Albuterol

Indications : Asthma

Pregnancy Category C

Top 200 Drugs; WHO Formulary

FDA Approval Pre 1982 ; Patent Expiration 2014 Feb

DRUG CLASS :

BRAND NAMES : Aerolin (Greece, Brazil, Chile); Airet (US); Airomir (Australia, France, Canada, Philippines, Thailand); Albuterol Sulfate (US); Almotex (Philippines); Anebron *; Asmadil (Benin, Burkina-Faso, Ethiopia, Gambia, Ghana, Guinea, Ivory-Coast, Kenya, Liberia, Malawi, Mali, Mauritania, Mauritius, Morocco, Niger, Nigeria, Senegal, Seychelles, Sierra-Leone, Sudan, Tanzania, Tunia, Uganda, Zambia, Zimbabwe); Asmalin *; Asmanil *; Asmasal (Thailand); Asmatol (Argentina); Asmaven (England); Asmavent (US); Asmidon (Japan); Asmol Uni-Dose (New-Zealand); Asthalin (India); Broncho-Spray (Germany, South-Africa); Broncovaleas (Italy); Bronter (Colombia); Bugonol (Colombia); Butamol *; Buto-Asma (Spain); Butotal (Chile); Buventol (US); Cobutolin (England); Dilatamol (Indonesia); Farcolin (Bahrain, Cyprus, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Oman, Qatar, Republic-of-Yemen, Saudi-Arabia, Syria, United-Arab-Emirates); Grafalin (Indonesia); Instavent (US); Libretin (Philippines); Medolin (Thailand); Mozal (Taiwan); Novosalmol (Canada); Parasma (Colombia); Proventil (US); Respax (Australia, New-Zealand, New-Zealand); Salbetol (India); Salbron (Indonesia); Salbulin (England, Costa-Rica, Dominican-Republic, El-Salvador, Guatemala, Honduras, Panama); Salbusian *; Salbutalan (Mexico); Salbutamol *; Salbutan (Venezuela); Salbutol (Peru, Korea); Salbuven (Indonesia); Salbuvent (Norway); Salmaplon (India); Salomol (Taiwan); Sedalin (Philippines); Sultanol (Germany, Austria, Japan); Suprasma (Indonesia); Theosal *; Tobybron (Indonesia); Vencronyl (Philippines); Venetlin (Japan); Ventilan (Portugal, Colombia); Ventimax (US); Ventolin (US); Ventoline (Denmark, France, Finland, Norway, Sweden); Ventolin Rotacaps (US); Volmax (US);
(International brand names outside U.S. in italics)
* Indicates foreign drugs without region specification at time of publication.

COST OF THERAPY : $ 29.23 (Asthma; Tablet; 2 mg; 3/day; 365 days)

HCFA JCODES : J7620 0.083%, per ml INH

Albuterol (Oral)

DESCRIPTION :

The World Health Organization recommended name for Albuterol base is salbutamol.

Albuterol sulfate is the racemic form of Albuterol and a relatively selective beta2-adrenergic bronchodilator. Albuterol sulfate has the chemical name (±)alpha1-[(tert -butylamino)methyl]-4-hydroxy-m -xylene-alpha,alpha-diol sulfate (2:1) (salt).

Albuterol sulfate has a molecular weight of 576.7, and the empirical formula is (C13H21NO3)2·H2SO4. Albuterol sulfate is a white crystalline powder, soluble in water and slightly soluble in ethanol.

Ventolin Tablets : Each Ventolin tablet contains 2 or 4 mg of Albuterol as 2.4 or 4.8 mg, respectively, of Albuterol sulfate for oral administration. Each tablet also contains the inactive ingredients corn starch, lactose, and magnesium stearate.

Proventil Repetabs : Each Proventil repetab extended-release tablet contains a total of 4 mg (2 mg in the coating for immediate release and 2 mg in the core for release after several hours) of Albuterol as 4.8 mg of Albuterol sulfate. The inactive ingredients for Proventil Repetabs (extended-release) tablets include: acacia, butylparaben, calcium phosphate, calcium sulfate, carnauba wax, corn starch, lactose, magnesium stearate, neutral soap, oleic acid, rosin, sugar, talc, titanium dioxide, white wax, and zein.

Ventolin Syrup : Ventolin syrup contains 2 mg of Albuterol as 2.4 mg of Albuterol sulfate in each teaspoonful (5 ml). The inactive ingredients for Ventolin syrup include: citric acid, FD&C yellow no. 6, flavor, hydroxypropyl methylcellulose, saccharin, sodium benzoate, sodium citrate, and water.

CLINICAL PHARMACOLOGY :

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.

Albuterol Syrup

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. Based on pharmacologic studies in animals, Albuterol appears to exert direct and preferential action on beta2-adrenoceptors, including those of the bronchial tree and uterus, and may have less cardiac stimulant effect than isoproterenol when given in the usual recommended dose.

After oral administration of 10 ml of Albuterol syrup (4 mg of Albuterol) in normal volunteers, Albuterol is rapidly absorbed. Maximum plasma Albuterol concentrations of about 18 ng/ml are achieved within 2 hours, and the drug is eliminated with a half-life of about 5 hours. In other studies, the analysis of urine samples of patients given 8 mg of titrated Albuterol orally showed that 76% of the dose was excreted over 3 days, with the majority of the dose being excreted within the first 24 hours. Sixty percent of this radioactivity was shown to be the metabolite. Feces collected over this period contained 4% of the administered dose.

Animal studies show that Albuterol does not pass the blood-brain barrier.

Tablets

In vitro studies and in vivo pharmacologic studies have demonstrated that Albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established (see WARNINGS).

Immediate-Release Tablets

The pharmacologic effects of beta-adrenergic agonist drugs, including Albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3, 5-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects.

Preclinical : Intravenous studies in rats with Albuterol sulfate have demonstrated that Albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the brain barrier (pineal and pituitary glands), Albuterol concentrations were found to be 100 times those in the 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 were administered concurrently. The clinical significance of these findings is currently unknown.

Pharmacokinetics : Albuterol is rapidly absorbed following oral administration of 4 mg Albuterol tablets in normal volunteers. Maximum plasma concentrations of about 18 ng/ml of Albuterol are achieved within 2 hours, and the drug eliminated with a half-life of about 5 hours.

In other studies, the analysis of urine samples of patients given 8 mg of titrated Albuterol orally showed that 76% of the dose was excreted over 3 days, with the majority of the dose being excreted within the first 24 hours. Sixty percent of this radioactivity was shown to be the metabolite. Feces collected over this period contained 4% of the administered dose.

Extended-Release Tablets

Animal studies show that Albuterol does not pass the blood-brain barrier. Studies in laboratory animals (minipigs, rodents, and dogs) recorded the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanimines were administered concurrently. The significance of these findings when applied to humans is currently unknown.

Albuterol extended-release tablets have been formulated to provide a duration of action of up to 12 hours. In studies conducted in normal adult volunteers, the mean steady-state peak and trough plasma levels of Albuterol were 6.5 and 3.0 ng/ml, respectively, following dosing with a 4 mg Albuterol extended-release tablet every 12 hours. In addition, it has been shown that administration of a 4 mg Albuterol extended-release tablet every 12 hours and a 2 mg Albuterol tablet every 6 hours for 5 days gave comparable peak Albuterol levels and similar extent of absorption at steady state.

Pharmacokinetics : Albuterol is rapidly and well absorbed following oral administration. In studies involving normal volunteers, the mean steady-state peak and trough plasma levels of Albuterol were 6.7 and 3.8 ng/ml, respectively, following dosing with a 2 mg Albuterol tablet every 6 hours and 14.8 and 8.6 ng/ml, respectively, following dosing with a 4 mg Albuterol tablet every 6 hours. Maximum Albuterol plasma levels are usually obtained between 2 and 3 hours after dosing and the elimination half-life is 5 to 6 hours. These data indicate that Albuterol, administered orally, is dose proportional and exhibits dose independent pharmacokinetics.

In other studies, the analysis of urine samples of patients given titrated Albuterol (4-10 mg) orally showed that 65% to 90% of the dose was excreted over 3 days, with the majority of the dose being excreted within the first 24 hours. Sixty percent of this radioactivity was shown to be the metabolite of Albuterol. Feces collected over this period contained 4% of the administered dose.

CLINICAL STUDIES :

In controlled clinical trials in patients with asthma, the onset of improvement in pulmonary function, as measured by maximal midexpiratory flow rate (MMEF), was within 30 minutes after a dose of Albuterol tablets, with peak improvement occurring between 2 and 3 hours. In controlled clinical trials in which measurements were conducted for 6 hours, clinically significant improvement (defined as maintaining a 15% or more increase in forced expiratory volume in 1 second [FEV1] and a 20% or more increase in MMEF over baseline values) was observed in 60% of patients at 4 hours and in 40% at 6 hours. In other single-dose, controlled clinical trials, clinically significant improvement was observed in at least 40% of the patients at 8 hours. No decrease in the effectiveness of Albuterol tablets was reported in patients who received long-term treatment with the drug in uncontrolled studies of periods for 6 months.

