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The active component of MAXAIR Inhaler is (R,S)(alpha) 6 -{[(1,1-dimethylethyl)amino]methyl}-3-hydroxy-2,6-pyridine-dimethanol monoacetate salt, a beta-2 adrenergic bronchodilator, having the following chemical structure:
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Pirbuterol acetate is a white, crystalline racemic mixture of two optically active isomers. It is a powder, freely soluble in water, with a molecular weight of 300.3 and empirical formula of C 12 H 20 N 2 O 3 ·C 2 H 4 O 2 .
MAXAIR Inhaler is a metered dose aerosol unit for oral inhalation. It provides a fine-particle suspension of pirbuterol acetate in the propellant mixture of trichloromonofluoromethane and dichlorodifluoromethane, with sorbitan trioleate. Each actuation delivers from the mouthpiece pirbuterol acetate equivalent to 0.2 mg of pirbuterol with the majority of particles less than 5 microns in diameter. Each canister provides at least 300 inhalations.
In vitro studies and in vivo pharmacologic studies have demonstrated that MAXAIR 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 pirbuterol, 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.
Bronchodilator activity of MAXAIR was manifested clinically by an improvement in various pulmonary function parameters (FEV 1 , MMF, PEFR, airway resistance [RAW] and conductance [GA/V tg ]).
In controlled double-blind single dose clinical trials, the onset of improvement in pulmonary function occurred within 5 minutes in most patients as determined by forced expiratory volume in one second (FEV 1 ). FEV 1 and MMF measurements also showed that maximum improvement in pulmonary function generally occurred 30-60 minutes following one (1) or two (2) inhalations of pirbuterol (0.2-0.4 mg). The duration of action of MAXAIR is maintained for 5 hours (the time at which the last observations were made) in a substantial number of patients, based on a 15% or greater increase in FEV 1 . In controlled repetitive dose studies of 12 weeks' duration, 74% of 156 patients on pirbuterol and 62% of 141 patients on metaproterenol showed a clinically significant improvement based on a 15% or greater increase in FEV 1 on at least half of the days. Onset and duration were equivalent to that seen in single dose studies. Continued effectiveness was demonstrated over the 12-week period in the majority (94%) of responding patients; however, chronic dosing was associated with the development of tachyphylaxis (tolerance) to the bronchodilator effect in some patients in both treatment groups.
A placebo-controlled double-blind single dose study (24 patients per treatment group), utilizing continuous Holter monitoring for 5 hours after drug administration, showed no significant difference in ectopic activity between the placebo control group and MAXAIR at the recommended dose (0.2-0.4 mg), and twice the recommended dose (0.8 mg). As with other inhaled beta adrenergic agonists, supraventricular and ventricular ectopic beats have been seen with MAXAIR (see ).
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.
As expected by extrapolation from oral data, systemic blood levels of pirbuterol are below the limit of assay sensitivity (2-5 ng/ml) following inhalation of doses up to 0.8 mg (twice the maximum recommended dose). A mean of 51% of the dose is recovered in urine as pirbuterol plus its sulfate conjugate following administration by aerosol. Pirbuterol is not metabolized by catechol-O-methyltransferase. The percent of administered dose recovered as pirbuterol plus its sulfate conjugate does not change significantly over the dose range of 0.4 mg to 0.8 mg and is not significantly different from that after oral administration of pirbuterol. The plasma half-life measured after oral administration is about two hours.
MAXAIR Inhaler is indicated for the prevention and reversal of bronchospasm in patients with reversible bronchospasm including asthma. It may be used with or without concurrent theophylline and/or steroid therapy.
MAXAIR is contraindicated in patients with a history of hypersensitivity to any of its ingredients.
As with other beta adrenergic aerosols, MAXAIR should not be used in excess. Controlled clinical studies and other clinical experience have shown that MAXAIR like other inhaled 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, the potential for paradoxical bronchospasm (which can be life threatening) should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted.
Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
The contents of MAXAIR Inhaler are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperature above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children.
Since pirbuterol 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 aerosol bronchodilator.
MAXAIR effects may last up to five 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 asking 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. The patient should be advised to see the Illustrated Directions for Use.
Other beta adrenergic aerosol bronchodilators should not be used concomitantly with MAXAIR 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.
