Accuneb (Albuterol sulfate) inhalation solution is a sterile, clear, colorless solution of the sulfate salt of racemic albuterol, albuterol sulfate. Albuterol sulfate is a relatively selective beta-adrenergic bronchodilator (see ). The chemical name for albuterol sulfate is α [(tert-butylamino) methyl]-4-hydroxy-m-xylene-α, α'-diol sulfate (2:1) (salt), and its established chemical structure is as follows:

The molecular weight of albuterol sulfate is 576.7 and the empirical formula is (CHNO)•HSO. Albuterol sulfate is a white crystalline powder, soluble in water and slightly soluble in ethanol. The World Health Organization recommended name for albuterol is salbutamol.

Accuneb (Albuterol sulfate) Inhalation Solution is supplied in two strengths in unit dose vials. Each unit dose vial contains either 0.75 mg of albuterol sulfate (equivalent to 0.63 mg of albuterol) or 1.50 mg of albuterol sulfate (equivalent to 1.25 mg of albuterol) with sodium chloride and sulfuric acid in a 3-mL isotonic, sterile, aqueous solution. Sodium chloride is added to adjust isotonicity of the solution and sulfuric acid is added to adjust pH of the solution to 3.5 (see ).

Accuneb (Albuterol sulfate) Inhalation Solution does not require dilution prior to administration by nebulization. For Accuneb (Albuterol sulfate) , like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari LC Plus™ nebulizer (with face mask or mouthpiece) connected to a Pari PRONEB™ compressor, under in vitro conditions, the mean delivered dose from the mouth piece (% nominal dose) was approximately 43% of albuterol (1.25 mg strength) and 39% of albuterol (0.63 mg strength) at a mean flow rate of 3.6 L/min. The mean nebulization time was 15 minutes or less. Accuneb (Albuterol sulfate) should be administered from a jet nebulizer at an adequate flow rate, via a mouthpiece or face mask (see ).

The prime action of beta-adrenergic drugs is to stimulate adenyl cyclase, the enzyme which catalyzes the formation of cyclic-3',5'-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP). The cyclic AMP thus formed mediates the cellular responses. In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta-adrenergic receptors compared with isoproterenol. While it is recognized that beta-adrenergic receptors are the predominant receptors in bronchial smooth muscle, recent data indicate that 10% to 50% of the beta-receptors in the human heart may be beta-receptors. The precise function of these receptors, however, is not yet established. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other 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. Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-O-methyl transferase.

Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those found in whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

The safety and efficacy of Accuneb (Albuterol sulfate) was evaluated in a 4-week, multi-center, randomized, double-blind, placebo-controlled, parallel group study in 349 children 6 to 12 years of age with mild-to-moderate asthma (mean baseline FEV 60% to 70% of predicted). Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive Accuneb (Albuterol sulfate) 0.63 mg, Accuneb (Albuterol sulfate) 1.25 mg, or placebo three times a day administered via a Pari LC Plus™ nebulizer and a Pari PRONEB™ compressor. Racemic albuterol, delivered by a chlorofluorocarbon (CFC) metered dose inhaler (MDI) or nebulized, was used on an as-needed basis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline in the area under the 6-hour curve for FEV, was demonstrated for both active treatment regimens (n=112 [1.25 mg group] and n=110 [0.63 mg group]) compared with placebo (n=110) on day 1 and day 28. Figures 1 and 2 illustrate the mean percentage change from pre-dose FEV on day 1 and day 28, respectively. The mean baseline FEV for all patients was 1.49 L. 

 

The onset of a 15% increase in FEV over baseline for both doses of Accuneb (Albuterol sulfate) was seen at 30 minutes (the first post-dose assessment). The mean time to peak effect was approximately 30 to 60 minutes for both doses on day 1 and after 4 weeks of treatment. The mean duration of effect, as measured by a >15% increase from baseline in FEV, was approximately 2.5 hours for both doses on day 1 and approximately 2 hours for both doses after 4 weeks of treatment. In some patients, the duration of effect was as long as 6 hours.

Accuneb (Albuterol sulfate) is indicated for the relief of bronchospasm in patients 2 to 12 years of age with asthma (reversible obstructive airway disease).

Accuneb (Albuterol sulfate) is contraindicated in patients with a history of hypersensitivity to any of its components.

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of Accuneb (Albuterol sulfate) than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration of the possible need for anti-inflammatory treatment (e.g., corticosteroids).

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs and with the home use of nebulizers. It is, therefore, essential that the physician instruct the patient in the need for further evaluation, if his/her asthma becomes worse.

