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PROVENTIL REPETABS Tablets contain albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta 2 -adrenergic bronchodilator. Albuterol sulfate has the chemical name (alpha) 1 -[ (tert -Butylamino)methyl]-4- hydroxy- m -xylene-(alpha), (alpha)'-diol sulfate (2:1) (salt), and the following chemical structure:
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The molecular weight of albuterol sulfate is 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.
Each PROVENTIL REPETABS Tablet for oral administration 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 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.
The primary action of beta-adrenergic drugs, including albuterol, is to stimulate adenyl cyclase, the enzyme which catalyzes the formation of cyclic-3',5'-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) in beta-adrenergic cells. The cyclic AMP thus formed mediates the cellular responses. 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.
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.
In controlled clinical trials, albuterol has been shown 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 ECG 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.
Preclinical: Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations that are amounting to approximately 5.0% of the plasma concentrations. In structures outside the blood-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.
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 PROVENTIL Tablet every 6 hours and 14.8 and 8.6 ng/mL, respectively, following dosing with a 4 mg PROVENTIL 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.
PROVENTIL REPETABS Tablets have been formulated to provide a duration of action of up to 12 hours. In studies conducted in normal 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 PROVENTIL REPETABS Tablet every 12 hours. In addition, it has been shown that administration of a 4 mg PROVENTIL REPETABS Tablet every 12 hours, and a 2 mg PROVENTIL Tablet every 6 hours for 5 days gave comparable peak albuterol levels and similar extent of absorption at steady state.
In other studies, the analysis of urine samples of patients given tritiated albuterol (4 to 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. Feces collected over this period contained 4% of the administered dose.
Clinical Trials: In controlled clinical trials in patients with asthma, the onset of improvement in pulmonary function, as measured by maximal mid-expiratory flow rate, MMEF, was noted within 30 minutes after a dose of PROVENTIL Tablets with peak improvement occurring between 2 and 3 hours. In controlled clinical trials, in which measurements were conducted for 6 hours, significant clinical improvement in pulmonary function (defined as maintaining a 15% or more increase in FEV 1 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 with the 4 mg PROVENTIL Tablet. No decrease in the effectiveness of PROVENTIL Tablets has been reported in patients who received long-term treatment with the drug in uncontrolled studies for periods up to 6 months.
In another controlled clinical study in asthmatic patients, it has been demonstrated that the initiation of therapy with either the 4 mg PROVENTIL REPETABS Tablet dosed every 12 hours, or the 2 mg PROVENTIL Tablet dosed every 6 hours, achieve therapeutically comparable effects.
PROVENTIL REPETABS Tablets are indicated for the relief of bronchospasm in adults and children 6 years of age and older with reversible obstructive airway disease.
PROVENTIL REPETABS Tablets are contraindicated in patients with a history of hypersensitivity to albuterol or any of their components.
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 PROVENTIL REPETABS Tablets than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and the 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.
Cardiovascular Effects: PROVENTIL REPETABS Tablets, 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 PROVENTIL REPETABS Tablets 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, PROVENTIL REPETABS Tablets, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
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.
Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with the administration of oral albuterol sulfate in children.
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. Clinically significant changes in systolic and diastolic blood pressure have been seen 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 pre-existing 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.
Information for Patients: Patients being treated with PROVENTIL REPETABS 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.
The action of PROVENTIL REPETABS Tablets may last up to 12 hours or longer. PROVENTIL REPETABS Tablets should not be taken more frequently than recommended. Do not increase the dose or frequency of PROVENTIL REPETABS Tablets without consulting your physician. If you find that treatment with PROVENTIL REPETABS Tablets becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to take the product more frequently than usual, you should seek medical attention immediately. While you are taking PROVENTIL REPETABS Tablets, 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, tremor, or nervousness. If you are pregnant or nursing, contact your physician about the use of PROVENTIL REPETABS Tablets. Effective and safe use of PROVENTIL REPETABS Tablets includes an understanding of the way that it should be administered.
Drug Interactions: The concomitant use of PROVENTIL REPETABS Tablets 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 PROVENTIL REPETABS Tablets. 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.
Beta Blockers: Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as PROVENTIL REPETABS Tablets, 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 this finding 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.
