Levalbuterol tartrate

Uses and Indications

Levalbuterol tartrate HFA is indicated for the treatment or prevention of bronchospasm in patients aged 4 years and older with reversible obstructive airway disease. This drug is also indicated for the prevention of exercise-induced bronchospasm.

Limitations of Use

There are no specific teratogenic or nonteratogenic effects mentioned in the provided information.

Dosage and Administration

Levalbuterol tartrate HFA inhalation aerosol is supplied as a pressurized aluminum canister containing 200 metered actuations (or inhalations). Prior to use, the canister must be shaken well. The canister should be discarded when the dose indicator display window shows zero, indicating that all 200 actuations have been used. When the dose indicator displays a red zone, approximately 20 inhalations remain, and a refill is necessary.

For oral inhalation only, the recommended dosage for adults and children aged 4 years and older is 2 inhalations repeated every 4 to 6 hours. In some patients, 1 inhalation every 4 hours may be sufficient. The inhalation should be administered using the blue plastic actuator mouthpiece provided with the canister.

Before using the inhaler for the first time or if it has not been used for more than 3 days, it must be primed. To prime the inhaler, 4 sprays should be released into the air away from the face. Additionally, the actuator should be washed with warm water at least once a week and allowed to air-dry completely to maintain proper function.

Contraindications

Do not use Levalbuterol tartrate HFA inhalation aerosol or XOPENEX HFA in patients with a known hypersensitivity to levalbuterol, racemic albuterol, or any of the ingredients in these products. Due to the risk of serious adverse effects, including cardiac arrest and death, the use of these inhalation aerosols is contraindicated in individuals with a history of abuse.

Warnings and Precautions

Levalbuterol tartrate HFA inhalation aerosol and XOPENEX HFA are associated with several important warnings and precautions that must be considered during their use.

Serious Warnings

• Both Levalbuterol tartrate HFA and XOPENEX HFA can produce life-threatening paradoxical bronchospasm. Patients should discontinue use immediately and seek alternative therapy if this occurs.

• Sudden shortness of breath (bronchospasm) may happen right after using either medication.

• Excessive use of these inhalation aerosols can lead to severe heart or lung problems, potentially resulting in death. Patients must not exceed the recommended dose.

• Serious allergic reactions, including immediate hypersensitivity reactions, may occur. Patients should stop using the medication and contact their doctor if they experience symptoms such as swelling of the face, throat, or tongue, hives, rash, or breathing difficulties.

General Precautions

• Patients should be advised not to use Levalbuterol tartrate HFA or XOPENEX HFA more frequently than recommended.

• A need for more doses than usual may indicate a deterioration of asthma and requires immediate medical evaluation.

• These medications are not substitutes for corticosteroids and should not be used as such.

• Caution is advised when administering these medications to patients with underlying cardiovascular disorders, as cardiovascular effects may occur.

Monitoring Requirements

• It may be beneficial to monitor renal function in patients with impaired renal function while using these medications.

• Patients who are pregnant or nursing should consult their physicians regarding the use of these inhalation aerosols.

Emergency Medical Help Instructions

• Patients should seek emergency medical help if their asthma symptoms worsen, if the medication does not provide the expected relief, or if they need to use the inhaler more frequently than usual.

Stop Taking and Call Your Doctor Instructions

• Patients should call their doctor or go to the nearest hospital emergency room immediately if they experience any serious side effects or worsening lung symptoms.

Side Effects

Patients using Levalbuterol Tartrate HFA Inhalation and XOPENEX HFA may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious Adverse Reactions

• Life-threatening paradoxical bronchospasm: This may occur with both Levalbuterol Tartrate HFA and XOPENEX HFA. Immediate discontinuation of the medication and alternative therapy are required.

• Cardiovascular effects: Patients may experience arrhythmias, tachycardia (with rates up to 200 beats/minute), hypertension, or hypotension. Discontinuation of the medication should be considered if these effects occur, particularly in patients with underlying cardiovascular disorders.

• Hypokalemia: This condition may arise with both medications and can lead to serious complications.

• Immediate hypersensitivity reactions: These reactions may necessitate the immediate discontinuation of the medication.

• Excessive use: Overuse of either medication may be fatal. Patients are advised not to exceed the recommended dose.

• Maternal pulmonary edema: Serious adverse reactions, including this condition, have been reported during or following treatment of premature labor with beta-2 agonists.

Common Adverse Reactions

• Accidental injury

• Bronchitis

• Dizziness

• Pain

• Pharyngitis

• Rhinitis

• Vomiting

Overdosage Symptoms

Symptoms of excessive beta-adrenergic receptor stimulation may include:

• Seizures

• Angina

• Hypertension or hypotension

• Tachycardia

• Arrhythmias

• Nervousness

• Headache

• Tremor

• Dry mouth

• Palpitation

• Nausea

• Dizziness

• Fatigue

• Malaise

• Sleeplessness

Pediatric Use

In pediatric patients below the age of 4 years, there is an increased incidence of asthma-related adverse reactions when treated with either Levalbuterol Tartrate HFA or XOPENEX HFA compared to placebo. In clinical trials, 12% of subjects reported asthma-related adverse reactions, including asthma, cough, hypoxia, status asthmaticus, and tachypnea, compared to 4% in the placebo group. One subject in each treatment group discontinued due to asthma.

