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Xopenex HFA (Levalbuterol Tartrate) - Warnings and Precautions

 
 



WARNINGS

  1. Paradoxical Bronchospasm: Like other inhaled beta-adrenergic agonists, XOPENEX HFA Inhalation Aerosol can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, XOPENEX HFA (levalbuterol tartrate) Inhalation Aerosol 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.
  2. 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 Inhalation Aerosol 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.
  3. 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.
  4. Cardiovascular Effects: XOPENEX HFA Inhalation Aerosol, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of XOPENEX HFA Inhalation Aerosol 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 HFA Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
  5. 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.
  6. 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 Inhalation Aerosol.

PRECAUTIONS

General

XOPENEX HFA (levalbuterol tartrate) Inhalation Aerosol, 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.

Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-adrenergic agonist medications, XOPENEX HFA Inhalation Aerosol 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.

Information for Patients

See illustrated Patient's Instructions for Use. SHAKE WELL BEFORE USING. Patients should be given the following information: It is recommended to prime the inhaler 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.

KEEPING THE PLASTIC ACTUATOR CLEAN IS VERY IMPORTANT TO PREVENT MEDICATION BUILD-UP AND BLOCKAGE. THE ACTUATOR SHOULD BE WASHED, SHAKEN TO REMOVE EXCESS WATER, AND AIR-DRIED THOROUGHLY AT LEAST ONCE A WEEK. THE INHALER MAY CEASE TO DELIVER MEDICATION IF NOT PROPERLY CLEANED.

The actuator should be cleaned (with the canister removed) by running warm water through the top and bottom for 30 seconds at least once a week. Do not attempt to clean the metal canister or allow the metal canister to become wet. Never immerse the metal canister in water. The actuator must be shaken to remove excess water, then air-dried thoroughly (such as overnight). Blockage from medication build-up or improper medication delivery may result from failure to clean and thoroughly air-dry the actuator.

If the actuator becomes blocked (little or no medication coming out of the mouthpiece), the blockage may be removed by washing the actuator as described above.

If it is necessary to use the inhaler before it is completely dry, shake excess water off the plastic actuator, replace canister, shake well, test-spray twice away from face, and take the prescribed dose. After such use, the actuator should be rewashed and allowed to air-dry thoroughly.

The action of XOPENEX HFA Inhalation Aerosol should last for 4 to 6 hours. XOPENEX HFA Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of doses of XOPENEX HFA Inhalation Aerosol without consulting your physician. If you find that treatment with XOPENEX HFA Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are using XOPENEX HFA Inhalation Aerosol, other inhaled drugs and asthma medication should be taken only as directed by your physician.

Common adverse effects of treatment with inhaled beta-agonists include palpitations, chest pain, rapid heart rate, tremor, and nervousness. If you are pregnant or nursing, contact your physician about use of XOPENEX HFA Inhalation Aerosol. Effective and safe use of XOPENEX HFA Inhalation Aerosol includes an understanding of the way that it should be administered.

Use XOPENEX HFA Inhalation Aerosol 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 Inhalation Aerosol to children is similar to that for adults. Children should use XOPENEX HFA Inhalation Aerosol under adult supervision, as instructed by the patient's physician. (See Patient's Instructions for Use.)

Drug Interactions

Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should be used with caution with XOPENEX HFA Inhalation Aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

  1. Beta-blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists, such as XOPENEX HFA Inhalation Aerosol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.
  2. Diuretics: The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop and thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics.
  3. Digoxin: Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving XOPENEX HFA Inhalation Aerosol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and XOPENEX HFA Inhalation Aerosol.
  4. Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: XOPENEX HFA Inhalation Aerosol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No carcinogenesis or impairment of fertility studies have been carried out with levalbuterol tartrate. However, racemic albuterol sulfate has been evaluated for its carcinogenic potential and ability to impair fertility.

In a 2-year study in Sprague-Dawley rats, racemic albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at, and above, dietary doses of 2 mg/kg/day (approximately 30 times the maximum recommended daily inhalation dose of levalbuterol tartrate for adults on a mg/m2 basis and approximately 15 times the maximum recommended daily inhalation dose of levalbuterol tartrate for children on a mg/m2 basis). In another study, this effect was blocked by the coadministration of propranolol, a nonselective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, racemic albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg/day (approximately 3800 times the maximum recommended daily inhalation dose of levalbuterol tartrate for adults on a mg/m2 basis and approximately 1800 times the maximum recommended daily inhalation dose of levalbuterol tartrate for children on a mg/m2 basis). In a 22-month study in the Golden hamster, racemic albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg/day (approximately 500 times the maximum recommended daily inhalation dose of levalbuterol tartrate for adults on a mg/m2 basis and approximately 240 times the maximum recommended daily inhalation 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 negative in an in vitro chromosomal aberration assay in CHO cell cultures.

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).

Teratogenic Effects - Pregnancy Category C

A reproduction study in New Zealand White rabbits demonstrated that levalbuterol HCl was not teratogenic when administered orally 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, racemic albuterol sulfate has been shown to be teratogenic in mice and rabbits. A study in CD-1 mice given racemic albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg/day (approximately 2 times the maximum recommended daily inhalation dose of levalbuterol tartrate for adults on a mg/m2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg/day (approximately 20 times the maximum recommended daily inhalation 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 (less than the maximum recommended daily inhalation dose of levalbuterol tartrate for adults on a mg/m2 basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg/day of isoproterenol (positive control).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when racemic albuterol sulfate was administered orally at a dose of 50 mg/kg/day (approximately 1500 times the maximum recommended daily inhalation 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.

There are no adequate and well-controlled studies of XOPENEX HFA Inhalation Aerosol in pregnant women. Because animal reproduction studies are not always predictive of human response, XOPENEX HFA Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

During marketing experience of racemic albuterol, various congenital anomalies, including cleft palate and limb defects, have been rarely reported in the offspring of patients being treated with racemic albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between racemic albuterol use and congenital anomalies has not been established.

Use in Labor and Delivery

Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of XOPENEX HFA Inhalation Aerosol for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Tocolysis

XOPENEX HFA Inhalation Aerosol 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.

Nursing Mothers

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 Inhalation Aerosol 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 Inhalation Aerosol is administered to a nursing woman.

Pediatrics

The safety and efficacy of XOPENEX HFA Inhalation Aerosol have been established in pediatric patients 4 years of age and older in an adequate and well-controlled clinical trial (see Clinical Trials). Use of XOPENEX HFA Inhalation Aerosol in children is also supported by evidence from adequate and well-controlled studies of XOPENEX HFA Inhalation Aerosol 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 HFA Inhalation Aerosol in pediatric patients below the age of 4 years have not been established.

Geriatrics

Clinical studies of XOPENEX HFA Inhalation Aerosol 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.

Page last updated: 2012-05-07

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