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XOPENEX HFA can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, XOPENEX HFA should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister.
Deterioration Of Asthma
Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of XOPENEX HFA than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
Use Of Anti-Inflammatory Agents
The use of a beta-adrenergic agonist alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.
XOPENEX HFA, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms. Although such effects are uncommon after administration of XOPENEX HFA at recommended doses, if they occur, the drug may need to be discontinued. In addition, betaagonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, XOPENEX HFA, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Do Not Exceed Recommended Dose
Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of racemic albuterol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving XOPENEX HFA.
XOPENEX HFA, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.
As with other beta-adrenergic agonist medications, XOPENEX HFA may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Using XOPENEX HFA).
Patients should be given the following information:
Frequency of Use
The action of XOPENEX HFA should last for 4 to 6 hours. Do not use XOPENEX HFA more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of XOPENEX HFA without consulting their physician. If patients find that treatment with XOPENEX HFA becomes less effective for symptomatic relief, symptoms become worse, or they need to use the product more frequently than usual, they should seek medical attention immediately.
Priming, Cleaning and Storage
Priming: SHAKE WELL BEFORE USING. Patients should be instructed that priming XOPENEX HFA is essential to ensure appropriate levalbuterol content in each actuation. Patients should prime XOPENEX HFA before using for the first time and in cases where the inhaler has not been used for more than 3 days by releasing 4 test sprays into the air, away from the face.
Cleaning: To ensure proper dosing and prevent actuator orifice blockage, instruct patients to wash the actuator in warm water and air-dry thoroughly at least once a week. Patients should be informed that detailed cleaning instructions are included in the FDA-Approved Patient Labeling.
Storage: Store canister between 20° and 25°C (68° and 77°F). Protect from freezing temperatures and direct sunlight.
Inform patients that XOPENEX HFA can produce paradoxical bronchospasm. Instruct patients to discontinue XOPENEX HFA if paradoxical bronchospasm occurs.
Concomitant Drug Use
While patients are using XOPENEX HFA, other inhaled drugs and asthma medications should be taken only as directed by the physician.
Common Adverse Reactions
Patients who are pregnant or nursing should contact their physicians about the use of XOPENEX HFA.
General Information on Use
Effective and safe use of XOPENEX HFA includes an understanding of the way that it should be administered.
Shake the inhaler well immediately before each use.
Use XOPENEX HFA only with the actuator supplied with the product. Discard the canister after 200 sprays have been used from the 15 g canister or after 80 sprays have been used from the 8.4 g canister. Never immerse the canister in water to determine how full the canister is (“float test”).
In general, the technique for administering XOPENEX HFA to children is similar to that for adults. Children should use XOPENEX HFA under adult supervision, as instructed by the patient's physician [see FDA-approved patient labeling – (PATIENT INFORMATION and Instructions for Using XOPENEX HFA)].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Although there have been no carcinogenesis studies with levalbuterol tartrate, racemic albuterol sulfate has been evaluated for its carcinogenic potential.
In a 2-year study in 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 (approximately 30 times the MRDI) dose of levalbuterol tartrate for adults and approximately 15 times the MRDI dose of levalbuterol tartrate for children on a mg/m² basis). In an 18-month study in CD-1 mice and a 22-month study in the golden hamster, dietary administration of racemic albuterol sulfate showed no evidence of tumorigenicity. Dietary doses in CD-1 mice were up to 500 mg/kg/day (approximately 3800 times the MRDI dose of levalbuterol tartrate for adults and approximately 1800 times the MRDI dose of levalbuterol tartrate for children on a mg/m² basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 500 times the MRDI dose of levalbuterol tartrate for adults on a mg/m² basis and approximately 240 times the MRDI dose of levalbuterol tartrate for children on a mg/m² basis).
Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Levalbuterol HCl was not clastogenic in the in vivo micronucleus test in mouse bone marrow. Racemic albuterol sulfate was not clastogenic in an in vitro chromosomal aberration assay in CHO cell cultures.
No fertility studies have been conducted with levalbuterol tartrate. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 750 times the maximum recommended daily inhalation dose of levalbuterol tartrate for adults on a mg/m² basis).
