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Prescribing Information
Alupent® (metaproterenol sulfate USP) Inhalation Aerosol is a bronchodilator administered by oral inhalation. The Alupent Inhalation Aerosol containing 150 mg of metaproterenol sulfate as micronized powder is sufficient medication for 200 inhalations. Each metered dose delivers through the mouthpiece 0.65 mg of metaproterenol sulfate (each ml contains 15 mg). The inert ingredients are dichlorodifluoromethane, dichlorotetrafluoroethane and trichloromonofluoromethane as propellants, and sorbitan trioleate.
Alupent Inhalation Solution is administered by oral inhalation with the aid of a nebulizer or an intermittent positive pressure breathing apparatus (IPPB). It contains Alupent 5% in a pH-adjusted aqueous solution containing benzalkonium chloride and edetate disodium as preservatives.
Alupent Inhalation Solution Unit-dose Vial is administered by oral inhalation with the aid of an IPPB. It contains Alupent 0.4% or 0.6% in a sterile pH-adjusted aqueous solution with edetate disodium and sodium chloride.
Alupent Syrup is an oral bronchodilator. Each teaspoonful (5 ml) of syrup contains 10 mg of metaproterenol sulfate. The inactive ingredients are edetate disodium, FD&C Red No. 40, hydroxyethylcellulose, imitation black cherry flavor, methylparaben, propylparaben, saccharin, sorbitol solution.
Alupent Tablets are administered orally. Each tablet contains metaproterenol sulfate 10 mg or 20 mg. The inactive ingredients are colloidal silicon dioxide, corn starch, dibasic calcium phosphate, lactose, magnesium stearate.
Chemically, Alupent is 1-(3,5 dihydroxyphenyl)-2-isopropylaminoethanol sulfate, a white crystalline, racemic mixture of two optically active isomers.
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Alupent® (metaproterenol sulfate USP) is a potent beta-adrenergic stimulator. Alupent Inhalation Solutions have a rapid onset of action. It is postulated that beta-adrenergic stimulants produce many of their pharmacological effects by activation of adenyl cyclase, the enzyme which catalyzes the conversion of adenosine triphosphate to cyclic adenosine monophosphate.
In vitro studies and in vivo pharmacologic studies have demonstrated that Alupent® (metaproterenol sulfate USP) 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 10-50%. The precise function of these, however, is not yet established (see section).
The pharmacologic effects of beta adrenergic agonist drugs, including Alupent, are at least in part attributable to stimulation through beta adrenergic receptors of intracellular adenyl cyclase, the enzyme which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (c-AMP). Increased c-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.
: Absorption, biotransformation and excretion studies in humans following administration by inhalation have shown that approximately 3 percent of the actuated dose is absorbed intact through the lungs.
Absorption, biotransformation and excretion studies in humans following oral administration indicate that an average of less than 10% of the drug is absorbed intact; it is not metabolized by catechol-O-methyl-transferase nor converted to glucuronide conjugates but is excreted primarily as the sulfate conjugate formed in the gut.
When administered orally or by inhalation, Alupent decreases reversible bronchospasm. Pulmonary function tests performed concomitantly usually show improvement following aerosol Alupent administration, e.g., an increase in the one-second forced expiratory volume (FEV 1 ), an increase in maximum expiratory flow rate, an increase in peak expiratory flow rate, an increase in forced vital capacity, and/or a decrease in airway resistance. The resultant decrease in airway obstruction may relieve the dyspnea associated with bronchospasm.
Controlled single- and multiple-dose studies have been performed with pulmonary function monitoring. The duration of effect of a single dose of Alupent Tablets 20 mg or Alupent Syrup (that is, the period of time during which there is a 15% or greater increase in FEV 1 ) was up to 4 hours.
Controlled single- and multiple-dose studies have been performed with pulmonary function monitoring. The duration of effect of a single dose of two to three inhalations of Alupent Inhalation Aerosol (that is, the period of time during which there is a 20% or greater increase in FEV 1 ) has varied from 1 to 5 hours.
