructions are included in the FDA-approved patient labeling, which patients should be encouraged to review.

Patients should store the canister between 20° and 25°C (68° and 77°F) and protect it from freezing temperatures and direct sunlight. It is crucial to inform patients that XOPENEX HFA can produce paradoxical bronchospasm, and they should discontinue use if this occurs.

While using XOPENEX HFA, patients should take other inhaled drugs and asthma medications only as directed by their physician. Additionally, common adverse effects associated with inhaled beta-agonists, such as palpitations, chest pain, rapid heart rate, tremor, and nervousness, should be communicated to patients to ensure they are aware of potential side effects.

Storage and Handling

The product is supplied in a canister format, with specific handling and storage requirements to ensure its efficacy and safety. It should be stored at a controlled room temperature between 20° and 25°C (68° and 77°F), in accordance with USP guidelines. It is essential to protect the product from freezing temperatures and direct sunlight.

For optimal performance, the inhaler must be stored with the actuator mouthpiece facing down. Care should be taken to avoid puncturing or incinerating the canister, as well as keeping it away from heat sources or open flames. Exposure to temperatures exceeding 120°F may lead to bursting of the canister.

The container should never be disposed of in fire or incinerators. Additionally, it is crucial to keep the product out of reach of children. The canister must be discarded once the dose indicator display window shows zero, which signifies that all 200 actuations have been utilized.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Xopenex Hfa as submitted by Lupin Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)