Syrup : In controlled clinical trials in patients with asthma, the onset of improvement in pulmonary function, as measured by maximum midexpiratory flow rate (MMEF) and forced expiratory volume in 1 second (FEV1), was within 30 minutes after a dose of Albuterol syrup. Peak improvement of pulmonary function occurred between 2 and 3 hours. In a controlled clinical trial involving 55 children, clinically significant improvement (defined as maintenance of mean values over baseline of 15% or 20% or more in the FEV1 and MMEF, respectively) continued to be recorded up to 6 hours. No decrease in the effectiveness was reported in one uncontrolled study of 32 children who took Albuterol syrup for a 3-month period.

Additional Information for Extended-Release Tablets : In another controlled clinical study in adult asthmatic patients, it has been demonstrated that the initiation of therapy with either the 4 mg Albuterol extended-release tablet dosed every 12 hours, or the 2 mg Albuterol immediate-release tablet dosed every 6 hours, achieve therapeutically equivalent effects.

INDICATIONS AND USAGE :

Albuterol immediate-release tablets and extended-release tablets are indicated for the relief of bronchospasm in adults and children 6 years of age and older with reversible obstructive airway disease.

Albuterol syrup is indicated for the relief of bronchospasm in adults and in children 2 years of age and older with reversible obstructive airway disease.

CONTRAINDICATIONS :

Albuterol formulations are contraindicated in patients with a history of hypersensitivity to any of its components.

WARNINGS :

Syrup

Immediate hypersensitivity reactions may occur after administration of Albuterol, as demonstrated by rare cases of anaphylaxis, angioedema, oropharyngeal edema, bronchospasm, urticaria and rash.

Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with the administration of Albuterol sulfate syrup in children.

Immediate-Release Tablets

Paradoxical Bronchospasm : Albuterol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, Albuterol should be discontinued immediately and alternative therapy instituted.

Cardiovascular Effects : Albuterol, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of Albuterol 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, Albuterol like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

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 Albuterol 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 regimen, giving special consideration to the possible need for anti-inflammatory treatment (e.g., corticosteroids).

Use of Anti-Inflammatory Agents : The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents (e.g., corticosteroids).

Immediate Hypersensitivity Reactions : Immediate hypersensitivity reactions may occur after administration of Albuterol, as demonstrated by rare cases or urticaria, angiodema, rash, bronchospasm, and oropharyngeal edema. Albuterol, like other beta-adrenergic agonists, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with the administration of oral Albuterol sulfate in children.

PRECAUTIONS :

General

Syrup : Although Albuterol usually has minimal effects on the beta1-adrenoceptors of the cardiovascular system at the recommended dosage, occasionally the usual cardiovascular and CNS stimulatory effects common to all sympathomimetic agents have been seen with patients treated with Albuterol necessitating discontinuation.

Syrup, Tablets and Extended-Release Tablets : Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, including (Extended-Release Tablets Only: ischemic heart disease, (Syrup and Immediate-Release Tablets Only: coronary insufficiency), hypertension, or cardiac arrhythmias, in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Tablets: 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 use of any beta-adrenergic bronchodilator.

Large doses of intravenous Albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, Albuterol may produce significant hypokalemia in some patients through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

Information for the Patient

Syrup : The action of Albuterol syrup may last up to 6 hours and therefore it should not be taken more frequently than recommended. Do not increase the dose or frequency of medication without medical consultation. If symptoms get worse, medical consultation should be sought promptly. If pregnant or nursing, consult with your physician.

Immediate-Release Tablets : The action of Albuterol immediate-release tablets may last up to 8 hours or longer. Albuterol should not be taken more frequently than recommended. Do not increase the dose or frequency of Albuterol tablets without consulting your physician. If you find that treatment with Albuterol becomes less effective for symptomatic relief, your symptoms get worse, and/or you need to take the product more frequently than usual, you should seek medical attention immediately. While you are taking Albuterol, other asthma medications and inhaled drugs should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, and tremor or nervousness. If you are pregnant or nursing, contact your physician about use of Albuterol. Effective and safe use of Albuterol includes an understanding of the way that it should be administered.

Extended-Release Tablets : Patients being treated with Albuterol extended-release tablets should receive the following information and instructions. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Albuterol extended-release tablets should not be chewed, crushed or mixed in food.

Albuterol extended-release tablets should not be taken more frequently than recommended. Do not increase the dose or frequency of medication, or add other medications to your therapy without medical consultation. If symptoms get worse, medical consultation should be sought promptly. If pregnant or nursing, consult your physician.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
Extended-Release Tablets and Syrup

Albuterol sulfate, like other agents in its class, caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium in a 2-year study in the rat, at doses corresponding to 3, 16, and 78 times the maximum human oral dose (or in syrup, 2, 9, and 46 times the maximum human [child weighing 21 kg] oral dose). In another study this effect was blocked by the coadministration of propranolol. The relevance of these findings to humans is not known. An 18-month study in mice and a lifetime study in hamsters revealed no evidence of tumorigenicity. Studies with Albuterol revealed no evidence of mutagenesis. Reproduction studies in rats revealed no evidence of impaired fertility.

Immediate-Release Tablets

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 at dietary doses of 2.0, 10, and 50 mg/kg (approximately ½, 3, and 15 times, respectively, the maximum recommended daily oral dose for adults on a mg/m2 basis or 2/5, 2, and 10 times, respectively, the maximum recommended daily oral dose for children on a mg/m2 basis. In another study this effect was blocked by the coadministration 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 of up to 500 mg/kg (approximately 65 times the maximum recommended daily oral dose for adults on a mg/m2 basis or approximately 50 times the maximum recommended daily oral dose for children on a mg/m2 basis). In a 22-month study in the Golden hamster, Albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 8 times the maximum recommended daily oral dose for adults on a mg/m2 basis or approximately 7 times the maximum recommended daily oral dose for children on a mg/m2 basis).

Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester strains S. typhimurium TA1537, TA1538, and TA98 or E. coli WP2, WP2UVRA, and WP67. No forward mutation was seen in yeast strain S. cerevisiae S9 nor any mitotic gene conversion in yeast strain S. cerevisiae JD1 with or without metabolic activation. Fluctuation assays in S. typhimurium TA98 and E. coli WP2, both with metabolic activation, were negative. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 15 times the maximum recommended daily oral dose for adults on a mg/m 2 basis).

Pregnancy, Teratogenic Effects, Pregnancy Category C

Albuterol has been shown to be teratogenic in mice when given subcutaneously in doses corresponding to 0.4 times the maximum human oral dose [in syrup 0.2 times the maximum human [child weighing 21 kg] oral dose). There are no adequate and well-controlled studies in pregnant women. Albuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg (approximately 3/1000, 3/100, and 3/10 times, respectively, the maximum recommended daily oral dose for adults on a mg/m2 basis) showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg. The drug did not induce cleft palate formation at the lowest dose, at 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg isoproterenol (positive control) subcutaneous (approximately 3/10 times the maximum recommended daily oral dose for adults on a mg/m2 basis. A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses at 50 mg/kg, corresponding to 78 times the maximum human oral dose of Albuterol (in syrup, 46 times the maximum human [child weighing 21 kg] oral dose of Albuterol sulfate).

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

Labor and Delivery

Syrup and Extended-Release Tablets : Oral Albuterol has been shown to delay preterm labor in some reports. There are presently no well-controlled studies that demonstrate that it will stop preterm labor or prevent labor at term. Therefore, cautious use of Albuterol is required in pregnant patients when given for relief of bronchospasm so as to avoid interference with uterine contractility. Use in such patients should be restricted to those patients in whom the benefits clearly outweigh the risks.

Immediate-Release Tablets : Because of the potential for beta-agonist interference with uterine contractility, use of Albuterol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Tocolysis: Albuterol has not been approved for the management of preterm labor. The benefit:risk ration when Albuterol 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 Albuterol.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for Albuterol in some animal studies, 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.

Pediatric Use

Syrup : Safety and effectiveness in children below the age of 2 years have not yet been adequately demonstrated.

Immediate-Release Tablets : Safety and effectiveness in children below the age of 6 years for Albuterol have not been established.

Extended-Release Tablets : The safety and effectiveness of Albuterol extended-release tablets have been established in pediatric patients 6 years of age and older. Use of Albuterol extended-release tablets in these age groups is supported by evidence from adequate and well-controlled studies of Albuterol extended-release tablets in adults; the likelihood that the disease course, pathophysiology, and the drug’s effect in pediatric and adult patients are substantially similar; the established safety and effectiveness of Albuterol immediate-release tablets in pediatric patients 6 years of age and older; and one clinical trial that provides evidence of the safety of Albuterol extended-release tablets in pediatric patients aged 6 to 12 years. The recommended dose of Albuterol extended-release tablets for the pediatric population is based upon the recommended pediatric dosing of Albuterol immediate-release tablets and pharmacokinetic studies in adults showing Albuterol extended-release tablets to have similar peak Albuterol levels (i.e., Cmax) and exposures (i.e., AUC) as Albuterol immediate-release tablets administered every 6 hours at one-half of the Albuterol extended-release tablets dose. Safety and effectiveness in children below the age of 6 years have not been established for Albuterol extended-release tablets.

