PROVENTIL REPETABS Tablets and PROVENTIL 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:
The molecular weight of albuterol sulfate is 576.7, and the empirical formula (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.
Each PROVENTIL Tablet for oral administration contains 2 or 4 mg of albuterol as 2.4 and 4.8 mg of albuterol sulfate, respectively.
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 inactive ingredients for PROVENTIL Tablets, 2 and 4 mg include: corn starch food grade, lactose monohydrate, and magnesium stearate, NF.
In vitro studies and in vivo pharmacologic studies have demonstrated that PROVENTIL 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, recent 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, however, is not yet established.
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 methylxanthines were administered concurrently. The significance of these findings when applied to humans is currently unknown.
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.
and Disposition: 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 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 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 subjects 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 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 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 adult 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 equivalent effects.
PROVENTIL REPETABS Tablets and PROVENTIL Tablets are indicated for the relief of bronchospasm in patients 6 years of age or older with reversible obstructive airway disease.
PROVENTIL REPETABS Tablets and PROVENTIL Tablets are contraindicated in patients with a history of hypersensitivity to any of their components.
Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. Additionally, albuterol and other beta agonists, when given intravenously, may cause a decrease in serum potassium, possibly through intracellular shunting. The decrease is usually transient not requiring supplementation. The relevance of these observations to the use of PROVENTIL REPETABS Tablets and PROVENTIL Tablets is unknown.
Information for Patients : Patients being treated with PROVENTIL REPETABS Tablets or PROVENTIL 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.
PROVENTIL REPETABS Tablets should not be chewed, crushed, or mixed in food.
PROVENTIL REPETABS Tablets and PROVENTIL Tablets should not be taken more frequently than recommended. Do not increase the dose or frequency of either 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 with your physician.
Drug Interactions: The concomitant use of PROVENTIL REPETABS Tablets or PROVENTIL 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 or PROVENTIL 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.
Albuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of albuterol on the vascular system may be potentiated.
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.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: 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. 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.
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. 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 reproduction study in CD-1 mice with albuterol 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; none were observed at 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses treated with 2.5 mg/kg isoproterenol (positive control). A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses of 50 mg/kg, corresponding to 78 times the maximum human oral dose of albuterol.
During marketing, 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 cannot be established.
Labor and Delivery: Oral albuterol has been shown to delay preterm labor in some reports. There are presently no well-controlled studies which demonstrate what it will stop preterm labor or prevent labor at term. Therefore, cautious use of PROVENTIL REPETABS Tablets or PROVENTIL Tablets is required in pregnant patients when given for relief of bronchospasm so as to avoid interference with uterine contractibility.
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 for 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 (ie, C max ) and exposures (ie, 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 have not been established for PROVENTIL Tablets and PROVENTIL REPETABS Tablets.
The adverse reactions to albuterol are similar in nature to those of other sympathomimetic agents. The most frequent adverse reactions to PROVENTIL 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 less than 1 of 100 patients (less than 1%).
In a clinical study of 1 week duration in adults, comparing a 4 mg PROVENTIL REPETABS Tablet administered every 12 hours to a 2 mg PROVENTIL 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 PROVENTIL REPETABS Tablets and PROVENTIL Tablets, respectively; nausea in 2 of 50 (4%) for both; vomiting in 1 of 50 (2%) and 2 of 50 (4%) for PROVENTIL REPETABS Tablets and PROVENTIL Tablets, respectively; somnolence in 1 of 50 (2%) for both. The following adverse reactions were reported for PROVENTIL 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 PROVENTIL REPETABS Tablets in the above study in adults, 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: (22% PROVENTIL REPETABS Tablets, 9% placebo); tremor (10% PROVENTIL REPETABS Tablets, 1% placebo); tachycardia and palpitations (8% PROVENTIL REPETABS Tablets, 1% placebo); insomnia (11% PROVENTIL REPETABS Tablets, 5% placebo); and nervousness (13% PROVENTIL REPETABS Tablets, 6% placebo). 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.
In addition to those adverse reactions reported above, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vomiting, vertigo, central nervous system 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 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.
Manifestations of overdosage include anginal pain, hypertension, hypokalemia, and exaggeration of the pharmacological effects listed in ADVERSE REACTIONS.
The oral LD 50 in rats and mice was greater than 2,000 mg/kg.
There is insufficient evidence to determine if dialysis is beneficial for overdosage of PROVENTIL REPETABS Tablets or PROVENTIL Tablets.
The following dosages of PROVENTIL REPETABS Tablets and PROVENTIL Tablets are expressed in terms of albuterol base.
PROVENTIL REPETABS Tablets
Usual Dose: Pediatric Patients 6 to 11 years of age: The usual starting dosage of PROVENTIL REPETABS Tablets is 4 mg (one tablet) every 12 hours.
Adults and Pediatric Patients 12 years and over: 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 aged 6 to 11 years: Doses of PROVENTIL REPETABS 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 PROVENTIL REPETABS 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 PROVENTIL REPETABS 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 PROVENTIL REPETABS Tablets above 8 mg twice a day should be used only when the patient fails to respond to this dose while on otherwise optimized asthma therapy. The PROVENTIL REPETABS Tablets dose may be increased cautiously stepwise as tolerated if a favorable response does not occur with the 8 mg twice daily dose. The maximum recommended dose of PROVENTIL REPETABS Tablets in adults and pediatric patients over 12 years of age is 16 mg twice a day.
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.
Usual Dose: Pediatric Patients 6 to 12 years of age: The usual starting dosage for pediatric patients 6 to 12 years of age is 2 mg three or four times a day.
Adults and Pediatric Patients 12 years and over: The usual starting dosage for adults and pediatric patients 12 years and over is 2 mg or 4 mg three or four times a day.
Dosage Adjustment: For pediatric patients 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 per day (given in divided doses).
For adults and pediatric patients 12 years and over, a dosage above 4 mg four times a day should be used only when the patient fails to respond to lower doses. The dose should be increased cautiously stepwise up to a maximum of 8 mg four times a day as tolerated if a favorable response does not occur with the 4 mg initial dose.
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 24 mg per day in pediatric patients from 6 to 12 years of age, and 32 mg per day in adults and pediatric patients 12 years and over.
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, 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).
PROVENTIL Tablets, 2 mg albuterol as the sulfate, white, round, compressed tablets, impressed with the product name (PROVENTIL) and the number 2 on one side, and product identification numbers, 252, and scored on the other, bottles of 100 (NDC 0085-0252-02) and 500 (NDC 0085-0252-03).
PROVENTIL Tablets, 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, bottles of 100 (NDC 0085-0573-02) and 500 (NDC 0085-0573-03).
Store PROVENTIL REPETABS Tablets between 2° and 25°C (36° and 77°F), and PROVENTIL Tablets between 2° and 30°C (36° and 86°F). Protect PROVENTIL REPETABS Tablets in the unit dose box from excessive moisture.
Kenilworth, NJ 07033 USA
Rev. 10/97 17543342
Copyright © 1982, 1993, 1995, 1998,
Schering Corporation. All rights reserved.