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 µm) 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.
The active component of VENTOLIN ROTACAPS for Inhalation is albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta 2 -adrenergic bronchodilator. It has the chemical name (alpha) 1 -[( 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 (C 13 H 21 NO 3 ) 2 ·H 2 SO 4 . Albuterol sulfate is a white crystalline powder, soluble in water and slightly soluble in ethanol.
The World Health Organization recommended name for albuterol base is salbutamol.
In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta 2 -receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established (see ).
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 normal cellular uptake processes for catecholamines nor for catechol- O -methyl transferase.
: Studies undertaken with four subjects administered tritiated albuterol from a metered-dose aerosol inhaler 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 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.
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 are administered concurrently. The clinical significance of these findings is unknown.
Clinical Trials: In single, dose-range, crossover trials with VENTOLIN ROTACAPS 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 (FEV 1 ) following administration of either a 200- or 400-mcg dose. Maximum increases in FEV 1 occurred within 60 minutes following inhalation of either dose. The duration of effect (defined as an increase in FEV 1 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 (FEF 25%-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 VENTOLIN ROTACAPS for Inhalation capsule versus two inhalations of VENTOLIN® (albuterol, USP) Inhalation Aerosol, the two dosage regimens were found to be clinically comparable. Based on a 15% or more increase in FEV 1 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 FEV 1 , or 20% in FEF 25%-75% ). Therapeutic improvement of FEF 25%-75% persisted for 3 to 5 hours in over 50% of the children throughout the study. Continued effectiveness and safety of VENTOLIN ROTACAPS 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 VENTOLIN ROTACAPS for Inhalation capsule taken approximately 15 minutes before exercise prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV 1 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.
VENTOLIN ROTACAPS for Inhalation are 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 VENTOLIN ROTACAPS 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. VENTOLIN ROTACAPS for Inhalation can be used with or without concomitant steroid therapy.
VENTOLIN ROTACAPS for Inhalation are contraindicated in patients with a history of hypersensitivity to albuterol or any of its components.
Paradoxical Bronchospasm: VENTOLIN ROTACAPS for Inhalation can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, VENTOLIN ROTACAPS for Inhalation should be discontinued immediately and alternative therapy instituted.
Cardiovascular Effects: VENTOLIN ROTACAPS for Inhalation, 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 VENTOLIN ROTACAPS for Inhalation 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 QT c interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, VENTOLIN ROTACAPS for Inhalation, 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 VENTOLIN ROTACAPS for Inhalation 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 of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.
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.
Inhalation of capsule particles may result if damage to the capsule has occurred from handling by the patient.
General: Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmia; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. 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.
Information for Patients: The action of VENTOLIN ROTACAPS for Inhalation may last for up to 6 hours or longer. VENTOLIN ROTACAPS for Inhalation should not be used more frequently than recommended. Do not increase the dose or frequency of VENTOLIN ROTACAPS for Inhalation without consulting your physician. If you find that treatment with VENTOLIN ROTACAPS for Inhalation 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 VENTOLIN ROTACAPS for Inhalation, 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 VENTOLIN ROTACAPS for Inhalation. Effective and safe use of VENTOLIN ROTACAPS for Inhalation includes an understanding of the way that it should be administered.
Children should use VENTOLIN ROTACAPS for Inhalation under adult supervision, as instructed by the patient' physician.
See illustrated Patient' Instructions for Use section of the full prescribing information.
Drug Interactions: Other short-acting sympathomimetic aerosol bronchodilators 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 VENTOLIN ROTACAPS for Inhalation, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they could 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.
Carcinogenesis, Mutagenesis, 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 (approximately 7, 35, and 170 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m 2 basis or approximately 3, 15, and 80 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m 2 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 850 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis or approximately 400 times the maximum recommended daily inhalation dose for children on a mg/m 2 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 120 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis or approximately 55 times the maximum recommended daily inhalation dose for children on a mg/m 2 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 170 times the maximum recommended daily inhalation dose for adults on a mg/m 2 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 1/25, 2/5, and 4 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m 2 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 four times the maximum recommended daily inhalation dose for adults on a mg/m 2 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 340 times the maximum recommended daily inhalation dose for adults on a mg/m 2 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.
Use in Labor and Delivery: Because of the potential for beta-agonist interference with uterine contractility, use of VENTOLIN ROTACAPS for Inhalation 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 beta 2 -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: Safety and effectiveness in children below 4 years of age have not been established.
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 VENTOLIN ROTACAPS® 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 the following tables:
Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported after the use of VENTOLIN ROTACAPS for Inhalation.
In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, and CNS stimulation.
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. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of VENTOLIN ROTACAPS for Inhalation. Treatment consists of discontinuation of VENTOLIN ROTACAPS for Inhalation 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 VENTOLIN ROTACAPS for Inhalation.
The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 3400 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis or approximately 1600 times the maximum recommended daily dose for children on a mg/m 2 basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 1500 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis or approximately 700 times the maximum recommended daily dose for children on a mg/m 2 basis). In small young rats, the subcutaneous median lethal dose is approximately 2000 mg/kg (approximately 6800 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis or approximately 3200 times the maximum recommended daily inhalation dose for children on a mg/m 2 basis). The inhalational median lethal dose has not been determined in animals.
Dialysis is not appropriate treatment for overdosage of VENTOLIN ROTACAPS for Inhalation.
The usual dosage of VENTOLIN ROTACAPS 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 VENTOLIN ROTACAPS 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 VENTOLIN ROTACAPS 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 VENTOLIN ROTACAPS 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.
VENTOLIN ROTACAPS for Inhalation, 200 mcg, are 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 one white plastic HDPE bottle of 100 capsules and one ROTAHALER inhalation device with patient' instructions (NDC 0173-0389-01). Also available, VENTOLIN ROTACAPS for Inhalation Refill in white plastic HDPE bottle of 100 capsules with patient' instructions (NDC 0173-0389-02).
Store between 2° and 30°C (36° and 86°F). Replace cap securely after each opening.
Glaxo Wellcome Inc., Research Triangle Park, NC 27709