DRUG INTERACTIONS :

Syrup and Tablets

The concomitant use of Albuterol and other oral sympathomimetic agents is not recommended since such combined use may lead to deleterious cardiovascular effects. This recommendation does not preclude the judicious use of an aerosol bronchodilator of the adrenergic stimulant type in patients receiving Albuterol tablets or syrup. Such concomitant use, however, should be individualized and not given on a routine basis. If regular coadministration is required, then alternative therapy should be considered.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants : Albuterol 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.

Syrup and Extended-Release Tablets

Beta-receptor blocking agents and Albuterol inhibit the effect of each other.

Since Albuterol may lower serum potassium, care should be taken in patients also using other drugs which lower serum potassium as the effects may be additive.

After single-dose administration of Albuterol to normal volunteers who had received digoxin for 10 days, a 16% to 22% decrease in serum digoxin levels was demonstrated. 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 concurrently receiving digoxin and Albuterol.

Tablets

Beta-Blockers : Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as Albuterol, 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 could be considered, although they should be administered with caution.

Diuretics : The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or 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 nonpotassium-sparing diuretics.

Digoxin : 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 concurrently receiving digoxin and Albuterol.

ADVERSE REACTIONS

: Syrup and Tablets

In addition to the reactions listed separately below, Albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vomiting, vertigo, CNS stimulation, unusual taste, and drying or irritation of the oropharynx.

The reactions are generally transient in nature, and it is usually not necessary to discontinue treatment with Albuterol. In selected cases, however, dosage may be reduced temporarily; after the reaction has subsided, dosage should be increased in small increments to the optimal dosage.

Syrup

The adverse reactions to Albuterol are similar in nature to those to other sympathomimetic agents. The most frequent adverse reactions to Albuterol syrup in adults and older children were tremor, 10 of 100 patients; nervousness and shakiness, each 9 of 100 patients. Other reported adverse reactions were headache, 4 of 100 patients; dizziness and increased appetite, each 3 of 100 patients; hyperactivity and excitement, each 2 of 100 patients; tachycardia, epistaxis, irritable behavior, and sleeplessness, each 1 of 100 patients. The following adverse effects occurred in less than 1 of 100 patients each: muscle spasm; disturbed sleep; epigastric pain; cough; palpitations; stomach ache; irritable behavior; dilated pupils; sweating; chest pain; weakness.

In young children 2 to 6 years of age, some adverse reactions were noted more frequently than in adults and older children. Excitement was noted in approximately 20% of patients and nervousness in 15%. Hyperkinesia occurred in 4% of patients; insomnia, tachycardia, and gastrointestinal symptoms in 2% each. Anorexia, emotional lability, pallor, fatigue, and conjunctivitis were seen in 1%.

Immediate-Release Tablets

In clinical trials, the most frequent adverse reactions to Albuterol tablets were as shown in TABLE 1.

TABLE 1 Percent Incidence of Adverse Reactions
Reaction
Percent Incidence
Central Nervous System
Nervousness
20%
Tremor
20%
Headache
7%
Sleeplessness
2%
Weakness
2%
Dizziness
2%
Drowsiness
<1%
Restlessness
<1%
Irritability
<1%
Cardiovascular
Tachycardia
5%
Palpitations
5%
Chest discomfort
<1%
Flushing
<1%
Musculoskeletal
Muscle cramps
3%
Gastrointestinal
Nausea
2%
Genitourinary
Difficulty in micturition
<1%

 

Cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported after the use of Albuterol immediate-release tablets.

Extended-Release Tablets

The adverse reactions to Albuterol are similar in nature to those of other sympathomimetic agents. The most frequent adverse reactions to Albuterol tablets were nervousness and tremor, with each occurring in approximately 20 of 100 patients (20%). Other reported reactions were headache, 7 of 100 patients (7%); tachycardia and palpitations, 5 of 100 patients (5%); muscle cramps, 3 of 100 patients (3%); insomnia, nausea, weakness, and dizziness, each occurred in 2 of 100 patients (2%). Drowsiness, flushing, restlessness, irritability, chest discomfort, and difficulty in micturition each occurred in fewer than 1 of 100 patients (less than 1%).

In a clinical study of 1 week duration comparing a 4 mg Albuterol extended-release tablet administered every 12 hours to a 2 mg Albuterol immediate-release tablet administered every 6 hours, the following adverse reactions considered to be possibly or probably treatment related were reported: nervousness in 1 of 50 (2%) and 3 of 50 patients (6%) for Albuterol extended-release and Albuterol immediate-release tablets, respectively; nausea in 2 of 50 (4%) for both; vomiting in 1 of 50 (2%) and 2 of 50 (4%) for Albuterol extended-release and Albuterol immediate-release tablets, respectively; somnolence in 1 of 50 (2%) for both. The following adverse reactions were reported for Albuterol immediate-release tablets only: tremor in 3 of 50 patients (6%), tinnitus, dyspepsia, and rash each occurred in 1 of 50 patients (2%).

Although not reported for Albuterol extended-release tablets in the above study, there have been reports of tremor in other trials. When all clinical experience is considered, the incidence of tremor is approximately the same as that seen with Albuterol tablets.

A placebo-controlled trial of 4 weeks duration in 157 mild-to-moderate asthmatic children aged 6 to 12 years, demonstrated the safety of escalating doses of Albuterol extended-release tablets. In this study, the starting dose of Albuterol extended-release tablets was 4 mg twice daily. Patients were advanced to a maximum of 12 mg Albuterol extended-release tablets twice daily by the investigator, based on patient tolerance and response. Only one of the 79 children treated with Albuterol extended-release tablets advanced to the maximum daily dose of 12 mg twice daily. The following treatment-related adverse events occurred in more than 5% of treated patients and were greater in Albuterol extended-release tablets patients when compared to placebo: headache (22% Albuterol extended-release tablets, 9% placebo); tremor (10% Albuterol extended-release tablets, 1% placebo); tachycardia and palpitations (8% Albuterol extended-release tablets, 1% placebo); and nervousness (13% Albuterol extended-release tablets, 6% placebo). Other adverse events were found in 5% or fewer patients, or had equal or greater rates of occurrence in placebo patients than in Albuterol extended-release tablets patients.

OVERDOSAGE :

Syrup and Extended-Release Tablets : Manifestations of overdosage include anginal pain, hypertension, hypokalemia, and exaggeration of the effects listed in ADVERSE REACTIONS.

The oral LD50 in rats and mice was greater than 2000 mg/kg.

There is insufficient evidence to determine if dialysis is beneficial for overdosage of Albuterol tablets.

Syrup : Dialysis is not appropriate treatment for overdosage of Albuterol syrup. The judicious use of a cardioselective beta-receptor blocker, such as metoprolol tartrate, is suggested, bearing in mind the danger of inducing an asthmatic attack.

Immediate-Release Tablets : The expected symptoms with overdosage are those of excessive beta-adrenergic 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 may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of Albuterol. Treatment consists of discontinuation of Albuterol 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 Albuterol immediate-release tablets.

The oral median lethal dose of Albuterol sulfate in mice is greater than 2000 mg/kg (approximately 250 times the maximum recommended daily oral dose for adults on a mg/m2 basis or approximately 200 times the maximum recommended daily oral dose for children on a mg/m2 basis. In mature rats, the subcutaneous median lethal dose of Albuterol sulfate is approximately 450 mg/kg (approximately 110 times the maximum recommended daily oral dose for adults on a mg/m2 basis) or approximately 90 times the maximum recommended daily oral dose for children on a mg/m2 basis). In small young rats, the subcutaneous median lethal dose is approximately 2000 mg/kg (approximately 500 times the maximum recommended daily oral dose for adults on a mg/m2 basis or approximately 400 times the maximum recommended daily oral dose for children on a mg/m2 basis).

DOSAGE AND ADMINISTRATION :

The following dosages of Albuterol immediate-release tablets and extended-release tablets are expressed in terms of Albuterol base.

Extended-Release Tablets

Usual Dose : Pediatric Patients 6 to 11 Years of Age : The usual starting dosage of Albuterol extended-release tablets is 2 mg (one tablet) every 12 hours. Adults and Pediatric Patients 12 Years and Over: The usual starting dosage of Albuterol extended-release tablets is 4 or 8 mg (one or two tablets) every 12 hours.

Dosage Adjustment in Pediatric Patients Aged 6 to 11 Years : Doses of Albuterol extended-release tablets above 4 mg twice a day should be used only when the patient fails to respond to this dose while on otherwise optimized asthma therapy. In such instances, the Albuterol extended-release tablets dose may be increased cautiously stepwise as tolerated if a favorable response does not occur with the 4 mg twice daily initial dose. The maximum recommended dose of Albuterol extended-release tablets in pediatric patients aged 6 to 11 years is 12 mg twice a day.