In repetitive-dosing studies (up to q.i.d.) the duration of effect for a similar dose of Alupent Inhalation Aerosol has ranged from about 1 to 2.5 hours. Present studies are inadequate to explain the divergence in duration of the FEV 1 effect between single- and repetitive-dosing studies, respectively.
Following controlled single dose studies with Alupent Inhalation Solution by an intermittent positive pressure breathing apparatus (IPPB) and by hand-bulb nebulizers, significant improvement (15% or greater increase in FEV 1 ) occurred within 5 to 30 minutes and persisted for periods varying from 2 to 6 hours.
In these studies, the longer duration of effect occurred in the studies in which the drug was administered by IPPB, i.e., 6 hours, versus 2 to 3 hours when administered by hand-bulb nebulizer. In these studies, the doses used were 0.3 ml by IPPB and 10 inhalations by hand-bulb nebulizer.
In controlled repetitive-dosing studies with Alupent Inhalation Solution by IPPB and by hand-bulb nebulizer the onset of effect occurred within 5 to 30 minutes and duration ranged from 4 to 6 hours. In these studies, the doses used were 0.3 ml b.i.d. or t.i.d. when given by IPPB, and 10 inhalations q.i.d. (no more often than q4h) when given by hand-bulb nebulizer. As in the single dose studies, effectiveness was measured as a sustained increase in FEV 1 of 15% or greater. In these repetitive-dosing studies there was no apparent difference in duration between the two methods of delivery.
Clinical studies were conducted in which the effectiveness of Alupent® (metaproterenol sulfate USP) Inhalation Solution was evaluated by comparison with that of isoproterenol hydrochloride over periods of two to three months. Both drugs continued to produce significant improvement in pulmonary function throughout this period of treatment.
In two well-controlled studies in children 6 to 12 years of age with acute exacerbation of asthma, 70% of patients receiving Alupent Inhalation Solution (0.1 mL to 0.2 mL) showed improvement in pulmonary function as demonstrated by a 15% increase in FEV 1 above baseline.
Recent 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.
Alupent® (metaproterenol sulfate USP) is indicated as a bronchodilator for bronchial asthma and for reversible bronchospasm which may occur in association with bronchitis and emphysema. Alupent Inhalation Solution 5% is additionally indicated for the treatment of acute asthmatic attacks in children age 6 years and older.
Use in patients with cardiac arrhythmias associated with tachycardia is contraindicated.
Although rare, immediate hypersensitivity reactions and for Alupent Inhalation Solution 5% paradoxical bronchospasm can occur. Therefore, Alupent® (metaproterenol sulfate USP) is contraindicated in patients with a history of hypersensitivity to any of its components.
Excessive use of adrenergic aerosols is potentially dangerous. Fatalities have been reported following excessive use of Alupent® (metaproterenol sulfate USP) as with other sympathomimetic inhalation preparations, and the exact cause is unknown. Cardiac arrest was noted in several cases.
Alupent, like other beta-adrenergic agonists, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms and/or ECG changes. As with other beta-adrenergic aerosols, Alupent can produce paradoxical bronchospasm (which can be life threatening). If it occurs, the preparation should be discontinued immediately and alternative therapy instituted.
Alupent® (metaproterenol sulfate USP) should not be used more often than prescribed. Patients should be advised to contact their physician in the event that they do not respond to their usual dose of a sympathomimetic amine aerosol.
General: Extreme care must be exercised with respect to the administration of additional sympathomimetic agents.
Since metaproterenol is a sympathomimetic amine it should be used with caution in patients with cardiovascular disorders, including ischemic heart disease, hypertension or cardiac arrhythmias, in patients with hyperthyroidism or diabetes mellitus, and in patients who are unusually responsive to sympathomimetic amines or who have convulsive disorders. Significant changes in systolic and diastolic blood pressure could be expected to occur in some patients after use of any beta-adrenergic bronchodilator.
