Levalbuterol Tartrate Hfa Inhalation

Description

The active component of Levalbuterol tartrate HFA inhalation aerosol is levalbuterol tartrate, the (R)-enantiomer of albuterol. Levalbuterol tartrate is a relatively selective beta2-adrenergic receptor agonist with the chemical name (R)-α1-[(1,1-dimethylethyl)aminomethyl]-4-hydroxy-1,3-benzenedimethanol L-tartrate (2:1 salt). It has a molecular weight of 628.71 and an empirical formula of (C13H21NO3)2 · C4H6O6.

Levalbuterol tartrate appears as a white to light-yellow solid, which is freely soluble in water and very slightly soluble in ethanol. In the United States, levalbuterol tartrate is recognized as the generic name for (R)-albuterol tartrate.

Levalbuterol tartrate HFA inhalation aerosol is delivered via a pressurized metered-dose inhaler (MDI) equipped with a dose indicator, producing an aerosol intended 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 with four actuations, each actuation of the inhaler delivers 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 provides a total of 200 actuations (or inhalations).

Uses and Indications

Levalbuterol tartrate HFA inhalation aerosol is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease.

Limitations of Use: The safety and efficacy of levalbuterol tartrate HFA inhalation aerosol have not been established in pediatric patients under 4 years of age. No teratogenic or nonteratogenic effects have been reported in the available data.

Dosage and Administration

For oral inhalation only, the recommended dosage for adults and children aged 4 years and older is 2 inhalations every 4 to 6 hours. In some 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 the Levalbuterol tartrate HFA inhalation aerosol. 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 Levalbuterol tartrate HFA inhalation aerosol is contraindicated in patients with 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 Levalbuterol tartrate HFA inhalation aerosol. In the event of such an occurrence, it is imperative to discontinue the medication immediately and initiate alternative therapy.

Healthcare professionals should be vigilant for signs indicating a need for more doses of Levalbuterol tartrate HFA inhalation aerosol than usual, as this may signify a deterioration of the patient's asthma condition. Such a situation necessitates a thorough reevaluation of the patient's treatment plan.

It is important to note that Levalbuterol tartrate HFA inhalation aerosol is not a substitute for corticosteroids and should not be used as such in the management of asthma.

Cardiovascular effects, including but not limited to increased heart rate and hypertension, may arise during treatment. In patients with pre-existing cardiovascular disorders, Levalbuterol tartrate HFA inhalation aerosol should be used with caution, and discontinuation should be considered if any cardiovascular effects manifest.

Excessive use of Levalbuterol tartrate HFA inhalation aerosol can be fatal. Therefore, it is crucial that patients adhere strictly to the recommended dosing guidelines and do not exceed the prescribed amount.

Immediate hypersensitivity reactions, such as urticaria or angioedema, may occur in some individuals. Should any signs of hypersensitivity arise, the use of Levalbuterol tartrate HFA inhalation aerosol must be discontinued without delay.

Additionally, healthcare providers should monitor patients for potential hypokalemia and changes in blood glucose levels, as these adverse effects may occur during treatment. Regular laboratory assessments may be warranted to ensure patient safety and effective management of any arising complications.

Side Effects

Patients using Levalbuterol tartrate HFA inhalation aerosol may experience a range of adverse reactions. The most common adverse reactions reported include accidental injury, bronchitis, dizziness, pain, pharyngitis, rhinitis, and vomiting.

Serious side effects have also been observed. Life-threatening paradoxical bronchospasm may occur, necessitating immediate discontinuation of the inhalation aerosol and treatment with alternative therapy. An increased need for doses of Levalbuterol tartrate HFA inhalation aerosol may indicate a deterioration of asthma, warranting a reevaluation of the patient's treatment plan. Cardiovascular effects, which may arise during treatment, require careful monitoring, and discontinuation of the aerosol should be considered if these effects manifest. Patients with underlying cardiovascular disorders should use this medication with caution.

Excessive use of Levalbuterol tartrate HFA inhalation aerosol can be fatal; therefore, it is critical not to exceed the recommended dosage. Immediate hypersensitivity reactions may also occur, and in such cases, the inhalation aerosol should be discontinued immediately. Additionally, hypokalemia and changes 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 occur, and there have been reports of cardiac arrest and even death associated with the abuse of Levalbuterol tartrate HFA inhalation aerosol.

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 Levalbuterol Tartrate Hfa Inhalation (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 Levalbuterol tartrate HFA inhalation aerosol, as established in an adequate and well-controlled clinical trial. In this trial, the primary efficacy endpoint, measured by the mean change in Pediatric Asthma Caregiver Assessment (PACA) total score over a 4-week treatment period, showed no statistically significant difference between Levalbuterol tartrate HFA inhalation aerosol and placebo.

For pediatric patients less than 4 years of age, Levalbuterol tartrate HFA inhalation aerosol is not indicated. A clinical trial involving 196 pediatric patients in this age group (68 patients aged birth to < 2 years and 128 patients aged 2 to < 4 years) revealed no statistically significant difference in the primary efficacy endpoint between treatment groups. Furthermore, there was an increased incidence of asthma-related adverse reactions in patients under 4 years treated with Levalbuterol tartrate HFA inhalation aerosol compared to those receiving placebo, with 8 subjects reporting such reactions versus 3 in the placebo group. Notably, one subject in the Levalbuterol group discontinued treatment due to asthma, while no subjects in the placebo group did.