Dosage Adjustment in Adults and Pediatric Patients 12 Years of Age and Over : Doses of Albuterol extended-release tablets above 8 mg twice a day should be used only when the patient fails to this dose while on otherwise optimized asthma therapy. The Albuterol extended-release dose may be increased cautiously stepwise as tolerated if a favorable response does not occur with the twice daily initial dose. The maximum recommended dose of Albuterol extended-release tablets in adults and pediatric patients over 12 years of age is 16 mg twice daily.

Switching to Albuterol Extended-Release Tablets : Patients currently maintained on Albuterol immediate-release tablets can be switched to Albuterol extended-release tablets. For example, the administration of a 4 mg Albuterol extended-release tablet every 12 hours is clinically comparable to one 2 mg Albuterol immediate-release tablet every 6 hours. Multiples of this regimen up to the maximum recommended daily dose also apply.

Immediate-Release Tablets

Usual Dosage : Adults and Children Over 12 Years of Age: The usual starting dosage for adults and children 12 years and over is 2 mg or 4 mg three or four times a day. Children 6 to 12 Years of Age: The usual starting dosage for children 6 to 12 years of age is 2 mg three or four times a day.

Dosage Adjustment : Adults and Children Over 12 Years of Age: For adults and children 12 years and over, a dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4-mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. Children 6 to 12 Years of Age Who Fail to Respond to the Initial Starting Dosage of 2 mg Four Times a Day: For children from 6 to 12 years of age who fail to respond to the initial starting dosage of 2 mg four times a day, the dosage may be cautiously increased stepwise, but not to exceed 24 mg/day (given in divided doses).

Elderly Patients and Those Sensitive to Beta-Adrenergic Stimulators : An initial dosage of 2 mg three or four times a day is recommended for elderly patients and for those with a history of unusual sensitivity to beta-adrenergic stimulators. If adequate bronchodilation is not obtained, dosage may be increased gradually to as much as 8 mg three or four times a day.

The total daily dose should not exceed 32 mg in adults and children 12 years and older.

Syrup

The following dosages of Albuterol syrup are expressed in terms of Albuterol base.

Usual Dosage : The usual starting dosage for adults and children over 14 years of age is 2 mg (1 teaspoonful) or 4 mg (2 teaspoonfuls) three or four times a day.

The usual starting dosage for children 6 to 14 years of age is 2 mg (1 teaspoonful) three or four times a day.

For children 2 to 6 years of age, dosing should be initiated at 0.1 mg/kg of body weight three times a day. This starting dosage should not exceed 2 mg (1 teaspoonful) three times a day.

Dosage Adjustment : For adults and children over age 14, a dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur, the dosage may be cautiously increased stepwise, but the dosage should not exceed 8 mg four times a day.

For children from 6 to 14 years of age who fail to respond to the initial starting dosage of 2 mg four times a day, the dosage may be cautiously increased stepwise, but not to exceed 24 mg per day (given in divided doses).

For children 2 to 6 years of age who do not respond satisfactorily to the initial dosage, the dosage may be increased stepwise to 0.2 mg/kg of body weight three times a day, but not to exceed a maximum of 4 mg (2 teaspoonfuls) given three times a day.

For elderly patients and those sensitive to beta-adrenergic stimulation, the initial dosage should be restricted to 2 mg three or four times a day and individually adjusted thereafter.

HOW SUPPLIED :

Ventolin Tablets

Ventolin 2 mg Tablets : Contain 2 mg of Albuterol as the sulfate, are white, round, compressed tablets impressed with the product name (VENTOLIN) and the number 2 on one side and scored on the other with “GLAXO” impressed on each side of the score.

Ventolin 4 mg Tablets : Contain 4 mg of Albuterol as the sulfate, are white, round, compressed tablets impressed with the product name (VENTOLIN) and the number 4 on one side and scored on the other with “GLAXO” impressed on each side of the score.

Storage : Store between 2-25°C (36-77°F). Replace cap securely after each opening.

Proventil Repetabs

Proventil 4 mg Repetabs : Contain 4 mg Albuterol as the sulfate, white, round, compressed tablets, impressed with the product name (PROVENTIL) and the number 4 on one side, and product identification numbers, 573, and scored on the other.

Storage : Store between 2-25°C (36-77°F). Protect Proventil Repetabs from excessive moisture.

Ventolin Syrup

Syrup is a clear, orange-yellow liquid with a strawberry flavor. It contains 2 mg Albuterol as the sulfate per 5 ml.

Storage : Store between 2-30°C (36-86°F).

Albuterol (Inhalation)

DESCRIPTION :

The World Health Organization recommended name for Albuterol base is salbutamol.

Inhalation Aerosol

The active component of this formulation is Albuterol racemic (alpha1-[(tert -butylamino)methyl]-4-hydroxy-m -xylene-alpha, alpha-diol) and a relatively selective beta2-adrenergic bronchodilator. The molecular weight is 239.3 and the empirical formula is C13H21NO3. Albuterol is a white to off-white crystalline solid. It is soluble in ethanol, sparingly soluble in water, and very soluble in chloroform.

Ventolin inhalation aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline (95% 10 mum) suspension of Albuterol in propellants (trichloromonofluoromethane and dichlorodifluoromethane) with oleic acid. Each actuation delivers 100 mcg of Albuterol from the valve and 90 mcg of Albuterol from the mouthpiece. Each 6.8-g canister provides 80 inhalations and each 17-g canister provides 200 inhalations.

Inhalation Solutions and Capsules for Inhalation

The active component in these Albuterol inhalation formulations is Albuterol sulfate, the racemic form of Albuterol and a relatively selective beta2-adrenergic bronchodilator. It has the chemical name (alpha1-[(tert -butylamino)methyl]-4-hydroxy-m -xylene-alpha, alpha-diol) (2:1)(salt). Albuterol sulfate has a molecular weight of 576.7 and the empirical formula is C13H21NO3·H2SO4. Albuterol sulfate is a white crystalline powder, soluble in water and slightly soluble in ethanol.

Ventolin Inhalation Solution, 0.5% : Ventolin inhalation solution, 0.5% is in concentrated form. Dilute the appropriate volume of the solution (see DOSAGE AND ADMINISTRATION) with sterile normal saline solution to a total volume of 3 ml and administer by nebulization. Each milliliter of Ventolin inhalation solution contains 5 mg of Albuterol (as 6 mg of Albuterol sulfate) in an aqueous solution containing benzalkonium chloride; sulfuric acid is used to adjust the pH to between 3 and 5. Ventolin inhalation solution contains no sulfiting agents and is a clear, colorless to light yellow solution.

Ventolin Nebules Inhalation Solution, 0.083% : Ventolin Nebules inhalation solution requires no dilution before administration by nebulization. Each milliliter of Ventolin Nebules inhalation solution contains 0.83 mg of Albuterol (as 1 mg of Albuterol sulfate) in an isotonic, sterile, aqueous solution containing sodium chloride; sulfuric acid is used to adjust the pH to between 3 and 5. Ventolin Nebules inhalation solution contains no sulfiting agents or preservatives and is a clear, colorless solution.

Ventolin Rotacaps : Ventolin Rotacaps for inhalation contain a dry powder presentation of Albuterol sulfate intended for oral inhalation only. Each light blue and clear, hard gelatin capsule contains a mixture of 200 mcg of microfine (95% 10 mum) Albuterol (as the sulfate) with 25 mg of lactose. The contents of each capsule are inhaled using a specially designed plastic device for inhaling powder called the Rotahaler. When turned, this device opens the capsule and facilitates dispersion of the Albuterol sulfate into the airstream created when the patient inhales through the mouthpiece. Ventolin Rotacaps for inhalation are an alternative inhalation form of Albuterol to the metered-dose pressurized inhaler.

CLINICAL PHARMACOLOGY :

In vitro studies and in vivo pharmacologic studies have demonstrated that Albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established (see WARNINGS).

The pharmacologic effects of beta-adrenergic agonist drugs, including Albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic- 3, 5-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects.

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.

Additional Information for Inhalation Aerosol : The effects of rising doses of Albuterol and isoproterenol aerosols were studied in volunteers and asthmatic patients. Results in normal volunteers indicated that Albuterol is one half to one quarter as active as isoproterenol in producing increases in heart rate. In asthmatic patients similar cardiovascular differentiation between the two drugs was also seen.

Pharmacokinetics

Inhalation Aerosol and Capsules for Inhalation : Because of its gradual absorption from the bronchi, systemic levels of Albuterol inhalation aerosol are low after inhalation of recommended doses. Studies undertaken with four subjects administered tritiated Albuterol resulted in maximum plasma concentrations occurring within 2 to 4 hours. Due to the sensitivity of the assay method, the metabolic rate and half-life of elimination of Albuterol in plasma could not be determined. However, urinary excretion provided data indicating that Albuterol has an elimination half-life of 3.8 hours. Approximately 72% of the inhaled dose is excreted within 24 hours in the urine, and consists of 28% as unchanged drug and 44% as metabolite.