Pirbuterol hydrochloride administered in the diet to rats for 24 months and to mice for 18 months was free of carcinogenic activity at doses corresponding to 200 times the maximum human inhalation dose. In addition, the intragastric intubation of the drug at doses corresponding to 6250 times the maximum recommended human daily inhalation dose resulted in no increase in tumors in a 12-month rat study. Studies with pirbuterol revealed no evidence of mutagenesis. Reproduction studies in rats revealed no evidence of impaired fertility.
Reproduction studies have been performed in rats and rabbits by the inhalation route at doses up to 12 times (rat) and 16 times (rabbit) the maximum human inhalation dose and have revealed no significant findings. Animal reproduction studies in rats at oral doses up to 300 mg/kg and in rabbits at oral doses up to 100 mg/kg have shown no adverse effect on reproductive behavior, fertility, litter size, peri- and postnatal viability or fetal development. In rabbits at the highest dose level given, 300 mg/kg, abortions and fetal mortality were observed. There are no adequate and well controlled studies in pregnant women and MAXAIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether MAXAIR is excreted in human milk. Therefore, MAXAIR should be used during nursing only if the potential benefit justifies the possible risk to the newborn.
MAXAIR Inhaler is not recommended for patients under the age of 12 years because of insufficient clinical data to establish safety and effectiveness.
The following rates of adverse reactions to pirbuterol are based on single and multiple dose clinical trials involving 761 patients, 400 of whom received multiple doses (mean duration of treatment was 2.5 months and maximum was 19 months).
The following were the adverse reactions reported more frequently than 1 in 100 patients:
CNS: nervousness (6.9%), tremor (6.0%), headache (2.0%), dizziness (1.2%).
Cardiovascular: palpitations (1.7%), tachycardia (1.2%).
Respiratory: cough (1.2%).
Gastrointestinal: nausea (1.7%).
The following adverse reactions occurred less frequently than 1 in 100 patients and there may be a causal relationship with pirbuterol:
CNS: depression, anxiety, confusion, insomnia, weakness, hyperkinesia, syncope.
Cardiovascular: hypotension, skipped beats, chest pain.
Gastrointestinal: dry mouth, glossitis, abdominal pain/cramps, anorexia, diarrhea, stomatitis, nausea and vomiting.
Ear, Nose and Throat: smell/taste changes, sore throat.
Dermatological: rash, pruritus.
Other: numbness in extremities, alopecia, bruising, fatigue, edema, weight gain, flushing.
Other adverse reactions were reported with a frequency of less than 1 in 100 patients but a causal relationship between pirbuterol and the reaction could not be determined: migraine, productive cough, wheezing, and dermatitis.
The following rates of adverse reactions during three-month controlled clinical trials involving 310 patients are noted. The table does not include mild reactions.
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The expected symptoms with overdosage are those of excessive beta-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 pirbuterol together with appropriate symptomatic therapy.
The oral acute lethal dose in male and female rats and mice was greater than 2000 mg base/kg. The aerosol acute lethal dose was not determined.
The usual dose for adults and children 12 years and older is two inhalations (0.4 mg) repeated every 4-6 hours. One inhalation (0.2 mg) repeated every 4-6 hours may be sufficient for some patients.
A total daily dose of 12 inhalations should not be exceeded.
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 which would require reassessment of therapy.
MAXAIR Inhaler box of one, is supplied in a pressurized aluminum canister with a light-blue plastic actuator and attached white mouthpiece. Each actuation delivers pirbuterol acetate equivalent to 256 mcg of pirbuterol (as pirbuterol acetate) from the value and 200 mcg of pirbuterol (as pirbuterol acetate) from the mouthpiece.
Net content weight 25.6 g, 300 actuations (NDC 0089-0790-21 ). The correct amount of medication in each canister cannot be assured after 300 actuations even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations has been used.
Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's).
WARNING: Contains trichloromonofluoromethane and dichlorodifluoromethane, substances which harm public health and environment by destroying ozone in the upper atmosphere.
A notice similar to the above WARNING has been placed in the "Patient' Instructions for Use" of this product pursuant to EPA regulations. The patient' warning states that the patient should consult his or her physician if there are questions about alternatives.
Rx only
Store between 15° and 30°C (59° to 86°F).
Failure to use this product within this temperature range may result in improper dosing. For optimal results, the canister should be at room temperature before use. Shake well before using.
The contents of MAXAIR Inhaler are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperature above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children. Avoid spraying in eyes.
The light blue plastic actuator supplied with MAXAIR Inhaler should not be used with any other product canisters, and actuators from other products should not be used with the MAXAIR Inhaler canister.
3M Pharmaceuticals
Northridge, CA 91324
620901 May 1998
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