Additional Notes

Adverse reactions observed in clinical trials for patients aged 4 years and older were consistent with those reported in pediatric populations. Monitoring for increased need for doses may indicate a deterioration of asthma and necessitate reevaluation of treatment.

Drug Interactions

Levalbuterol tartrate HFA inhalation aerosol and XOPENEX HFA may influence the pharmacokinetics and pharmacodynamics of other medications, and vice versa. It is essential for patients to inform their healthcare provider about all medications they are taking, particularly the following classes:

Inhaled Medicines and Asthma Medications

• Both Levalbuterol and XOPENEX should be used with caution alongside other inhaled drugs or asthma medications. These should only be taken as directed by a physician to avoid potential interactions.

Cardiovascular Medications

• The use of beta-blockers in patients receiving Levalbuterol or XOPENEX is discouraged, as these agents may block the bronchodilatory effects of beta-agonists, potentially leading to severe bronchospasm.

Diuretics

• Co-administration with diuretics may exacerbate electrocardiographic changes or hypokalemia. Monitoring of potassium levels is recommended in patients taking both diuretics and either Levalbuterol or XOPENEX.

Digoxin

• There is a potential for Levalbuterol and XOPENEX to decrease serum digoxin levels. Monitoring of digoxin levels is advised for patients on this combination.

Antidepressants

• The use of monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants may enhance the cardiovascular effects of albuterol, a component of both Levalbuterol and XOPENEX. Alternative therapies should be considered for patients on these antidepressants.

Other Sympathomimetics

• The concurrent use of other short-acting sympathomimetic aerosol bronchodilators or adrenergic drugs may potentiate the effects of Levalbuterol and XOPENEX, necessitating careful monitoring of the patient's response.

In summary, careful consideration and monitoring are warranted when Levalbuterol tartrate HFA inhalation aerosol or XOPENEX HFA is used in conjunction with other medications, particularly those affecting the cardiovascular system, electrolytes, and respiratory function.

Pediatric Use

Pediatric patients 4 years of age and older have established safety and efficacy for both Levalbuterol tartrate HFA inhalation aerosol and XOPENEX HFA in adequate and well-controlled clinical trials.

In pediatric patients less than 4 years of age, both Levalbuterol tartrate HFA inhalation aerosol and XOPENEX HFA are not indicated. Clinical trials involving 196 pediatric patients aged birth to <4 years with asthma or reactive airway disease demonstrated no statistically significant difference in the primary efficacy endpoint between treatment groups. The primary efficacy endpoint was the mean change in Pediatric Asthma Caregiver Assessment (PACA) total score from baseline over a 4-week treatment period.

Dosing for both medications included Levalbuterol tartrate HFA inhalation aerosol 45 mcg (N=23), Levalbuterol tartrate HFA inhalation aerosol 90 mcg (N=42), XOPENEX HFA 45 mcg (N=23), XOPENEX HFA 90 mcg (N=42), levalbuterol inhalation solution 0.31 mg (N=63), and placebo HFA (N=68), administered three times daily. Delivery was facilitated using the Monaghan AeroChamber MAX™ Valved Holding Chamber with mask.

Safety concerns were noted, with an increased incidence of asthma-related adverse reactions reported in pediatric patients below 4 years of age treated with either Levalbuterol tartrate HFA inhalation aerosol or XOPENEX HFA compared to placebo. In the clinical trials, 8 subjects treated with Levalbuterol tartrate HFA inhalation aerosol and 8 subjects treated with XOPENEX HFA reported asthma-related adverse reactions, compared to 3 subjects in the placebo group. One subject in each treatment group discontinued due to asthma, while no subjects in the placebo group discontinued treatment.

Overall, the findings indicate that while these medications are effective for older pediatric patients, caution is warranted when considering their use in younger patients due to safety concerns.

Geriatric Use

Clinical studies of Levalbuterol tartrate HFA inhalation aerosol and XOPENEX HFA did not include sufficient numbers 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 younger individuals.

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. Regular monitoring of these patients is recommended to ensure safety and efficacy.

Pregnancy

There are no adequate and well-controlled studies of Levalbuterol tartrate HFA inhalation aerosol (XOPENEX HFA) in pregnant patients. Clinical considerations should be taken into account when prescribing this medication to pregnant women.

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 (cleft palate) and rabbits (cranioschisis) at doses slightly above the human therapeutic range.

The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20%, respectively. In pregnant patients with poorly or moderately controlled asthma, there is an increased risk of preeclampsia, as well as prematurity, low birth weight, and small for gestational age in the neonate. Therefore, pregnant women should be closely monitored, and medication should be adjusted as necessary to maintain optimal asthma control.