Inhalation Solution : Studies in asthmatic patients have shown that less than 20% of a single Albuterol dose was absorbed following either intermittent positive-pressure breathing (IPPB) or nebulizer administration; the remaining amount was recovered from the nebulizer and apparatus and expired air. Most of the absorbed dose was recovered in the urine 24 hours after drug administration. Following a 3-mg dose of nebulized Albuterol in adults, the maximal Albuterol plasma levels at 0.5 hours were 2.1 ng/ml (range, 1.4 to 3.2 ng/ml). There was a significant dose-related response in FEV1 (forced expiratory volume in 1 second) and peak flow rate. It has been demonstrated that following oral administration of 4 mg of Albuterol, the elimination half-life was 5 to 6 hours.

Preclinical

Intravenous studies in rats with Albuterol sulfate have demonstrated that Albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the brain barrier (pineal and pituitary glands), Albuterol concentrations were found to be 100 times those in the 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 were administered concurrently. The clinical significance of these findings is unknown.

CLINICAL STUDIES :

Inhalation Aerosol

In controlled clinical trials involving adults with asthma, the onset of improvement in pulmonary function was within 15 minutes, as determined by both MMEF (maximum midexpiratory flow rate) and FEV1 (forced expiratory volume in 1 second). MMEF measurements also showed that near maximum improvement in pulmonary function generally occurs within 60 to 90 minutes following two inhalations of Albuterol and that clinically significant improvement generally continues for 3 to 4 hours in most patients. Some patients showed a therapeutic response (defined by maintaining FEV1 values 15% or more above baseline) that was still apparent at 6 hours. Continued effectiveness of Albuterol was demonstrated over a 13-week period in these same trials.

In controlled clinical trials involving children 4 to 12 years of age, FEV1 measurements showed that maximum improvement in pulmonary function occurs within 30 to 60 minutes. The onset of clinically significant (15%) improvement in FEV1 was observed as soon as 5 minutes following 180 mcg of Albuterol in 18 of 30 (60%) children in a controlled dose-ranging study. Clinically significant improvement in FEV1 continued in the majority of patients for 2 hours and in 33% to 47% for 4 hours among 56 patients receiving inhalation aerosol in one pediatric study. In a second study among 48 patients receiving inhalation aerosol, clinically significant improvement continued in the majority for up to 1 hour and in 23% to 40% for 4 hours. In addition, at least 50% of the patients in both studies achieved an improvement in FEF25%-75% (forced expiratory flow rate between 25% and 75% of the forced vital capacity) of at least 20% for 2 to 5 hours. Continued effectiveness of Albuterol was demonstrated over the 12-week study period.

In other clinical studies in adults and children, two inhalations of Albuterol inhalation aerosol taken approximately 15 minutes before exercise prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV1 within 80% of baseline values in the majority of patients. One study in adults also evaluated the duration of the prophylactic effect to repeated exercise challenges, which was evident at 4 hours in the majority of patients and at 6 hours in approximately one third of the patients.

Inhalation Solution

In controlled clinical trials in adults, most patients exhibited an onset of improvement in pulmonary function within 5 minutes as determined by FEV1. FEV1 measurements also showed that the maximum average improvement in pulmonary function usually occurred at approximately 1 hour following inhalation of 2.5 mg of Albuterol by compressor-nebulizer and remained close to peak for 2 hours. Clinically significant improvement in pulmonary function (defined as maintenance of a 15% or more increase in FEV1 over baseline values) continued for 3 to 4 hours in most patients, with some patients continuing up to 6 hours.

Published reports of trials in asthmatic children aged 3 years or older have demonstrated significant improvement in either FEV1 or PEFR within 2 to 20 minutes following single doses of Albuterol inhalation solution. An increase of 15% or more in baseline FEV1 has been observed in children aged 5 to 11 years up to 6 hours after treatment with doses of 0.10 mg/kg or higher of Albuterol inhalation solution. Single doses of 3, 4, or 10 mg resulted in improvement in baseline PEFR that was comparable in extent and duration to a 2-mg dose, but doses above 3 mg were associated with heart rate increases of more than 10%.

Capsules for Inhalation

In single, dose-range, crossover trials with Albuterol capsules for inhalation in patients 12 years of age and older, the onset of improvement in pulmonary function was within 5 minutes as determined by a 15% increase in forced expiratory volume in 1 second (FEV1) following administration of either a 200- or 400-mcg dose. Maximum increases in FEV1 occurred within 60 minutes following inhalation of either dose. The duration of effect (defined as an increase in FEV1 of 15% or greater in a single-dose study) was 1 to 2 hours after the 200-mcg dose and 3 to 4 hours after the 400 mcg dose. In a single-dose study, an increase in forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF25%-75%) of 20% or greater continued for 3 to 4 hours after the 200-mcg dose and for 3 to 6 hours following the 400 mcg dose. A therapeutic response continued for 4 hours in the majority of patients and for 6 hours in 38% of the patients following the 400-mcg dose. Twenty-two percent of the patients receiving the 200-mcg dose had a duration of effect of 8 hours.

In 12-week, double-blind, comparative evaluations in patients 12 years of age and older of one 200-mcg Albuterol capsule for inhalation versus two inhalations of Albuterol inhalation aerosol, the two dosage regimens were found to be clinically comparable. Based on a 15% or more increase in FEV1 determinations, both provided a therapeutic response that persisted for 2 or 3 hours in 50% of 231 patients aged 12 years and older. Similar results were found in two controlled, 12-week clinical trials involving 204 children aged 4 to 11 years. Both formulations produced a therapeutic response (defined as maintenance of mean increase over baseline of at least 15% in FEV1, or 20% in FEF25%- 75%). Therapeutic improvement of FEF25%-75% persisted for 3 to 5 hours in over 50% of the children throughout the study. Continued effectiveness and safety of Albuterol capsules for inhalation were demonstrated over the 12-week study periods in both adults and children.

In other clinical studies in adults and children, one 200-mcg Albuterol capsule for inhalation taken approximately 15 minutes before exercise prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV1 within 80% of baseline values in the majority of patients. One study in adults also evaluated the duration of the prophylactic effect to repeated exercise challenges, which was evident at 4 hours in the majority of patients and at 6 hours in approximately one third of the patients.

INDICATIONS AND USAGE :

Inhalation Aerosol and Capsules for Inhalation : Albuterol inhalation aerosol is indicated for the prevention and relief of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm in patients 4 years of age and older. The capsules for inhalation formulation is particularly useful in patients who are unable to properly use the pressurized aerosol form of Albuterol or who prefer an alternative formulation.

Albuterol inhalation aerosol can be used with or without concomitant steroid therapy.

Inhalation Solution : Albuterol inhalation solution is indicated for the relief of bronchospasm in patients 2 years of age or older with reversible obstructive airway disease and acute attacks of bronchospasm.

CONTRAINDICATIONS :

Albuterol formulations are contraindicated in patients with a history of hypersensitivity to Albuterol or any of the formulation components.

WARNINGS :

Paradoxical Bronchospasm : Albuterol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, Albuterol 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 or vial. Solutions: 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.

Cardiovascular Effects : Albuterol, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of Albuterol 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, Albuterol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

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 Albuterol 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).

Immediate Hypersensitivity Reactions : Immediate hypersensitivity reactions may occur after administration of Albuterol, as demonstrated by rare cases or urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema and, for inhalation aerosol and capsules for inhalation, anaphylaxis.

Use of Anti-Inflammatory Agents : The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents (e.g., corticosteroids).

Additional Information for Inhalation Aerosol : The contents of Albuterol inhalation aerosol are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children.

Additional Information for Inhalation Solution 0.05% : Microbial Contamination: To avoid microbial contamination, proper aseptic technique should be used each time the bottle is opened. Precautions should be taken to prevent contact of the dropper tip of the bottle with any surface, including the nebulizer reservoir and associated ventilatory equipment. In addition, if the solution changes color or becomes cloudy, it should not be used.

Additional Information for Inhalation Capsules : Inhalation of capsule particles may result if damage to the capsule has occurred from handling by the patient.

PRECAUTIONS :

General

Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous Albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, Albuterol 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. Inhalation Aerosol and Inhalation Solutions: 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 use of any beta-adrenergic bronchodilator.

Additional Information for Inhalation Aerosol : Although there have been no reports concerning the use of Albuterol inhalation aerosol during labor and delivery, it has been reported that high doses of Albuterol administered intravenously inhibit uterine contractions. Although this effect is extremely unlikely as a consequence of aerosol use, it should be kept in mind.

Additional Information for Inhalation Solution : Repeated dosing with 0.15 mg/kg of Albuterol inhalation solution in children aged 5 to 17 years who were initially normokalemic has been associated with an asymptomatic decline of 20% to 25% in serum potassium levels.

Information for the Patient

The action of Albuterol may last up to 6 hours or longer. Albuterol should not be used more frequently than recommended. Do not increase the dose or frequency of Albuterol without consulting your physician. If you find that treatment with Albuterol 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 Albuterol, 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, and tremor or nervousness. If you are pregnant or nursing, contact your physician about use of Albuterol. Effective and safe use of Albuterol includes an understanding of the way that it should be administered.

