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XOPENEX Inhalation Solution can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, XOPENEX Inhalation Solution 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 vial.
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 Inhalation Solution 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
XOPENEX Inhalation Solution is not a substitute for corticosteroids. The use of 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 Inhalation Solution, 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 Inhalation Solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists 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 Inhalation Solution, 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
Do not exceed the 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 levalbuterol or racemic albuterol. Reactions have included 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 Inhalation Solution.
XOPENEX Inhalation Solution, 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 Inhalation Solution 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 Inhalation Solution).
Patients should be given the following information:
Query patients about previously experienced hypersensitivity to levalbuterol or racemic albuterol and counsel patients to report any hypersensitivity reactions to their physician.
Frequency of Use
Inform patients not to increase the dose or use XOPENEX Inhalation Solution more frequently than recommended without consulting their physician. If patients find that treatment with XOPENEX Inhalation Solution 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.
Inform patients that XOPENEX Inhalation Solution can produce paradoxical bronchospasm. Instruct patients to discontinue XOPENEX Inhalation Solution if paradoxical bronchospasm occurs.
Concomitant Drug Use
Inform patients using XOPENEX Inhalation Solution, that other inhaled drugs and asthma medications should be taken only as directed by their physician.
Common Adverse Reactions
Advise patients who are pregnant or nursing to contact their physician about the use of XOPENEX Inhalation Solution.
General Information on Use
Advise patients to store XOPENEX Inhalation Solution in the foil pouch between 20°C and 25°C (68°F and 77°F) protected from light and excessive heat. 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 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.
Advise patients not to mix XOPENEX Inhalation Solution with other drugs in a nebulizer.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Although there have been no carcinogenesis studies with levalbuterol HCl, 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 4 times the MRDI dose of levalbuterol HCl for adults and approximately 5 times the MRDI dose of levalbuterol HCl 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 540 times the MRDI dose of levalbuterol HCl for adults and approximately 630 times the MRDI dose of levalbuterol HCl for children on a mg/m² basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 90 times the MRDI dose of levalbuterol HCl for adults on a mg/m² basis and approximately 105 times the MRDI dose of levalbuterol HCl 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 hydrochloride. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 108 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m² basis).
Use In Specific Populations
Teratogenic Effects - Pregnancy Category C
There are no adequate and well-controlled studies of XOPENEX Inhalation Solution in pregnant women. Because animal reproduction studies are not always predictive of human response, XOPENEX Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in newborns of women treated with racemic albuterol which contains the levalbuterol isomer (active drug substance of XOPENEX Inhalation Solution). However, since multiple medications were taken during some of the 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 108 times the maximum recommended daily inhalation [MRDI] dose of levalbuterol HCl for adults on a mg/m² basis).
However, other studies demonstrated that racemic albuterol sulfate was teratogenic in mice and rabbits at doses comparable to the human therapeutic range. Pregnant mice administered racemic albuterol sulfate subcutaneously had 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 0.3 times the MRDI dose, 9.3% of fetuses at 2.5 mg/kg/day, approximately 3 times the MRDI dose of levalbuterol HCl 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 0.03 times the MRDI dose of levalbuterol HCl 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 215 times the MRDI dose of levalbuterol HCl 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 Inhalation Solution for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
XOPENEX Inhalation Solution has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol HCl 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 Inhalation Solution 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 Inhalation Solution is administered to a nursing woman.
The safety and efficacy of XOPENEX Inhalation Solution have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial [see ADVERSE REACTIONS and Clinical Studies]. Use of XOPENEX Inhalation Solution in children is also supported by evidence from adequate and well-controlled studies of XOPENEX Inhalation Solution in adults, considering that the pathophysiology, systemic exposure of the drug and clinical profile in pediatric and adult patients are substantially similar. Safety and effectiveness of XOPENEX Inhalation Solution in pediatric patients below the age of 6 years have not been established.
Clinical studies of XOPENEX Inhalation Solution did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Only 5 patients 65 years of age and older were treated with XOPENEX Inhalation Solution in a 4-week clinical study [see CLINICAL PHARMACOLOGY and Clinical Studies] (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. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of XOPENEX Inhalation Solution. If clinically warranted due to insufficient bronchodilator response, the dose of XOPENEX Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose [see DOSAGE AND ADMINISTRATION].
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: 4/11/2014
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