Xopenex Information
Xopenex (Levalbuterol)
Xopenex (Levalbuterol)
Xopenex (Levalbuterol) Description:
Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol. Levalbuterol HCl is a relatively selective beta-adrenergic receptor agonist (see ). The chemical name for levalbuterol HCl is (R)-α-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established chemical structure is as follows:
The molecular weight of levalbuterol HCl is 275.8, and its empirical formula is CHNO•HCl. It is a white to off-white, crystalline solid, with a melting point of approximately 187°C and solubility of approximately 180 mg/mL in water.
Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the United States.
Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution Concentrate supplied in 0.5 mL unit-dose vials should be diluted with sterile normal saline before administration by nebulization. Each 0.5 mL unit-dose vial contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, and hydrochloric acid to adjust the pH to 4.0 (3.3 to 4.5).
Xopenex (Levalbuterol) Clinical Pharmacology:
Activation of beta-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3´, 5´-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.
While it is recognized that beta-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta-receptors in the human heart that comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors has not been established (see ). However, all beta-adrenergic agonist drugs can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.
Xopenex (Levalbuterol) Indications And Usage:
Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.
Xopenex (Levalbuterol) Contraindications:
Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution is contraindicated in patients with a history of hypersensitivity to levalbuterol HCl or racemic albuterol.
Xopenex (Levalbuterol) Precautions:
Levalbuterol HCl, 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, levalbuterol 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.
See illustrated Patient's Instructions for Use.
The action of Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution may last up to 8 hours. Xopenex (Levalbuterol) Inhalation Solution should not be used more frequently than recommended. Do not increase the dose or frequency of dosing of Xopenex (Levalbuterol) Inhalation Solution without consulting your physician. If you find that treatment with Xopenex (Levalbuterol) Inhalation Solution 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 taking Xopenex (Levalbuterol) Inhalation Solution, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, headache, dizziness, and tremor or nervousness. If you are pregnant or nursing, contact your physician about the use of Xopenex (Levalbuterol) Inhalation Solution.
Effective and safe use of Xopenex (Levalbuterol) Inhalation Solution requires consideration of the following information in addition to that provided under Patient's Instructions for Use:
Xopenex (Levalbuterol) Inhalation Solution single-use low-density polyethylene (LDPE) vials should be protected from light and excessive heat. Store in the protective foil pouch between 20°C and 25°C (68°F and 77°F) [see USP Controlled Room Temperature]. Do not use after the expiration date stamped on the container. Open the foil pouch just prior to administration. Once the foil pouch is opened, the contents of the vial should be used immediately. Discard any vial if the solution is not colorless. Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution Concentrate should be diluted with sterile normal saline before administration by nebulization.
The drug compatibility (physical and chemical), efficacy, and safety of Xopenex (Levalbuterol) Inhalation Solution when mixed with other drugs in a nebulizer have not been established.
No carcinogenesis or impairment of fertility studies have been carried out with levalbuterol HCl alone. 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 (approximately 2 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m 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 (approximately 260 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m 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 (approximately 35 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m basis).
Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Although levalbuterol HCl has not been tested for clastogenicity, racemic albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m basis).
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 (approximately 110 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m 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 (less than the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg 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 (approximately 110 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m 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 (Levalbuterol) Inhalation Solution in pregnant women. Because animal reproduction studies are not always predictive of human response, Xopenex (Levalbuterol) Inhalation Solution 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.
Plasma levels of levalbuterol after inhalation of therapeutic doses are very low in humans, but 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 (Levalbuterol) 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 (Levalbuterol) Inhalation Solution is administered to a nursing woman.
Xopenex (Levalbuterol) Adverse Reactions (adults And Adolescents ≥ Years Old):
Adverse events reported in ≥2% of patients receiving Xopenex (Levalbuterol) Inhalation Solution or racemic albuterol and more frequently than in patients receiving placebo in a 4-week, controlled clinical trial are listed in .