The action of Accuneb (Albuterol sulfate) may last up to six hours, and therefore it should not be used more frequently than recommended. Do not increase the dose or frequency of medication without consulting your physician. If you find that treatment with Accuneb (Albuterol sulfate) 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. All asthma medication should only be used under the supervision and direction of a physician. Common effects with medications such as Accuneb (Albuterol sulfate) include palpitations, chest pain, rapid heart rate, tremor, or nervousness.

If you are pregnant or nursing, contact your physician about the use of Accuneb (Albuterol sulfate) . Effective and safe use of Accuneb (Albuterol sulfate) includes an understanding of the way it should be administered.

If the solution in the vial changes color or becomes cloudy, you should not use it.

The drug compatibility (physical and chemical), clinical efficacy, and safety of Accuneb (Albuterol sulfate) solution, when mixed with other drugs in a nebulizer, has not been established.

See illustrated Patient's Instructions for Use.

Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with Accuneb (Albuterol sulfate) .

Accuneb (Albuterol sulfate) 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, since the action of albuterol on the vascular system may be potentiated.

Beta-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as Accuneb (Albuterol sulfate) , 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., 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.

The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, caution is advised in the co-administration of beta-agonists with non-potassium sparing diuretics.

Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single dose intravenous and oral administration of 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 albuterol 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 albuterol.

In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium and above dietary doses of 2 mg/kg (approximately equivalent to the maximum recommended daily inhalation dose for Accuneb (Albuterol sulfate) on a mg/m basis). In another study, this effect was blocked by the co-administration of propranolol, a non-selective beta-adrenergic antagonist.

In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 140 times the maximum recommended daily inhalation dose of Accuneb (Albuterol sulfate) on a mg/m basis). In a 22-month study in Golden hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 20 times the maximum recommended daily inhalation dose of Accuneb (Albuterol sulfate) on a mg/m basis).

Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH strain mouse micronucleus assay.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 30 times the maximum recommended daily inhalation dose of Accuneb (Albuterol sulfate) on a mg/m basis).

Oral albuterol has been shown to delay pre-term labor in some reports. There are presently no well-controlled studies that demonstrate that it will stop pre-term labor or prevent labor at term. Because of the potential for beta agonist interference with uterine contractility, use of Accuneb (Albuterol sulfate) for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Albuterol has not been approved for the management of pre-term labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including pulmonary edema, have been reported following administration of albuterol to women in labor.

Adverse events reported in >1% of patients receiving Accuneb (Albuterol sulfate) and more frequently than in patients receiving placebo in a four-week double-blind study are listed in the following table.

There was one case of ST segment depression in the 1.25 mg Accuneb (Albuterol sulfate) treatment group.
No clinically relevant laboratory abnormalities related to Accuneb (Albuterol sulfate) administration were seen in this study.

The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of symptoms such as seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, and exaggeration of the pharmacological effects listed in ADVERSE REACTIONS. Hypokalemia may also occur. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of Accuneb (Albuterol sulfate) . Treatment consists of discontinuation of Accuneb (Albuterol sulfate) 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 Accuneb (Albuterol sulfate) .

The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 580 times the maximum recommended daily inhalation dose of Accuneb (Albuterol sulfate) on a mg/m basis). The subcutaneous median lethal dose of albuterol sulfate in mature rats and small young rats is approximately 450 mg/kg and 2000 mg/kg, respectively (approximately 260 and 1200 times the maximum recommended daily inhalation dose of Accuneb (Albuterol sulfate) on a mg/m basis). The inhalation median lethal dose has not been determined in animals.

The usual starting dosage for patients 2 to 12 years of age is 1.25 mg or 0.63 mg of Accuneb (Albuterol sulfate) administered 3 or 4 times daily, as needed, by nebulization. More frequent administration is not recommended.

To administer 1.25 mg or 0.63 mg of albuterol, use the entire contents of one unit-dose vial (3 mL of 1.25 mg or 0.63 mg inhalation solution) by nebulization. Adjust nebulizer flow rate to deliver Accuneb (Albuterol sulfate) over 5 to 15 minutes.

The use of Accuneb (Albuterol sulfate) can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimum benefit from regular use of the inhalation solution.

Patients 6 to 12 years of age with more severe asthma (baseline FEV less than 60% predicted), weight >40 kg, or patients 11 to 12 years of age may achieve a better initial response with the 1.25 mg dose.