Dosing for the clinical trial included Levalbuterol tartrate HFA inhalation aerosol at 45 mcg (N=23), 90 mcg (N=42), levalbuterol inhalation solution at 0.31 mg (N=63), and placebo HFA (N=68), administered three times daily. The delivery method utilized the Monaghan AeroChamber MAX™ Valved Holding Chamber with mask.

Geriatric Use

Clinical studies of Levalbuterol tartrate HFA inhalation aerosol did not include a sufficient number of subjects aged 65 and older to determine whether this population responds differently from younger patients. However, other reported clinical experiences have 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 in this population. Careful monitoring is recommended to ensure safety and efficacy in elderly patients receiving Levalbuterol tartrate.

Pregnancy

There are no adequate and well-controlled studies of Levalbuterol tartrate HFA inhalation aerosol in pregnant women. Clinical considerations exist regarding the use of Levalbuterol tartrate HFA inhalation aerosol 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 experience 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 Levalbuterol tartrate HFA inhalation aerosol for the treatment of bronchospasm during labor should be limited to those patients in whom the benefits clearly outweigh the risks. Levalbuterol tartrate HFA inhalation aerosol has not been approved for the management of preterm labor, and the benefit:risk ratio for its use in 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 organogenesis showed no teratogenic effects at doses up to 25 mg/kg/day. In a rat developmental study, a racemic albuterol sulfate/HFA-134a 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 significantly higher than the therapeutic range. For instance, in a rabbit study, cranioschisis was induced in 37% of fetuses at approximately 1500 times the MRHDID, while cleft palate formation was observed in a mouse study at exposures around 2 to 20 times the MRHDID. Similar teratogenic effects were not noted at approximately 0.2 times the MRHDID of levalbuterol tartrate for adults.

Lactation

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 alongside the lactating mother's clinical need for levalbuterol tartrate HFA inhalation aerosol. Additionally, potential adverse effects on the breastfed infant from levalbuterol tartrate HFA inhalation aerosol or from the underlying maternal condition should be evaluated.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in 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 with Levalbuterol tartrate HFA inhalation aerosol, 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.

Given the sympathomimetic nature of Levalbuterol, it is critical to recognize that severe outcomes, including cardiac arrest and death, may arise from its abuse. Therefore, immediate action is required upon suspicion of overdosage.

Management of overdosage involves the prompt discontinuation of Levalbuterol tartrate HFA inhalation aerosol. Appropriate symptomatic therapy should be initiated to address the specific symptoms presented by the patient. In certain cases, the judicious use of a cardioselective beta-receptor blocker may be considered; however, it is essential to note that such medications carry the risk of inducing bronchospasm.

Currently, there is insufficient evidence to ascertain the efficacy of dialysis in the management of overdosage with Levalbuterol tartrate HFA inhalation aerosol. Therefore, healthcare professionals should proceed with caution and prioritize symptomatic treatment and monitoring of the patient’s condition.

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. Conversely, in an 18-month study in CD-1 mice and a 22-month study in golden hamsters, dietary administration of racemic albuterol sulfate showed no evidence of tumorigenicity. 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 up to 50 mg/kg/day, approximately 500 times the MRHDID for adults and 240 times for children on a mg/m² basis.

Levalbuterol HCl has been evaluated for mutagenicity and clastogenicity. It was not found to be mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Additionally, levalbuterol HCl was not clastogenic in the in vivo micronucleus test conducted in mouse bone marrow. Racemic albuterol sulfate also demonstrated no 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 shown 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 with no evidence of accumulation. Based on animal studies, HFA-134a exhibited no detectable toxicological activity at amounts 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 important information regarding the use of Levalbuterol tartrate HFA inhalation aerosol. It is essential to inform patients that the action of this medication typically lasts for 4 to 6 hours. They should be cautioned against using the inhalation aerosol more frequently than recommended and instructed not to increase the dose or frequency of doses without consulting their physician.

Patients must be made aware that if they find the treatment becoming 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 crucial; patients should be instructed to shake the inhaler well before use. They must prime the inhalation aerosol before using it for the first time and if it has not been used for more than 3 days by releasing 4 test sprays into the air, away from their face.

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

Storage conditions are also important; patients should store the canister between 20° and 25°C (68° and 77°F) and protect it from freezing temperatures and direct sunlight.

Patients should be informed that Levalbuterol tartrate HFA inhalation aerosol can produce paradoxical bronchospasm, and they should discontinue use immediately if this occurs. While using this inhalation aerosol, patients should take other inhaled drugs and asthma medications only as directed by their physician.

Finally, it is important to discuss common adverse effects associated with inhaled beta-agonists, which may include palpitations, chest pain, rapid heart rate, tremor, and nervousness.

Storage and Handling

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

For optimal storage, the inhaler should be positioned with the actuator mouthpiece facing down. It is critical 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, and therefore, the canister should never be thrown into fire or an incinerator.

Additionally, the product must be kept out of reach of children. The canister should 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 Levalbuterol Tartrate Hfa Inhalation as submitted by Actavis Pharma, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)