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of XOPENEX HFA in pregnant women. Because animal reproduction studies are not always predictive of human response, XOPENEX HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Rare instances of congenital anomalies, including cleft palate and limb defects, were reported in newborns of women treated with racemic albuterol in which the levalbuterol isomer (active drug substance of XOPENEX HFA) is present. However, since multiple medications were taken during their pregnancies and there was no consistent pattern of anomalies, it was not possible to establish a relationship between racemic albuterol use and the occurrence of these congenital anomalies.
In animal studies, oral administration of levalbuterol HCl to pregnant New Zealand White rabbits found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 750 times the maximum recommended daily inhalation dose of levalbuterol tartrate for adults on a mg/m² basis).
However, other studies demonstrated that racemic albuterol sulfate was teratogenic in mice and rabbits at doses slightly higher than the human therapeutic range. Pregnant mice administered racemic albuterol sulfate subcutaneously resulted in a dose-related increased incidence of cleft palate in their fetuses (4.5% of fetuses at 0.25 mg/kg/day or greater, corresponding to approximately 2 times MRDI dose, 9.3% of fetuses at 2.5 mg/kg/day, approximately 20 times MRDI dose of levalbuterol tartrate for adults on a mg/m² basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg/day (approximately 0.2 times MRDI dose of levalbuterol tartrate for adults on a mg/m² basis). In addition, oral administration of racemic albuterol sulfate to pregnant rabbits resulted in an increased incidence of cranioschisis in fetuses (approximately 1500 times the MRDI dose of levalbuterol tartrate 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.
Labor And Delivery
Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of XOPENEX HFA for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
XOPENEX HFA has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol tartrate is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including racemic albuterol.
Plasma concentrations of levalbuterol after inhalation of therapeutic doses are very low in humans. 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 HFA by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when XOPENEX HFA is administered to a nursing woman.
Pediatric Patients 4 Years of Age and Older
The safety and efficacy of XOPENEX HFA have been established in pediatric patients 4 years of age and older in an adequate and well-controlled clinical trial [see ADVERSE REACTIONS and Clinical Studies].
Pediatric Patients less than 4 Years of Age
XOPENEX HFA is not indicated for pediatric patients less than 4 years of age. A clinical trial in pediatric patients below the age of 4 years showed no statistical significant difference between treatment groups in the primary efficacy endpoint. There was an increased incidence of asthma-related adverse reactions reported in pediatric patients below the age of 4 years treated with XOPENEX HFA compared to placebo.
XOPENEX HFA was evaluated in one 4-week, multicenter, randomized, modified-blind, placebo-controlled, parallel group trial of 196 pediatric patients ages birth to < 4 years of age with asthma or reactive airway disease (68 patients birth to < 2 years of age and 128 patients 2 to < 4 years of age). XOPENEX HFA 45 mcg (N=23), XOPENEX HFA 90 mcg (N=42), levalbuterol inhalation solution 0.31 mg (N=63), and placebo HFA (N=68) were administered three times daily. XOPENEX HFA or placebo HFA was delivered with the Monaghan AeroChamber MAX™ Valved Holding Chamber with mask. The primary efficacy endpoint was the mean change in Pediatric Asthma Caregiver Assessment (PACA) total score from baseline over the 4 week treatment period. There was no statistical difference in the change in PACA total score between Xopenex HFA and placebo. Regarding safety, an increased number of treatment-emergent asthma-related adverse reactions were reported in XOPENEX HFA-treated patients. Eight subjects reported asthma-related adverse reactions for Xopenex HFA compared to 3 subjects for placebo. There was one subject that discontinued treatment due to asthma in the Xopenex HFA group compared to zero subjects in the placebo group (Table 3). Other adverse reactions were consistent with those observed in the clinical trial population of patients 4 years of age and older [see ADVERSE REACTIONS].
Table 3: Asthma-related Adverse Reactions in a 4-Week
Clinical Trial in Children Birth to < 4 Years of Age*
|XOPENEX HFA 45-90 mcg
|Levalbuterol inhalation solution 0.31 mg
|Asthma-related adverse reactions*, n (%)||8 (12%)||6 (10%)||3 (4%)|
|Treatment discontinuations due to asthma, n (%)||1 (2%)||2 (3%)||0|
|*This table includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnea|
Clinical studies of XOPENEX HFA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.
Albuterol is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/26/2015
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