Physicians should recognize that a single dose of nebulized Alupent® (metaproterenol sulfate USP) in the treatment of acute asthma may alleviate symptoms and improve pulmonary function temporarily but fail to completely abort an attack.
Information for Patients: Extreme care must be exercised with respect to the administration of additional sympathomimetic agents. A sufficient interval of time should elapse prior to administration of another sympathomimetic agent.
Alupent Inhalation Solution 5% effects may last up to 6 hours or longer. It should not be used more often than recommended and the patient should not increase the number of inhalations or frequency of use without first consulting the physician. If symptoms of asthma get worse, adverse reactions occur, or the patient does not respond to the usual dose, the patient should be instructed to contact the physician immediately.
Alupent Tablets and Alupent Syrup should not be used more often than prescribed. If symptoms persist, patients should consult a physician promptly.
A single dose of nebulized Alupent in the treatment of an acute attack of asthma may not completely abort an attack.
Drug Interactions: Other beta-adrenergic aerosol bronchodilators should not be used concomitantly with Alupent® (metaproterenol sulfate USP) because they may have additive effects. Beta-adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta-adrenergic agonists on the vascular system may be potentiated.
Carcinogenesis/Mutagenesis/Impairment of Fertility: In an 18-month study in mice, Alupent produced a significant increase in benign hepatic adenomas in males and in benign ovarian tumors in females at doses corresponding to 31 and 62 times the maximum recommended dose (based on a 50 kg individual). In a 2-year study in rats, a nonsignificant incidence of benign leiomyomata of the mesovarium was noted at 62 times the maximum recommended dose. The relevance of these findings to man is not known. Mutagenic studies with Alupent have not been conducted. Reproduction studies in rats revealed no evidence of impaired fertility.
PREGNANCY CATEGORY C: Alupent has been shown to be teratogenic and embryotoxic in rabbits when given orally in doses 620 times the human inhalation dose and 100 mg/kg or 62 times the maximum recommended human oral dose. These effects included skeletal abnormalities, hydrocephalus and skull bone separation.
Embryotoxicity has also been shown in mice when given orally at doses of 50 mg/kg or 31 times the maximum recommended human oral dose. Results of other oral reproduction studies in rats (40 mg/kg) and rabbits (50 mg/kg) have not revealed any teratogenic, embryotoxic or fetotoxic effects. There are no adequate and well-controlled studies in pregnant women. Alupent should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether Alupent is excreted in human milk; therefore, Alupent should be used during nursing only if the potential benefit justifies the possible risk to the newborn.
Pediatric Use: Safety and effectiveness in the pediatric population have not established under the age of 6 for Alupent Tablets, Syrup & Inhalation Solutions 5% and under the age of 12 for Inhalation Aerosol and Solution 0.4% & 0.6% UDV. See DOSAGE AND ADMINISTRATION .
Adverse reactions are similar to those noted with other sympathomimetic agents. Adverse reactions such as tachycardia, hypertension, palpitations, nervousness, tremor, nausea and vomiting have been reported.
The most frequent adverse reaction to Alupent® (metaproterenol sulfate USP) administered by metered-dose inhaler among 251 patients in 90-day controlled clinical trials was nervousness. This was reported in 6.8% of patients. Less frequent adverse experiences, occurring in 1-4% of patients were headache, dizziness, palpitations, gastrointestinal distress, tremor, throat irritation, nausea, vomiting, cough and asthma exacerbation. Tachycardia occurred in less than 1% of patients.
Adverse experiences associated with Alupent Inhalation Solution 5% in at least 2% of 120 patients participating in multiple-dose clinical trial of 60 and 90-day (n=120) duration included nervousness (14.1%; n=17), cough (3.3%; n=4) headache (3.3%; n=4), tachycardia (2.5%; n=3) and tremor (2.5%; n=3).