The incidence of certain systemic beta-adrenergic adverse effects (e.g., tremor, nervousness) was slightly less in the Xopenex (Levalbuterol) 0.63 mg group compared with the other active treatment groups. The clinical significance of these small differences is unknown.
Changes in heart rate 15 minutes after drug administration and in plasma glucose and potassium 1 hour after drug administration on day 1 and day 29 were clinically comparable in the Xopenex (Levalbuterol) 1.25 mg and racemic albuterol 2.5 mg groups (see ). Changes in heart rate and plasma glucose were slightly less in the Xopenex (Levalbuterol) 0.63 mg group compared with the other active treatment groups (see ). The clinical significance of these small differences is unknown. After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were generally diminished compared with day 1 in all active treatment groups.
No other clinically relevant laboratory abnormalities related to administration of Xopenex (Levalbuterol) Inhalation Solution were observed in this study.
In the clinical trials, a slightly greater number of serious adverse events, discontinuations due to adverse events, and clinically significant ECG changes were reported in patients who received Xopenex (Levalbuterol) 1.25 mg compared with the other active treatment groups.
The following adverse events, considered potentially related to Xopenex (Levalbuterol) , occurred in less than 2% of the 292 subjects who received Xopenex (Levalbuterol) and more frequently than in patients who received placebo in any clinical trial:
Body as a Whole: chills, pain, chest pain
Cardiovascular System: ECG abnormal, ECG change, hypertension, hypotension, syncope
Digestive System: diarrhea, dry mouth, dry throat, dyspepsia, gastroenteritis, nausea
Hemic and Lymphatic System: lymphadenopathy
Musculoskeletal System: leg cramps, myalgia
Nervous System: anxiety, hypesthesia of the hand, insomnia, paresthesia, tremor
Special Senses: eye itch
The following events, considered potentially related to Xopenex (Levalbuterol) , occurred in less than 2% of the treated subjects but at a frequency less than in patients who received placebo: asthma exacerbation, cough increased, wheezing, sweating, and vomiting.
Xopenex (Levalbuterol) Adverse Reactions (children - Years Old):
Adverse events reported in ≥2% of patients in any treatment group and more frequently than in patients receiving placebo in a 3-week, controlled clinical trial are listed in
Changes in heart rate, plasma glucose, and serum potassium are shown in The clinical significance of these small differences is unknown.
Xopenex (Levalbuterol) Postmarketing Adverse Reactions:
In addition to the adverse events reported in clinical trials, the following adverse events have been observed in postapproval use of Xopenex (Levalbuterol) Inhalation Solution. These events have been chosen for inclusion due to their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), asthma, chest pain, cough increased, dyspnea, nausea, nervousness, rash, tachycardia, tremor, urticaria. Because these events have been reported spontaneously from a population of unknown size, estimates of frequency cannot be made.
Xopenex (Levalbuterol) Overdosage:
The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of Xopenex (Levalbuterol) Inhalation Solution. Treatment consists of discontinuation of Xopenex (Levalbuterol) Inhalation Solution together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Xopenex (Levalbuterol) Inhalation Solution.
The intravenous median lethal dose of levalbuterol HCl in mice is approximately 66 mg/kg (approximately 70 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m basis). The inhalation median lethal dose has not been determined in animals.
Xopenex (Levalbuterol) Dosage And Administration:
Children 6–11 years old:
Adults and Adolescents ≥12 years old:
Patients 12 years of age and older with more severe asthma or patients who do not respond adequately to a dose of 0.63 mg of Xopenex (Levalbuterol) Inhalation Solution may benefit from a dosage of 1.25 mg three times a day.
Patients receiving the highest dose of Xopenex (Levalbuterol) Inhalation Solution should be monitored closely for adverse systemic effects, and the risks of such effects should be balanced against the potential for improved efficacy.
The use of Xopenex (Levalbuterol) Inhalation Solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time, most patients gain optimal benefit from regular use of the inhalation solution.
If a previously effective dosage regimen fails to provide the expected relief, medical advice should be sought immediately, since this is often a sign of seriously worsening asthma that would require reassessment of therapy.
