Levalbuterol Tartrate Hfa Drug Information

Bronchospasm Levalbuterol tartrate

HFA inhalation aerosol is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 4 years of age and older with reversible obstructive airway disease.

• For Oral Inhalation Only ( 2.2 )
• Adults and children 4 years of age and older: 2 inhalations repeated every 4 to 6 hours; in some patients, 1 inhalation every 4 hours may be sufficient. ( 2.1 )
• Prime Levalbuterol tartrate HFA inhalation aerosol before using for the first time and when the inhaler has not been used for more than 3 days. To prime Levalbuterol tartrate HFA inhalation aerosol, release 4 sprays into the air away from the face. ( 2.2 )
• At least once a week, wash the actuator with warm water and let it air-dry completely. ( 2.2 ) 2.1 Recommended Dosages The recommended dosage of Levalbuterol tartrate HFA inhalation aerosol for adults and children 4 years of age and older is 2 inhalations (90 mcg of levalbuterol free base) repeated every 4 to 6 hours; in some patients, 1 inhalation (45 mg of levalbuterol free base) every 4 hours may be sufficient. More frequent administration or a larger number of inhalations is not routinely recommended. If a previously effective dosage regimen fails to provide the usual response, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. 2.2 Administration Information For oral inhalation only
• Shake well before use.
• Avoid spraying in the eyes.
• Prime the inhaler before using for the first time and when the inhaler has not been used for more than 3 days by releasing 4 test sprays into the air, away from the face.
• To maintain proper use of Levalbuterol tartrate HFA inhalation aerosol, it is critical to wash the actuator with warm water and air-dry thoroughly at least once a week. The inhaler may cease to deliver levalbuterol tartrate if not properly cleaned and dried thoroughly. Keep the plastic actuator clean to prevent medication build-up and blockage. If the actuator becomes blocked with levalbuterol tartrate, wash the actuator to remove the blockage.
• Discard after 200 actuations have been released from the 15 gram canister.

• Use of Levalbuterol tartrate HFA inhalation aerosol may be associated with the following:
• Paradoxical bronchospasm [see Warnings and Precautions (5.1) ]
• Cardiovascular effects [see Warnings and Precautions (5.4) ]
• Immediate hypersensitivity reactions [see Warnings and Precautions (5.6) ]
• Hypokalemia [see Warnings and Precautions (5.8) ] Most common adverse reactions (≥ 2% and > placebo) are accidental injury, bronchitis, dizziness, pain, pharyngitis, rhinitis, and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, call 1-877-737-7226 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults and Adolescents 12 Years of Age and Older Adverse reaction information concerning Levalbuterol tartrate HFA inhalation aerosol in adults and adolescents is derived from two 8-week, multicenter, randomized, double-blind, active- and placebo-controlled trials in 748 adult and adolescent patients with asthma that compared Levalbuterol tartrate HFA inhalation aerosol, a marketed albuterol HFA inhaler, and an HFA-134a placebo inhaler. Table 1 lists the incidence of all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of 2% or greater in the group treated with Levalbuterol tartrate HFA inhalation aerosol and more frequently than in the HFA-134a placebo inhaler group. Table 1: Adverse Reaction Incidence (% of Patients) in Two 8-Week Clinical Trials in Adults and Adolescents ≥ 12 Years of Age* Body System Preferred Term Levalbuterol tartrate HFA inhalation aerosol 90 mcg (n=403) Racemic Albuterol HFA 180 mcg (n=179) Placebo (n=166) Body as a Whole Pain 4% 3% 4% Central Nervous System Dizziness 3% 1% 2% Respiratory System Asthma 9% 7% 6% Pharyngitis 8% 2% 2% Rhinitis 7% 2% 3% * This table includes all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of 2% or greater in the group treated with Levalbuterol tartrate HFA inhalation aerosol and more frequently than in the HFA-134a placebo inhaler group. Adverse reactions reported by less than 2% and at least 2 or more of the adolescent and adult patients receiving Levalbuterol tartrate HFA inhalation aerosol and by a greater proportion than receiving HFA-134a placebo inhaler include cyst, flu syndrome, viral infection, constipation, gastroenteritis, myalgia, hypertension, epistaxis, lung disorder, acne, herpes simplex, conjunctivitis, ear pain, dysmenorrhea, hematuria, and vaginal moniliasis. There were no significant laboratory abnormalities observed in these studies. Pediatric Patients 4 to 11 Years of Age Adverse reaction information concerning Levalbuterol tartrate HFA inhalation aerosol in children is derived from a 4-week, randomized, double-blind trial of Levalbuterol tartrate HFA inhalation aerosol, a marketed albuterol HFA inhaler, and an HFA-134a placebo inhaler in 150 children aged 4 to 11 years with asthma. Table 2 lists the adverse reactions reported for Levalbuterol tartrate HFA inhalation aerosol in children at a rate of 2% or greater and more frequently than for placebo. Table 2: Adverse Reaction Incidence (% of Patients) in a 4-Week Clinical Trial in Children 4-11 Years of Age* Body System Preferred Term Levalbuterol tartrate HFA inhalation aerosol 90 mcg (n=76) Racemic Albuterol HFA 180 mcg (n=39) Placebo (n=35) Body as a Whole Accidental injury 9% 10% 6% Digestive System Vomiting 11% 8% 6% Respiratory System Bronchitis 3% 0% 0% Pharyngitis 7% 13% 6% * This table includes all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from the trial that occurred at a rate of 2% or greater in the group treated with Levalbuterol tartrate HFA inhalation aerosol and more frequently than in the HFA-134a placebo inhaler group. The incidence of systemic beta-adrenergic adverse reactions (e.g., tremor, nervousness) was low and comparable across all treatment groups, including placebo. 6.2 Post-marketing Experience In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been observed in post-approval use of levalbuterol inhalation solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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, dysphonia, dyspnea, gastrooesophageal reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, urticaria. In addition, Levalbuterol tartrate HFA inhalation aerosol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, headache, and drying or irritation of the oropharynx.

• Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with Levalbuterol tartrate 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.
• Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs : May potentiate effect. ( 7 )
• Beta-blockers : May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. Patients with asthma should not normally be treated with beta-blockers. ( 7.1 )
• Diuretics : May worsen electrocardiographic changes or hypokalemia associated with diuretics may worsen. Consider monitoring potassium levels. ( 7.2 )
• Digoxin : May decrease serum digoxin levels. Consider monitoring digoxin levels. ( 7.3 )
• Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants : May potentiate effect of albuterol on the cardiovascular system. ( 7.4 ) 7.1 Beta-blockers Beta-blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists, such as Levalbuterol tartrate 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. 7.2 Diuretics The ECG changes 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. Consider monitoring potassium levels. 7.3 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 Levalbuterol tartrate 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 Levalbuterol tartrate HFA inhalation aerosol. 7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants Levalbuterol tartrate 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. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

• Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies of Levalbuterol tartrate HFA inhalation aerosol in pregnant women. Because animal reproduction studies are not always predictive of human response, Levalbuterol tartrate HFA inhalation aerosol 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 Levalbuterol tartrate HFA inhalation aerosol) 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/m 2 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/m 2 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/m 2 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/m 2 basis).
• Non-Teratogenic Effects: 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.

Pediatric Use Pediatric Patients 4 Years of Age and Older The safety and efficacy of Levalbuterol tartrate HFA inhalation aerosol have been established in pediatric patients 4 years of age and older in an adequate and well-controlled clinical trial. Pediatric Patients less than 4 Years of Age Levalbuterol tartrate HFA inhalation aerosol 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 Levalbuterol tartrate HFA inhalation aerosol compared to placebo. Levalbuterol tartrate HFA inhalation aerosol 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). Levalbuterol tartrate HFA inhalation aerosol 45 mcg (N=23), Levalbuterol tartrate HFA inhalation aerosol 90 mcg (N=42), levalbuterol inhalation solution 0.31 mg (N=63), and placebo HFA (N=68) were administered three times daily. Levalbuterol tartrate HFA inhalation aerosol 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 Levalbuterol tartrate HFA inhalation aerosol and placebo. Regarding safety, an increased number of treatment-emergent asthma-related adverse reactions were reported in Levalbuterol tartrate HFA inhalation aerosol-treated patients.

Eight subjects reported asthma-related adverse reactions for Levalbuterol tartrate HFA inhalation aerosol compared to 3 subjects for placebo. There was one subject that discontinued treatment due to asthma in the Levalbuterol tartrate HFA inhalation aerosol 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. Table 3: Asthma-related Adverse Reactions in a 4-Week Clinical Trial in Children Birth to <4 Years of Age* Levalbuterol tartrate HFA inhalation aerosol 45-90 mcg (n=65) Levalbuterol inhalation solution 0.31 mg (n=63) Placebo (n=68) 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

Levalbuterol tartrate HFA inhalation aerosol is contraindicated in patients with a history of hypersensitivity to levalbuterol, racemic albuterol, or any other component of Levalbuterol tartrate HFA inhalation aerosol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. Hypersensitivity to levalbuterol, racemic albuterol or any other component of Levalbuterol tartrate HFA inhalation aerosol.

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 Adverse Reactions , e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/minute, 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 Levalbuterol tartrate HFA inhalation aerosol.

Treatment consists of discontinuation of Levalbuterol tartrate HFA inhalation aerosol 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 Levalbuterol tartrate HFA inhalation aerosol.