Additional Information for Inhalation Aerosol : In general, the technique for administering Albuterol inhalation aerosol to children is similar to that for adults, since children’s smaller ventilatory exchange capacity automatically provides proportionally smaller aerosol intake. Children should use Albuterol aerosol under adult supervision, as instructed by the patient’s physician. (See PATIENT PACKAGE INSERT.)

Additional Information for Inhalation Solutions : Drug compatibility (physical and chemical), efficacy, and safety of Albuterol inhalation solution when mixed with other drugs in a nebulizer have not been established. 0.05% Solution Only: To avoid microbial contamination, proper aseptic techniques should be used each time the bottle is opened. Precautions should be taken to prevent contact of the dropper tip of the bottle with any surface, including the nebulizer reservoir and associated ventilatory equipment. In addition, if the solution changes color or becomes cloudy, it should not be used.

See PATIENT PACKAGE INSERT.

Additional Information for Capsules for Inhalation : Children should use Albuterol capsules for inhalation under adult supervision, as instructed by the patient’s physician.

See PATIENT PACKAGE INSERT.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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 at dietary doses of 2.0, 10, and 50 mg/kg. [Inhalation Solutions: Approximately 2, 8, and 40 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 3/5, 3, and 15 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m2 basis.] [Capsules for Inhalation: Approximately 7, 35 and 170 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 3, 15 and 80 times, respectively, the maximum recommended daily dose in children on a mg/m2 basis.] [Inhalation Aerosol: Approximately 15, 70 and 340 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 6, 30 and 160 times, respectively, the maximum recommended daily inhalation dose for children on a mg/m2 basis.] In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, Albuterol sulfate showed no evidence of tumorgenicity at dietary doses of up to 500 mg/kg. [Inhalation Solutions: Approximately 200 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 75 times the maximum recommended daily inhalation dose for children on a mg/m2 basis.] [Capsules for Inhalation: Approximately 850 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis.] [Inhalation Aerosol: Approximately 1700 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m2 basis.] In a 22-month study in the Golden hamster, Albuterol sulfate showed no evidence of tumorgenicity at dietary doses of up to 50 mg/kg [approximately 25 times for adults, 10 times for children [inhalation solution], 120 times for adults, and 55 times for children [capsules for inhalation] and 225 times for adults and 110 times for children [inhalation aerosol] the maximum recommended daily inhalation dose a mg/m2 basis).

Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester strains S. typhimurium TA1537, TA1538, and TA98 or E. coli WP2, WP2uvrA, and WP67. No forward mutation was seen in yeast strain S. cerevisiae S9 nor any mitotic gene conversion in yeast strain S. cerevisiae JD1 with or without metabolic activation. Fluctuation assays in S. typhimurium TA98 and E. coli WP2, both with metabolic activation, were negative. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg approximately 40 times [inhalation solution], 170 times [capsules for inhalation] and 340 times [inhalation aerosol] the maximum recommended daily inhalation dose for adults on a mg/m2 basis.

Pregnancy, Teratogenic Effects, Pregnancy Category C

Albuterol has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous doses of 0.025, 0.25, and 2.5 mg/kg (approximately 2/25, 1.0, and 8.0 [inhalation aerosol]; 1/100, 1/10, and 1.0 [inhalation solution]; 1/25, 2/5, and 4 [capsules for inhalation] times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis), showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg. The drug did not induce cleft palate formation at the lowest dose, 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg of isoproterenol (positive control) subcutaneously (approximately 1.0 time [solution], 4 times [capsules] and 8 times [inhalation aerosol] the maximum recommended daily inhalation dose for adults on a mg/m2 basis).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when Albuterol was administered orally at a 50-mg/kg dose (approximately to 80 [inhalation solution] 340 [capsules for inhalation] 680 [inhalation aerosol] times the maximum recommended daily inhalation dose for adults on a mg/m2 basis.

There are no adequate and well-controlled studies in pregnant women. Albuterol 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 rarely reported in the offspring of patients being treated with Albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between Albuterol use and congenital anomalies has not been established.

Labor and Delivery

Because of the potential for beta-agonist interference with uterine contractility, use of Albuterol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Tocolysis : Albuterol has not been approved for the management of preterm labor. The benefit:risk ratio when Albuterol 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 Albuterol.

Nursing Mothers

It is not known whether this drug is excreted in human milk after inhalation of recommended doses. Because of the potential for tumorigenicity shown for Albuterol in some animal studies, 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.

Pediatric Use

Inhalation Aerosol and Capsules for Inhalation : Safety and effectiveness in children below 4 years of age have not been established.

Inhalation Solution : The safety and effectiveness of Albuterol inhalation solution have been established in children 2 years of age and older. Use of Albuterol inhalation solution in these age-groups is supported by evidence from adequate and well-controlled studies of inhalation solution in adults; the likelihood that the disease course, pathophysiology, and the drug’s effect in pediatric and adult patients are substantially similar; and published reports of trials in pediatric patients 3 years of age or older. The recommended dose for the pediatric population is based upon three published dose comparison studies of efficacy and safety in children 5 to 17 years, and on the safety profile in both adults and pediatric patients at doses equal to or higher than the recommended doses. The safety and effectiveness of Albuterol inhalation solution in children below 2 years of age have not been established.

DRUG INTERACTIONS :

Other short-acting sympathomimetic aerosol bronchodilators (and for inhalation solutions, epinephrine) should not be used concomitantly with Albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants : Albuterol 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.

Beta-Blockers : Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as Albuterol, 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 could be considered, although they should be administered with caution.

Diuretics : The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or 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 nonpotassium-sparing diuretics.

Digoxin : 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.

ADVERSE REACTIONS :

Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported after the use of Albuterol.

Inhalation Aerosol

The adverse reactions to Albuterol are similar in nature to reactions to other sympathomimetic agents, although the incidence of certain cardiovascular effects is lower with Albuterol.

TABLE 1 Percent Incidences of Adverse Reactions in Patients 12 Years of Age in a 13-Week Clinical Trial*
Percent Incidence
Reaction
Albuterol
Isoproterenol
Tremor
<15%
<15%
Nausea
<15%
<15%
Tachycardia
10%
10%
Palpitations
<10%
<15%
Nervousness
<10%
<15%
Increased blood pressure
<5%
<5%
Dizziness
<5%
<5%
Heartburn
<5%
<5%
* A 13-week double-blind study compared Albuterol and isoproterenol inhalation aerosols in 147 asthmatic patients.

 

TABLE 2 Percent Incidence of Adverse Reactions In Children 4 to 11 Years of Age in a 12-Week Trial*
Reaction
Percent Incidence
Central Nervous System
Headache
3%
Nervousness
1%
Lightheadedness
<1%
Tremor
<1%
Agitation
1%
Nightmares
1%
Hyperactivity
1%
Aggressive behavior
1%
Gastrointestinal
Nausea and/or vomiting
6%
Stomachache
3%
Diarrhea
1%
Oropharyngeal
Throat irritation
6%
Discoloration of teeth
1%
Respiratory
Epistaxis
3%
Cough
2%
Musculoskeletal
Muscle cramp
1%
* A 12-week double-blind trial in 104 patients aged 4 to 11 years.

In addition, Albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, and unusual taste.

Inhalation Solutions

The results of clinical trials with Albuterol inhalation solution in 135 patients showed the following side effects that were considered probably or possibly drug related.

Central Nervous System : Tremors (20%), dizziness (7%), nervousness (4%), headache (3%), sleeplessness (1%).
Gastrointestinal : Nausea (4%), dyspepsia (1%).
Ear, Nose and Throat : Nasal congestion (1%), pharyngitis (<1%).
Cardiovascular : Tachycardia (1%), hypertension (1%).
Respiratory : Bronchospasm (8%), cough (4%), bronchitis (4%), wheezing (1%).

No clinically relevant laboratory abnormalities related to Albuterol inhalation solution administration were determined in these studies.

Capsules for Inhalation

The adverse reactions to Albuterol are similar in nature to reactions to other sympathomimetic agents, although the incidence of certain cardiovascular effects is lower with Albuterol. Results of clinical trials with Albuterol capsules for inhalation 200 mcg in 172 patients aged 12 years and older (adults) and 129 patients aged 4 to 12 years (children) are shown in TABLE 3 and TABLE 4.

TABLE 3 Percent Incidence of Adverse Reactions In Patients 12 Years of Age
Reaction
Percent Incidence
Central Nervous System
Headache
2%
Nervousness
1%
Tremor
1%
Sleeplessness
<1%
Dizziness
<1%
Lightheadedness
<1%
Digestive System
Throat irritation
2%
Burning in the stomach
<1%
Dry mouth
<1%
Bad taste
<1%
Respiratory System
Coughing
5%
Bronchospasm
1%

 

TABLE 4 Percent Incidence of Adverse Reactions In Children 4 to 12 Years of Age
Reaction
Percent Incidence
Central Nervous System
Headache
5%
Dizziness
<1%
Hyperactivity
<1%
Gastrointestinal
Nausea and/or vomiting
4%
Stomachache
2%
Diarrhea
<1%
Respiratory System
Epistaxis
2%
Hoarseness
2%
Nasal congestion
2%
Cough
2%
Oropharyngeal
Throat irritation
2%
Unusual taste
2%

In addition, Albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, and CNS stimulation.