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.
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 and above dietary doses of 2 mg/kg (corresponding to less than the maximum recommended daily oral dose for adults and children, on an mg/m 2 basis). In another study this effect was blocked by the coadministration of propranolol, a nonselective beta-adrenergic antagonist.
In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 65 times the maximum recommended daily oral dose for adults on an mg/m 2 basis and approximately 50 times the maximum recommended daily oral dose for children on an mg/m 2 basis). In a 22-month study in the Golden Hamster, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 8 times the maximum recommended daily oral dose for adults and children on an 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.
Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 15 times the maximum recommended daily oral dose for adults on an mg/m 2 basis
Teratogenic Effects--Pregnancy Category C: Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses at and above 0.25 mg/kg (corresponding to less than the maximum recommended daily oral dose for adults on an mg/m 2 basis), induced cleft palate formation in 5 of 111 (4.5%) fetuses. At an sc dose of 2.5 mg/kg (corresponding to less than the maximum recommended daily oral dose for adults on an mg/m 2 basis) albuterol sulfate induced cleft palate formation in 10 of 108 (9.3%) fetuses. The drug did not induce cleft palate formation when administered at an sc dose of 0.025 mg/kg (significantly less than the maximum recommended daily oral dose for adults on an mg/m 2 basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg isoproterenol (positive control) administered subcutaneously.
A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 25 times the maximum recommended daily oral dose for adults on an mg/m 2 basis
Studies in pregnant rats with tritiated albuterol demonstrated that approximately 10% of the circulating maternal drug is transferred to the fetus. Disposition in the fetal lungs is comparable to maternal lungs, but fetal liver disposition is 1% of the maternal liver levels.
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, 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 reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.
Labor and Delivery--Use in Labor: Because of the potential for beta-agonist interference with uterine contractility, use of PROVENTIL REPETABS Tablets or PROVENTIL Tablets 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. 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: The safety and effectiveness of PROVENTIL Tablets and PROVENTIL REPETABS Tablets have been established in pediatric patients 6 years of age and older. Use of PROVENTIL REPETABS Tablets in these age groups is supported by evidence from adequate and well-controlled studies of PROVENTIL REPETABS Tablets in adults: the likelihood that the disease course, pathophysiology, and the drug' effect in pediatric and adult patients are substantially similar; the established safety and effectiveness of PROVENTIL Tablets in pediatric patients 6 years of age and older; and one clinical trial that provides evidence of the safety of PROVENTIL REPETABS Tablets in pediatric patients aged 6 to 12 years. The recommended dose of PROVENTIL REPETABS Tablets in the pediatric population is based upon the recommended pediatric dosing of PROVENTIL Tablets and pharmacokinetic studies in adults showing PROVENTIL REPETABS Tablets to have similar peak albuterol levels (i.e., C max ) and exposures (i.e., AUC) as PROVENTIL Tablets administered every 6 hours at one-half of the PROVENTIL REPETABS Tablets dose.
Safety and effectiveness in pediatric patients below the age of 6 years for PROVENTIL REPETABS Tablets and PROVENTIL Tablets have not been established.
The adverse reactions to albuterol are similar in nature to those of other sympathomimetic agents.
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Although not reported for PROVENTIL REPETABS 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 PROVENTIL 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 PROVENTIL REPETABS Tablets. In this study, the starting dose of PROVENTIL REPETABS Tablets was 4 mg twice daily. Patients were advanced to a maximum of 12 mg PROVENTIL REPETABS Tablets twice daily by the investigator, based on patient tolerance and response. Only one of the 79 children treated with PROVENTIL REPETABS Tablets was 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 PROVENTIL REPETABS Tablets patients when compared to placebo:
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Other adverse events were noted in 5% or fewer patients, or had equal or greater rates of occurrence in placebo patients than in PROVENTIL REPETABS Tablets patients.
Cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles) have been reported after the use of PROVENTIL Tablets and PROVENTIL REPETABS Tablets.
In addition to those adverse reactions reported above, albuterol, like other sympathomimetic agents, can cause adverse reactions such as angina, central nervous system stimulation, drying or irritation of the oropharynx, hypertension, unusual taste, and vertigo.