The drug compatibility (physical and chemical), efficacy, and safety of Xopenex (Levalbuterol) Inhalation Solution when mixed with other drugs in a nebulizer have not been established.
The safety and efficacy of Xopenex (Levalbuterol) Inhalation Solution have been established in clinical trials when administered using the PARI LC Jet™ and PARI LC Plus™ nebulizers, and the PARI Master Dura-Neb 2000 and Dura-Neb 3000 compressors. The safety and efficacy of Xopenex (Levalbuterol) Inhalation Solution when administered using other nebulizer systems have not been established.
Xopenex (Levalbuterol) How Supplied:
Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution Concentrate is supplied in 0.5 mL unit-dose, low-density polyethylene (LDPE) vials, and is a clear, colorless, sterile, preservative-free, aqueous solution. Each vial contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 30 (NDC 63402-515-30) individually pouched vials.
Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution is also available in 3 mL vials in three different strengths of levalbuterol: 0.31 mg (NDC 63402-511-24), 0.63 mg (NDC 63402-512-24), and 1.25 mg (NDC 63402-513-24).
Xopenex (Levalbuterol) Caution:
Federal law (U.S.) prohibits dispensing without prescription.
Store Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution Concentrate in the protective foil pouch at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. Protect from light and excessive heat. Open the foil pouch just prior to administration. Once the foil pouch is opened, the contents of the vial should be used immediately. Discard any vial if the solution is not colorless. Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution Concentrate should be diluted with sterile normal saline before administration by nebulization.
Manufactured for: Marlborough, MA 01752 USAFor customer service, call 1-888-394-7377.To report adverse events, call 1-877-737-7226.For medical information, call 1-800-739-0565.
August 2007400438R2
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Xopenex (Levalbuterol) Patient's Instructions For Use
Read complete instructions carefully before using.
Note: Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution should be used in a nebulizer only under the direction of a physician. More frequent administration or higher doses are not recommended without first discussing with your doctor. This solution should not be injected or administered orally. Protect from light and excessive heat. Store in the protective foil pouch at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. Open the foil pouch just prior to administration. Once the foil pouch is opened, the contents of the vial should be used immediately. Discard any vial if the solution is not colorless. Xopenex (Levalbuterol) (levalbuterol HCl) Inhalation Solution Concentrate should be diluted with sterile normal saline before administration by nebulization.
The safety and effectiveness of Xopenex (Levalbuterol) Inhalation Solution have not been determined when one or more drugs are mixed with it in a nebulizer. Check with your doctor before mixing any medications in your nebulizer.
Manufactured for: Marlborough, MA 01752 USAFor customer service, call 1-888-394-7377.To report adverse events, call 1-877-737-7226.For medical information, call 1-800-739-0565.
August 2007400438R2
Xopenex (Levalbuterol) . Concentrate Pouch - Principal Display Panel – . Mg / . Ml
NDC 63402-515-00
1.25 mg
Concentrate
Xopenex (Levalbuterol)
(levalbuterol HCl)
Inhalation Solution Concentrate 1.25 mg/0.5 mL*
*Potency expressed as levalbuterol
Open Foil Pouch Just Prior to Administration
Dilute Before Use
Keep out of reach of children. Rx Only.
Attention Pharmacist: Detach “Patient's Instructions for Use” from package insert and dispense with product. Use only as directed by your physician.
SEPRACOR
Manufactured for Sepracor Inc.
Marlborough, MA 01752 USA
Xopenex (Levalbuterol) . Concentrate Carton - Principal Display Panel – . Mg / . Ml
NDC 63402-515-30
1.25 mg
Concentrate in 0.5 mL
Xopenex (Levalbuterol)
(levalbuterol HCl)
Inhalation Solution
Concentrate
1.25 mg/0.5 mL*
*Potency expressed as levalbuterol
Dilution Required
For Oral Inhalation Only. Sterile Unit-Dose Vial
30 x 0.5 mL Sterile Unit-Dose Vials
Open the foil pouch just prior to administration
DILUTE BEFORE USE
SEPRACOR