OVERDOSAGE :

The expected symptoms with overdosage are those of excessive beta-adrenergic 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/min, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness.) Hypokalemia may also occur. Inhalation Solution Only: In isolated cases in children 2 to 12 years of age, tachycardia with rates >200 beats/min has been observed.

As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of Albuterol. Treatment consists of discontinuation of Albuterol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-recptor 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 Albuterol.

The oral median lethal dose of Albuterol sulfate in mice is greater than 2000 mg/kg (approximately 810 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 300 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation solution, and approximately 6800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 3200 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation aerosol or approximately 3400 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 1600 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation capsules). In mature rats, the subcutaneous median lethal dose of Albuterol sulfate is approximately 450 mg/kg (approximately 365 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 135 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation solution and approximately 3000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 1400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation aerosol or approximately 1500 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 1700 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation capsules). In small young rats, the subcutaneous median lethal dose is approximately 2000 mg/kg (approximately 1600 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 600 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation solution and approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 6400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation aerosol or approximately 6800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis or approximately 3200 times the maximum recommended daily inhalation dose for children on a mg/m2 basis for inhalation capsules). The inhalational median lethal dose has not been determined in animals.

Dialysis is not appropriate treatment for overdosage of Albuterol capsules for inhalation.

DOSAGE AND ADMINISTRATION :

Inhalation Aerosol

For treatment of acute episodes of bronchospasm or prevention of asthmatic symptoms, the usual dosage for adults and children 4 years of age and older is two inhalations repeated every 4 to 6 hours; in some patients, one inhalation every 4 hours may be sufficient. More frequent administration or a larger number of inhalations are not recommended. It is recommended to “test spray” Albuterol inhalation aerosol. Do this by spraying four times into the air before using for the first time and when the inhaler has not been used for a prolonged period of time (i.e., more than 4 weeks).

The use of Albuterol inhalation aerosol 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 inhaler. Safe usage for periods extending over several years has been documented.

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).

Exercise-Induced Bronchospasm Prevention : The usual dosage for adults and children 4 years and older is two inhalations 15 minutes before exercise.

For treatment, see above.

Inhalation Solution, 0.5%

To avoid microbial contamination, proper aseptic techniques should be used each time the bottle is opened. Precautions should be taken to prevent contact of the dropper tip of the bottle with any surface, including the nebulizer reservoir and associated ventilatory equipment. In addition, if the solution changes color or becomes cloudy, it should not be used.

Children 2 to 12 Years of Age : For children 2 to 12 years of age, initial dosing should be based upon body weight (0.1 to 0.15 mg/kg per dose), with subsequent dosing triated to achieve the desired clinical response. Dosing should not exceed 2.5 mg three to four times daily by nebulization. TABLE 5 outlines approximate dosing according to body weight.

TABLE 5
Approximate Weight (kg)
Approximate Weight (lb)
Dose (mg)
Volume of Inhalation Solution
10-15
22-33
1.25
0.25 ml
>15
>33
2.5
0.5 ml

The appropriate volume of the 0.5% inhalation solution should be diluted in sterile normal saline solution to a total volume of 3 ml prior to administration via nebulization.

Adults and Children Over 12 Years of Age : The usual dosage for adults and children 12 years of age and older is 2.5 mg of Albuterol administered three to four times daily by nebulization. More frequent administration or higher doses are not recommended. To administer 2.5 mg of Albuterol, dilute 0.5 ml of the 0.5% inhalation solution with 2.5 ml of sterile normal saline solution. The flow rate is regulated to suit the particular nebulizer so that Albuterol inhalation solution will be delivered over approximately 5 to 15 minutes.

The use of Albuterol sulfate inhalation solution 0.5% 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 usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma that would require reassessment of therapy.

Drug compatibility (physical and chemical), efficacy, and safety of Albuterol inhalation solution 0.5% when mixed with other drugs in a nebulizer have not been established.

Inhalation Solution, 0.083%

Adults and Children 2 to 12 Years of Age : The usual dosage for adults and children weighing at least 15 kg is 2.5 mg of Albuterol (one Ventolin Nebule) administered three to four times daily by nebulization. Children weighing less than 15 kg who require less than 2.5 mg/dose (i.e., less than a full Ventolin Nebule) should use Albuterol inhalation solution 0.5% instead of 0.083%. More frequent administration or higher doses are not recommended. To administer 2.5 mg of Albuterol, administer the contents of one sterile unit dose Nebule (3 ml of 0.083% inhalation solution) by nebulization. The flow rate is regulated to suit the particular nebulizer so that Albuterol inhalation solution 0.083% will be delivered over approximately 5 to 15 minutes.

The use of Albuterol inhalation solution 0.083% 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 usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma that would require reassessment of therapy.

Drug compatibility (physical and chemical), efficacy, and safety of Albuterol inhalation solution 0.083% when mixed with other drugs in a nebulizer have not been established.

Capsules for Inhalation

The usual dosage of capsules for inhalation for adults and children 4 years of age and older is the contents of one 200-mcg capsule inhaled every 4 to 6 hours using a Rotahaler inhalation device. In some patients, the contents of two 200 mcg capsules inhaled every 4 to 6 hours may be required. Larger doses or more frequent administration is not recommended.

The use of Albuterol capsules for inhalation 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 Albuterol capsules for inhalation formulation.

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 that would require reassessment of therapy.

Exercise-Induced Bronchospasm Prevention : The usual dosage of Albuterol capsules for inhalation for adults and children 4 years of age and older is the contents of one 200-mcg capsule inhaled using a Rotahaler 15 minutes before exercise.

PATIENT PACKAGE INSERT :

Ventolin Inhalation Aerosol

Before using your Ventolin inhalation aerosol, read complete instructions carefully.

Children should use Ventolin inhalation aerosol under adult supervision, as instructed by the patient’s doctor.

The blue adapter supplied with Ventolin inhalation aerosol should not be used with any other product canisters, and adapters from other products should not be used with a Ventolin inhalation aerosol canister. The refill canister is to be used only with the blue Ventolin inhalation aerosol adapter.

  1. SHAKE THE INHALER WELL immediately before each use. Then remove the cap from the mouthpiece; the strap on the cap will stay attached to the actuator. If the strap is removed from the actuator and lost, the inhaler mouthpiece should be inspected for the presence of foreign objects before each use. Make sure the cannister is fully and firmly inserted into the actuator.
  2. BREATHE OUT FULLY THROUGH THE MOUTH, expelling as much air from your lungs as possible. Place the mouthpiece fully into the mouth, holding the inhaler in its upright position and closing the lips around it.
  3. WHILE BREATHING IN DEEPLY AND SLOWLY THROUGH THE MOUTH. FULLY DEPRESS THE TOP OF THE METAL CANISTER with your index finger.
  4. HOLD YOUR BREATH AS LONG AS POSSIBLE. Before breathing out, remove the inhaler from your mouth and release your finger from the canister.
  5. Wait one minute and SHAKE the inhaler again. Repeat steps 2 through 4 for each inhalation prescribed by your doctor.
  6. CLEANSE THE INHALER THOROUGHLY AND FREQUENTLY. Remove the metal canister and cleanse the plastic case and cap by rinsing thoroughly in warm, running water at least once a day. After thoroughly drying the plastic case and cap, gently replace the canister into the case with a twisting motion and put the cap back on the mouthpiece.
  7. As with all aerosol medications, it is recommended to “test spray” the inhaler into the air before using for the first time and when the inhaler has not been used for a prolonged period of time (i.e., more than 4 weeks).
  8. DISCARD THE CANISTER AFTER YOU HAVE USED THE LABELED NUMBER OF INHALATIONS. The correct amount of medication in each inhalation cannot be assured after 80 actuations from the 6.8-g canister and 200 actuations from the 17.0-g canister, even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used. Before you reach the specific number of actuations, you should consult your physician to determine whether a refill is needed. Just as you should not take extra doses without consulting your physician, you also should not stop using Ventolin inhalation aerosol without consulting your physician.

 

Dosage : Use only as directed by your doctor.

WARNINGS : The action of Ventolin inhalation aerosol may last up to 6 hours or longer. Ventolin inhalation aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of Ventolin inhalation aerosol without consulting your doctor. If you find that treatment with Ventolin 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 taking Ventolin inhalation aerosol, other inhaled drugs and asthma medicines should be used only as prescribed by your doctor.

Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children. Avoid spraying in eyes.

Store between 15-30°C (59-86°F). As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold; for best results, the canister should be at room temperature before use. Shake well before using.

Note the statement below is required by the Federal government Clean Air Act for all products containing chlorofulorocarbons.

This product contains trichloromonofluoromethane and dichlorodifluoromethane, substances which harm the environment by depleting ozone in the upper atmosphere.

Your doctor has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR DOCTOR. If you have any questions about alternatives, consult your doctor.

Ventolin Inhalation Solution, 0.5%*

*Potency expressed as Albuterol.

Read complete instructions carefully before using.