Due to the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of Levalbuterol tartrate HFA inhalation aerosol for treating bronchospasm during labor should be limited to cases where the benefits clearly outweigh the risks. This medication 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 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 above the therapeutic range. Specifically, a rabbit study showed cranioschisis in 37% of fetuses at approximately 1500 times the MRHDID, while a mouse study indicated cleft palate formation in 4.5% to 9.3% of fetuses at exposures of approximately 2 to 20 times the MRHDID. No similar effects were observed at approximately 0.2 times the MRHDID of levalbuterol tartrate for adults. Cleft palate was also noted in 30.5% of fetuses from females treated with isoproterenol, a positive control.

In summary, the use of Levalbuterol tartrate HFA inhalation aerosol in pregnant patients requires careful consideration of the potential risks and benefits, with close monitoring and adjustments as necessary to ensure maternal and fetal safety.

Lactation

There are no available data on the presence of levalbuterol tartrate HFA inhalation aerosol or XOPENEX HFA in human milk, nor are there adequate and well-controlled studies assessing their effects on breastfed infants or milk production. Given the lack of information regarding excretion in breast milk, caution should be exercised when administering these medications to lactating mothers.

Healthcare providers should consider the developmental and health benefits of breastfeeding alongside the mother's clinical need for these medications. It is essential to weigh any potential adverse effects on the breastfed child from the medications or the underlying maternal condition.

Renal Impairment

Patients with renal impairment may experience altered pharmacokinetics when using Levalbuterol Tartrate HFA inhalation aerosol. Studies have shown that in subjects with creatinine clearance ranging from 7 to 53 mL/min, renal disease did not affect the half-life of racemic albuterol; however, there was a significant 67% reduction in its clearance.

Due to this decline in clearance, caution is advised when administering high doses of Levalbuterol Tartrate HFA to patients with renal impairment. While specific dosage adjustments or monitoring protocols are not detailed in the available data, healthcare providers should consider the potential for increased drug exposure and the associated risks when treating this patient population.

Overall, careful assessment and monitoring of patients with reduced kidney function are recommended to ensure safe and effective use of this medication.

Hepatic Impairment

The pharmacokinetics of Levalbuterol tartrate HFA inhalation aerosol and XOPENEX HFA have not been evaluated in patients with hepatic impairment. There is no specific information available regarding dosage adjustments, special monitoring, or precautions for patients with liver problems for either formulation. Therefore, healthcare providers should exercise caution when prescribing these medications to patients with hepatic impairment, as the lack of data necessitates careful consideration of potential risks and benefits. Regular monitoring of clinical response and any adverse effects is advisable in this patient population.

Overdosage

In cases of overdosage with Levalbuterol Tartrate HFA Inhalation or XOPENEX HFA, the expected symptoms are indicative of excessive beta-adrenergic receptor stimulation. 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 occur.

As with all sympathomimetic medications, there is a risk of serious outcomes, including cardiac arrest and even death, associated with the abuse of these inhalation aerosols.

Management of overdosage involves the immediate discontinuation of the inhalation aerosol, along with appropriate symptomatic therapy. The use of a cardioselective beta-receptor blocker may be considered judiciously; however, it is important to note that such medications can induce bronchospasm.

There is insufficient evidence to support the efficacy of dialysis in the treatment of overdosage with either Levalbuterol Tartrate HFA or XOPENEX HFA. Continuous monitoring and supportive care are recommended to address any emergent symptoms.

Nonclinical Toxicology

Teratogenic Effects

No information is provided regarding teratogenic effects.

Carcinogenesis

Although there have been no carcinogenesis studies specifically conducted with levalbuterol tartrate, racemic albuterol sulfate has been evaluated for its carcinogenic potential. 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, which is approximately 30 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol tartrate for adults and approximately 15 times 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 dietary doses in CD-1 mice reached up to 500 mg/kg/day (approximately 3800 times the MRHDID for adults and approximately 1800 times for children on a mg/m² basis), while doses in the golden hamster study were up to 50 mg/kg/day (approximately 500 times the MRHDID for adults and approximately 240 times for children on a mg/m² basis).

Mutagenesis

Levalbuterol HCl 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.

Impairment of Fertility

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.

Animal Pharmacology and Toxicology

In both animals and humans, the propellant HFA-134a was found to be rapidly absorbed and eliminated, 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 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.

Storage and Handling

Levalbuterol Tartrate HFA Inhalation and Xopenex HFA are supplied as metered aerosol inhalers.

These inhalers should be stored between 20° and 25°C (68° and 77°F; see USP controlled room temperature). It is essential to protect them from freezing temperatures and direct sunlight. The inhaler must be stored with the actuator mouthpiece down to ensure proper functioning.

Handling precautions include not puncturing or incinerating the canister, and avoiding storage near heat or open flame. Exposure to temperatures above 120°F may cause the canister to burst. It is critical never to throw the container into fire or incinerator.

Keep these products out of reach of children. The canister should be discarded when the dose indicator display window shows zero, indicating that 200 actuations have been used.