The reactions are generally transient in nature, and it is usually not necessary to discontinue treatment with PROVENTIL REPETABS Tablets or PROVENTIL Tablets. 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.
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., angina, hypertension, tachycardia with rates up to 200 beats per minute, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, and insomnia. In addition, seizures, hypotension, arrhythmias, fatigue, malaise, and hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of PROVENTIL REPETABS Tablets and PROVENTIL Tablets. Treatment consists of discontinuation of PROVENTIL REPETABS Tablets and PROVENTIL Tablets 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 PROVENTIL REPETABS Tablets or PROVENTIL 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 an mg/m 2 basis and approximately 200 times the maximum recommended daily oral dose for children on an mg/m 2 basis). In mature rats, the subcutaneous (sc) median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 110 times the maximum recommended daily oral dose for adults on an mg/m 2 basis, and approximately 90 times the maximum recommended daily oral dose for children on an mg/m 2 basis). In small young rats, the subcutaneous median lethal dose is approximately 2000 mg/kg (approximately 510 times the maximum recommended daily oral dose for adults on an mg/m 2 basis, and approximately 400 times the maximum recommended daily oral dose for children on an mg/m 2 basis
The following dosages of PROVENTIL REPETABS Tablets are expressed in terms of albuterol base.
PROVENTIL REPETABS Tablets
Usual Dose: Pediatric Patients 6 to 12 years of age: For pediatric patients 6 to 12 years of age, the usual starting dosage of PROVENTIL REPETABS Tablets is 4 mg (one tablet) every 12 hours.
Adults and Pediatric Patients over 12 years of age: For adults and children over 12 years of age, the usual starting dosage of PROVENTIL REPETABS Tablets is 4 or 8 mg (one or two tablets) every 12 hours.
Dosage Adjustment in Pediatric Patients 6 to 12 years of age: Dosages of PROVENTIL REPETABS Tablets above 4 mg twice a day should be used only when the patient fails to respond to this dosage while on otherwise optimized asthma therapy. In such instances, the PROVENTIL REPETABS Tablets dosage may be increased cautiously stepwise as tolerated if a favorable response does not occur with the 4 mg twice daily initial dosage. The maximum recommended dosage of PROVENTIL REPETABS Tablets in pediatric patients aged 6 to 11 years is 12 mg twice a day.
Dosage Adjustment in Adults and Pediatric Patients over 12 years of age: Dosages of PROVENTIL REPETABS Tablets above 8 mg twice a day should be used only when the patient fails to respond to this dosage while on otherwise optimized asthma therapy. The PROVENTIL REPETABS Tablets dosage may be increased cautiously stepwise as tolerated if a favorable response does not occur with the 8 mg twice daily dosage. The maximum recommended dosage of PROVENTIL REPETABS Tablets in adults and pediatric patients over 12 years of age is 16 mg twice a day.
The total daily dose should not exceed 32 mg per day in adults and children over 12 years of age.
Switching to PROVENTIL REPETABS Tablets: Patients currently maintained on PROVENTIL Tablets can be switched to PROVENTIL REPETABS Tablets. For example, the administration of a 4 mg PROVENTIL REPETABS Tablet every 12 hours is clinically comparable to one 2 mg PROVENTIL Tablet every 6 hours. Multiples of this regimen up to the maximum recommended daily dose also apply.
PROVENTIL REPETABS Tablets, 4 mg albuterol as the sulfate (2 mg in the coating for immediate release and 2 mg in the core for release after several hours), white, round, coated tablets, branded in red on one side with the Schering trademark, and product identification numbers, 431, high-density polyethylene bottles of 100 (NDC 0085-0431-02) and 500 (NDC 0085-0431-03) and boxes of 100 for unit-dose dispensing (NDC 0085- 0431-04).
Store PROVENTIL REPETABS Tablets between 2° and 25°C (36° and 77°F). Protect PROVENTIL REPETABS Tablets in the unit-dose box from excessive moisture.
Schering Corporation
Kenilworth, NJ 07033 USA
Rev. 10/00 B-17543369
23677911T
Copyright © 1982, 1999,
Schering Corporation. All rights reserved.
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