Alupent Inhalation Solution 5% may be associated with a somewhat higher incidence of adverse reactions in children. In controlled clinical trials conducted in 160 pediatric patients the incidence of adverse reactions observed at the recommended doses was as follows: tachycardia, 16.6%; tremor, 33%; nausea, 14%; vomiting, 7.7%. The corresponding incidence in placebo-treated patients was: tachycardia, 7.6%; tremor, 20%; nausea, 7.7%; vomiting, 2.5%.
In two well-controlled studies in children 6 to 12 years of age with acute exacerbation of asthma, Alupent Inhalation Solution 5% was not efficacious in approximately 30% of patients, where efficacy was defined as a 15% increase in FEV 1 above baseline at two or more time points during the 1-hour testing period. In 8% of patients there was a decrease in FEV 1 of 10% or more from baseline at two or more time points during the testing period. Insufficient information exists to assess the relationship of drug administration to the decline in pulmonary function observed in these patients, but paradoxical bronchospasm is one possibility.
The most frequent adverse reactions to Alupent Inhalation Solution 0.4% and 0.6% are nervousness and tachycardia which occur in about 1 in 7 patients, tremor which occurs in about 1 in 20 patients and nausea which occurs in about 1 in 50 patients. Less frequent adverse reactions are hypertension, palpitations, vomiting and bad taste which occur in approximately 1 in 300 patients.
The following table of adverse experiences is derived from 26 controlled clinical trials with 496 patients treated with Alupent® (metaproterenol sulfate USP) Tablets:
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The incidence of adverse events occurring in at least 1% of the 1,120 patients treated with Alupent Syrup in 44 clinical trials are tachycardia (6.1%; n=68), nervousness (4.8%; n=54), tremor (1.6%; n=18), nausea (1.3%; n=15) and headache (1.1%; n=12).
It is important to recognize that adverse reactions from beta agonist bronchodilator solutions for nebulization may occur with the use of a new container of a product in patients who have previously tolerated that same product without adverse effect. There have been reports that indicate that such patients may subsequently tolerate replacement containers of the same product without adverse effect.
The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or any of the symptoms listed under adverse reactions, e.g. angina, hypertension or hypotension, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise and insomnia.
Treatment consists of discontinuation of metaproterenol together with appropriate symptomatic therapy.
If Alupent® (metaproterenol sulfate USP) is administered before or after other sympathomimetic bronchodilators, caution should be exercised with respect to possible potentiation of adrenergic effects.
Inhalation Aerosol: The usual single dose is two to three inhalations. With repetitive dosing, inhalation should usually not be repeated more often than about every three to four hours. Total dosage per day should not exceed 12 inhalations. Alupent Inhalation Aerosol is not recommended for use in children under 12 years of age.
Usually, treatment need not be repeated more often than every four hours to relieve acute attacks of bronchospasm.
As with all medications, the physician should begin therapy with the lowest effective dose and then titrate the dosage according to the individual patient' requirements.
Alupent Inhalation Solution 5% is administered by oral inhalation with the aid of a nebulizer or an intermittent positive pressure breathing apparatus (IPPB).
Alupent Inhalation Solution 5% may be administered three to four times a day for the treatment of reversible airways disease in adults. A single dose of nebulized Alupent in the treatment of an acute attack of asthma may not completely abort an attack.
The dosage and administration are summarized in the table below:
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Inhalation Solution 0.4% and 0.6% Unit-dose Vials: Alupent Inhalation Solution Unit-dose Vial is administered by oral inhalation using an IPPB device. The usual adult dose is one vial per nebulization treatment. Each vial of Alupent Inhalation Solution 0.4% is equivalent to 0.2 ml Alupent Inhalation Solution 5% diluted to 2.5 ml with normal saline; each vial of Alupent Inhalation Solution 0.6% is equivalent to 0.3 ml Alupent Inhalation Solution 5% diluted to 2.5 ml with normal saline.
Usually, treatment need not be repeated more often than every 4 hours to relieve acute attacks of bronchospasm. As part of a total treatment program in chronic bronchospastic pulmonary diseases, Alupent Inhalation Solution Unit-dose vials may be administered three to four times a day.