Accuneb (Albuterol sulfate) has not been studied in the setting of acute attacks of bronchospasm. A 2.5 mg dose of albuterol provided by a higher concentration product (2.5 mg albuterol per 3 mL) may be more appropriate for treating acute exacerbations, particularly in children 6 years old and above.

If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of seriously worsening asthma which would require reassessment of therapy.

The drug compatibility (physical and chemical), clinical efficacy and safety of Accuneb (Albuterol sulfate) solution, when mixed with other drugs in a nebulizer have not been established.

The safety and efficacy of Accuneb (Albuterol sulfate) have been established in clinical trials when administered using the Pari LC Plus™ nebulizer and Pari PRONEB™ compressor. The safety and efficacy of Accuneb (Albuterol sulfate) when administered with other nebulizer systems have not been established.

Accuneb (Albuterol sulfate) should be administered via jet nebulizer connected to an air compressor with adequate air flow, equipped with a mouthpiece or suitable face mask.

Accuneb (Albuterol sulfate) Inhalation Solution is supplied as a 3 mL, clear, colorless, sterile, preservative-free, aqueous solution in two different strengths, 0.63 mg and 1.25 mg, of albuterol (equivalent to 0.75 mg of albuterol sulfate or 1.5 mg of albuterol sulfate per 3 mL) in unit-dose low-density polyethylene (LDPE) vials. Each unit-dose LDPE vial is protected in a foil pouch, and each foil pouch contains 5 unit-dose LDPE vials. Each strength of Accuneb (Albuterol sulfate) Inhalation Solution is available in a shelf carton containing multiple foil pouches.

NDC 49502-692-03                5 foil pouches, each containing 5 vials, total 25 vials per carton

NDC 49502-693-03                5 foil pouches, each containing 5 vials, total 25 vials per carton

Rx Only.

Store Accuneb (Albuterol sulfate) between 2° and 25° C (36° and 77° F). Vials should be protected from light before use, therefore, keep unused vials in the foil pouch. Do not use after the expiration (EXP) date printed on the vial.

Accuneb (Albuterol sulfate) is supplied as a single-dose, ready-to-use vial containing 3 mL of solution. No mixing or dilution is needed. Use one new vial with each nebulizer treatment.

Instructions for Use

Dey A Mylan Company

Dey Pharma, L.P., Napa, CA 94558

03-492-27MAR 11U.S. Pat. No. 6,702,997

Accuneb (Albuterol sulfate) is a medicine that is used for the relief of bronchospasms caused by asthma in children ages 2 to 12 years. Bronchospasm is the tightening and swelling of the muscles around the airways. Accuneb (Albuterol sulfate) can help relax these airway muscles for up to 6 hours so that your child may breathe more easily.

Do not give your child Accuneb (Albuterol sulfate) if he or she is allergic to any of its ingredients. The active ingredient is albuterol sulfate. See the end of this leaflet for a complete list of ingredients.

Tell your child's doctor about all of your child's medical conditions including if your child has:

Tell your child's doctor about all the medicines your child takes, including prescription and non-prescription medicines, vitamins and herbal supplements. Accuneb (Albuterol sulfate) and some other medicines can affect each other and may cause serious side effects. Especially tell your child's doctor if your child is taking or using:

Know the medicines your child takes. Keep a list of them and show it to your child's doctor and pharmacist each time your child gets a new medicine.

Read the Patient's Instructions for Use that comes with Accuneb (Albuterol sulfate) . Ask your pharmacist for these instructions if they are not with your medicine. Keep the instructions with Accuneb (Albuterol sulfate) because you may want to read them again.

The most common side effects with Accuneb (Albuterol sulfate) include a fast or irregular heartbeat, chest pain, shakiness, or nervousness.

Medicines are sometimes prescribed for conditions that are not mentioned in the patient information leaflets. Do not use Accuneb (Albuterol sulfate) for a condition for which it was not prescribed. Do not give Accuneb (Albuterol sulfate) to other people, even if they have the same symptoms your child has. It may harm them.

This leaflet summarizes the most important information about Accuneb (Albuterol sulfate) . If you would like more information, talk with your child's doctor. You can ask your child's doctor or pharmacist for information about Accuneb (Albuterol sulfate) that is written for health professionals. You can also call the company that makes Accuneb (Albuterol sulfate) toll free at 1-800-395-3376, or visit their website at .

Dey Pharma, L.P., Napa, CA 94558; 1-800-395-3376; © 2003 Printed in U.S.A. H9-307-00 April 2006U.S. Pat. No. 6,702,997