  1. Draw the appropriate volume of Ventolin inhalation solution into the specially marked dropper that comes with each multidose bottle. For children 12 years of age and under, the volume is based upon body weight. Use the dropper volume prescribed by your doctor.
  2. Squeeze the solution into the nebulizer reservoir through the appropriate opening, taking care not to touch the tip of the dropper.
  3. Add sterile normal saline solution, as your doctor has directed. A general guideline for the amount of saline to add is: For children using 0.25 ml or 1.25 mg of Ventolin inhalation solution, add 2.75 ml of sterile normal saline. For children or adults using 0.5 ml or 2.5 mg of Ventolin inhalation solution, add 2.5 mg of sterile normal saline.
  4. Gently swirl the nebulizer to mix the contents and connect it with the mouthpiece or face mask.
  5. Connect the nebulizer to the compressor.
  6. Sit in a comfortable, upright position; place the mouthpiece in your mouth (or put on the face mask); and turn on the compressor.
  7. Breathe as calmly, deeply, and evenly as possible until no more mist is formed in the nebulizer chamber (about 5 to 15 minutes). At this point, the treatment is finished.
  8. Clean the nebulizer (see manufacturer’s instructions).

Note : Use only as directed by your doctor. More frequent administration or higher doses are not recommended.

To avoid microbial contamination, proper aseptic techniques should be used each time the bottle is opened. Precautions should be taken to prevent contact of the dropper tip of the bottle with any surface, including the nebulizer reservoir and associated ventilatory equipment. In addition, if the solution changes color or becomes cloudy, it should not be used.

The safety and effectiveness of Ventolin 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.

Store between 2-25°C (36-77°F).

Ventolin Nebules Inhalation Solution, 0.083%*

*Potency expressed as Albuterol.

Read complete instructions carefully before using.

  1. Twist open the top of one Nebule unit-of-use container and squeeze the entire contents into the nebulizer reservoir.
  2. Connect the nebulizer reservoir to the mouthpiece or face mask.
  3. Connect the nebulizer to the compressor.
  4. Sit in a comfortable, upright position; place the mouthpiece in your mouth (or put on the face mask); and turn on the compressor.
  5. Breathe as calmly, deeply, and evenly as possible until no more mist is formed in the nebulizer chamber (about 5 to 15 minutes). At this point, the treatment is finished.
  6. Clean the nebulizer (see manufacturer’s instructions).

Note : Use only as directed by your doctor. More frequent administration or higher doses are not recommended.

The safety and effectiveness of Ventolin Nebules inhalation solution 0.083% 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.

Protect from light. Store in a refrigerator between 2-8°C (36-46°F). Ventolin Nebules inhalation solution may be held at room temperature for up to 2 weeks before use. (Nebules must be used within 2 weeks of removal from refrigerator; record date the nebules are removed from the refrigerator in the space provided on the product carton.) Discard if solution becomes discolored. (Note : Ventolin Nebules inhalation solution is colorless.)

Ventolin Rotacaps Capsules for Inhalation

Instructions for Administration of Ventolin for Inhalation with the Rotahaler Inhalation Device

Note : Ventolin Rotacaps for inhalation should be stored in a dry place and not exposed to temperature extremes. Ventolin Rotacaps for inhalation should be stored below 86°F. Do not remove Ventolin Rotacaps for inhalation from the original packaging until you are ready to use the Rotahaler inhalation device.

Bottle Packs : Store Ventolin Rotacaps for inhalation capsules in the original bottle. You may transfer a daily supply of capsules to the smaller, reusable bottle that fits into the carrying case. Do not remove capsules from the bottle until you are ready to use the Rotahaler inhalation device.

Hospital Unit Dose Pack : To remove a capsule from a unit dose blister pack, tear off one section of the paper backing starting at the corner marked “PEEL.”

The Ventolin Rotacaps for inhalation capsules appear partially filled; the partial filling of dry powder facilitates the delivery of the medication.

Children should use Ventolin Rotacaps for inhalation capsules under adult supervision, as instructed by the patient’s doctor.

Preparing the Rotahaler For Use :

  1. Remove the Rotahaler from its container and check to be sure it is clean and dry. Inspect the mouthpiece for the presence of foreign objects before each use.
  2. Keeping the Rotahaler upright (vertical), hold the darker colored end in one hand and turn the lighter colored end as far as it will go in either direction.
  3. Take a Ventolin Rotacaps for inhalation capsule from its pack and insert the clear (thinner) end into the raised octagonal hole located in the lighter colored end of the Rotahaler inhalation device. This will force the previously used capsule shell into the Rotahaler chamber. Push the new capsule in until it is level with the top of the hole. (Note: When first using or after washing the Rotahaler, the raised octagonal hole will be empty).
  4. Hold the Rotahaler level (horizontally) with the white dot uppermost and turn the lighter colored end (the end where the capsule was inserted) as far as it will go in the opposite direction. This will open the capsule.

YOUR ROTAHALER IS NOW READY FOR USE. KEEP LEVEL.

Using the Rotahaler :

  1. Keep the Rotahaler level. Breathe out fully. Raise the Rotahaler to your mouth and gently place the mouthpiece (darker colored end) between your teeth and lips. Avoid inserting the Rotahaler beyond teeth.
  2. Firmly grasp the Rotahaler on the dark blue portion prior to inhalation (breathing in) to avoid accidental inhalation of the device.
  3. Breathe in through your mouth as quickly and as deeply as you can.
  4. Hold your breath briefly; then remove the Rotahaler from your mouth and exhale.
  5. If a dose of two capsules is recommended by your doctor, repeat steps 2 through 8.

After Using the Rotahaler :

  1. After each use, pull the two halves of the Rotahaler apart and throw away the loose capsule shells.
  2. Reassemble the Rotahaler and replace it in its container.

Care of Your Rotahaler : Keep the Rotahaler clean and dry at all times. Once every 2 weeks wash the two halves of your Rotahaler in warm water. Make sure that the empty capsule shell is removed from the raised octagonal hole before washing your inhaler.

Dry your Rotahaler thoroughly before reassembling it. Avoid excessive heat.

Dosage : Use only as directed by your doctor.

Warnings : The action of Ventolin Rotacaps for inhalation capsules may last for 6 hours or longer. Ventolin Rotacaps for inhalation capsules should not be used more frequently than recommended. Do not increase the dose or frequency of Ventolin Rotacaps for inhalation capsules without consulting your doctor. If you find that treatment with Ventolin Rotacaps for inhalation capsules 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 taking Ventolin Rotacaps for inhalation capsules, other inhaled drugs and asthma medicines should be used only as directed by your doctor.

HOW SUPPLIED :

Ventolin Inhalation Aerosol

Supplied in 6.8-g canisters containing 80 metered inhalations and in 17-g canisters containing 200 metered inhalations. Each actuation delivers 100 mcg of Albuterol from the valve and 90 mcg of Albuterol from the mouthpiece. Each canister is supplied with a blue oral adapter and patient’s instructions. Also available, Ventolin inhalation aerosol refill 17-g canister only with patient’s instructions.

The blue adapter supplied with Ventolin inhalation aerosol should not be used with any other product canisters, and adapters from other products should not be used with Ventolin inhalation aerosol canister. The correct amount of medication in each canister cannot be assured after 80 actuations from the 6.8-g canister and 200 actuations from the 17.0-g canister, even though the canister is not completely empty. The canister should be discarded when the labelled number of actuations have been used.

Storage: Store between 15-30°C (59-86°F). As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold, for best results, the canister should be at room temperature before use. Shake well before using.

Note the indented statement below is required by the Federal government Clean Air Act for all products containing chlorofluorocarbons.

WARNING : This product contains trichloromonofluoromethane and dichlorodifluoromethane, substances which harm public health and environment by destroying ozone in the upper atmosphere.

A notice similar to the above warning has been placed in the patient instruction leaflet pursuant to regulations of the U.S. Environmental Protection Agency (EPA). The patient’s warning states that the patient should consult his or her physician if there are questions about alternatives.

Ventolin Inhalation Solution, 0.5%

Supplied as 20 ml with accompanying calibrated dropper.

Storage : Store between 2-25°C (36-77°F).

Ventolin Nebules Inhalation Solution, 0.083%

Contained in sterile, plastic dose nebules of 3 ml each.

Storage : Protect from light. Store in refrigerator between 2-8°C (36-46°F). Ventolin Nebules Inhalation Solution may be held at room temperature for up to 2 weeks before use. (Nebules must be used within 2 weeks of removal from refrigerator; record date the nebules are removed from the refrigerator in the space provided on the product carton.) Discard if solution becomes discolored. (Note: Ventolin Nebules inhalation solution is colorless.)

Ventolin Rotacaps for Inhalation

The 200-mcg capsule is light blue and clear with “VENTOLIN 200” printed on the blue cap and “GLAXO” printed on the clear body.

Ventolin Rotacaps for inhalation are supplied in a kit containing 100 capsules and one Rotahaler inhalation device with patient’s instructions. Also available, Ventolin Rotacaps for inhalation refill with patient’s instructions.

Storage : Store between 2-30°C (36-86°F). Replace cap securely after each opening.