As with all medications, the physician should begin therapy with the lowest effective dose and then titrate the dosage according to the individual patient' requirements.
Alupent Inhalation Solution Unit-dose Vial is not recommended for use in children under 12 years of age.
Syrup: Children: Aged six to nine years or weight under 60 lbs--one teaspoonful three or four times a day. Children over nine years or weight over 60 lbs--two teaspoonfuls three or four times a day. Clinical trial experience in children under the age of 6 is limited. Of 40 children treated with Alupent® (metaproterenol sulfate USP) Syrup for at least 1 month, daily doses of approximately 1.3 to 2.6 mg/kg were well tolerated. Adults--two teaspoonfuls three or four times a day.
It is recommended that the physician titrate the dosage according to each individual patient' response to therapy.
Tablets: Adults: The usual dose is 20 mg three or four times a day. Children: Aged six to nine years or weight under 60 lbs--10 mg three or four times a day. Over nine years or weight over 60 lbs--20 mg three or four times a day. Alupent tablets are not recommended for use in children under six years at this time. (Please refer to the section for further information on clinical experience with this product.) It is recommended that the physician titrate the dosage according to each individual patient's response to therapy.
Inhalation Aerosol: Each 200 inhalations of Alupent® (metaproterenol sulfate USP) Inhalation Aerosol contains 150 mg of metaproterenol sulfate as a micronized powder in inert propellants. Each metered dose delivers through the mouthpiece 0.65 mg metaproterenol sulfate (each ml contains 15 mg). Alupent Inhalation Aerosol with Mouthpiece (NDC 0597-0070-17), net contents 14g (10 mL).The mouthpiece is white with a clear, colorless sleeve and a blue protective cap. Alupent Inhalation Aerosol Refill (NDC 0597-0070-18), net contents 14g (10 mL).
Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs).
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WARNING Contains trichloromonofluoromethane (CFC-11), dichlorodifluoromethane (CFC-12) and dichlorotetrafluoroethane (CFC-114), substances which harm public health and the environment by destroying ozone in the upper atmosphere. |
A notice similar to the above WARNING has been placed in the "Instructions for Use" portion of the package insert pursuant to regulations of the United States Environmental Protection Agency.
Store between 59°F (15°C) and 77°F (25°C). Avoid excessive humidity.
Inhalation Solution: Alupent® (metaproterenol sulfate USP) Inhalation Solution is supplied as a 5% solution in bottles of 10 ml (NDC 0597-0071-75) or 30 ml (NDC 0597-0071-30) with accompanying calibrated dropper. Plastic cover on dropper should be discarded and not used to retain product. Store between 59°F (15°C) and 77°F (25°C). Protect from light. Do not use the solution if it is pinkish or darker than slightly yellow or contains a precipitate.
Alupent Inhalation Solution Unit-dose Vial is supplied as a 0.4% (NDC 0597-0078-62) or 0.6% (NDC 0597-0069-62) clear colorless or nearly colorless solution containing 2.5 ml with 25 vials per box. Each vial is made from a low-density polyethylene resin. Store below 77°F (25°C). Protect from light. Do not use the solution if it is pinkish or darker than slightly yellow or contains a precipitate.
Syrup: Alupent® (metaproterenol sulfate USP) is available as a cherry-flavored syrup, 10 mg per teaspoonful (5 ml) in 16 fl. oz. bottles (NDC 0597-0073-16). Store between 59°F (15°C) and 86°F (30°C). Protect from light.
Tablets: Alupent® (metaproterenol sulfate USP) is supplied in two dosage strengths as scored round white tablets in bottles of 100. Tablets of 10 mg coded BI/74 (NDC 0597-0074-01). Tablets of 20 mg coded BI/72 (NDC 0597-0072-01). Storage for bottles: Store between 59°F (15°C) and 86°F (30°C). Protect from light. Blisters no longer distributed.
Rx only.
AL-PI-7/95
Distributed by Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, CT 06877
Licensed from Boehringer Ingelheim
International GmbH
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