Proventil Information
Proventil (Albuterol) Description
The active component of Proventil (Albuterol) Inhalation Aerosol is albuterol, USP racemic α-[(-butylamino)methyl]-4-hydroxy--xylene-α,α'-diol), a relatively selective beta-adrenergic bronchodilator, having the chemical structure:
The molecular weight of albuterol is 239.3, and the empirical formula is CHNO. Albuterol is a white to off-white crystalline solid. It is soluble in ethanol, sparingly soluble in water, and very soluble in chloroform. The World Health Organization recommended name for albuterol base is salbutamol.
Proventil (Albuterol) Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline suspension of albuterol in propellants (trichloromonofluoromethane and dichlorodifluoromethane) with oleic acid. Each actuation delivers 100 mcg albuterol, USP from the valve and 90 mcg of albuterol, USP from the mouthpiece. Each 17.0 g canister provides 200 oral inhalations.
Proventil (Albuterol) Inhalation aerosol should be primed by actuating into air, away from the eyes and face, 4 times before using for the first time and 2 times when the aerosol has not been used for a period of at least 4 days.
Proventil (Albuterol) Clinical Pharmacology
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 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--methyl transferase.
The effects of rising doses of albuterol and isoproterenol aerosols were studied in volunteers and asthmatic patients. Results in normal volunteers indicated that the propensity for increase in heart rate for albuterol is ½ to ¼ that of isoproterenol. In asthmatic patients similar cardiovascular differentiation between the two drugs was also seen.
Proventil (Albuterol) Indications And Usage
Proventil (Albuterol) Inhalation Aerosol is indicated in patients 12 years of age and older, for the prevention and relief of bronchospasm in patients with reversible obstructive airway disease, and for the prevention of exercise-induced bronchospasm.
Proventil (Albuterol) Contraindications
Proventil (Albuterol) Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components.
Proventil (Albuterol) Precautions
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 preexisting 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.
The action of Proventil (Albuterol) Inhalation Aerosol may last up to 6 hours or longer. Proventil (Albuterol) Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of doses of Proventil (Albuterol) Inhalation Aerosol without consulting your physician. If you find that treatment with Proventil (Albuterol) Inhalation Aerosol 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 Proventil (Albuterol) Inhalation Aerosol, 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 (Albuterol) Inhalation Aerosol. Effective and safe use of Proventil (Albuterol) Inhalation Aerosol includes an understanding of the way that it should be administered. See Illustrated
The contents of Proventil (Albuterol) Inhalation Aerosol are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children. Avoid spraying in eyes.
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 2.0 mg/kg (approximately 15 times the maximum recommended daily inhalation dose for adults on a mg/m 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 1700 times the maximum recommended daily inhalation dose for adults on a mg/m 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 230 times the maximum recommended daily inhalation dose for adults on a mg/m basis).
Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester strains TA1537, TA1538, and TA98 or WP2, WP2uvrA, and WP67. No forward mutation was seen in yeast strain S9 nor any mitotic gene conversion in yeast strain JD1 with or without metabolic activation. Fluctuation assays in TA98 and 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 340 times the maximum recommended daily inhalation dose for adults on a mg/m basis).
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 (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m basis), induced cleft palate formation in 5 of 111 (4.5%) fetuses. At an sc dose of 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m 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 inhalation dose for adults on a mg/m 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 sulfate was administered orally at a dose of 50 mg/kg (approximately 680 times the maximum recommended daily inhalation dose for adults on a mg/m 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.
Proventil (Albuterol) Adverse Reactions
The adverse reactions of albuterol are similar in nature to those of other sympathomimetic agents, although the incidence of certain cardiovascular effects is less with albuterol.
Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles) have also been reported after the use of inhaled albuterol. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vomiting, vertigo, central nervous system stimulation, insomnia, headache, unusual taste, and drying or irritation of the oropharynx.
Proventil (Albuterol) Overdosage
The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under , eg, 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 aerosol medications, cardiac arrest and even death may be associated with abuse of Proventil (Albuterol) Inhalation Aerosol. Treatment consists of discontinuation of Proventil (Albuterol) Inhalation Aerosol 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 (Albuterol) Inhalation Aerosol.
The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 6800 times the maximum recommended daily inhalation dose for adults on a mg/m basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3000 times the maximum recommended daily inhalation dose for adults on a mg/m basis). In small young rats, the subcutaneous median lethal dose is approximately 2000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults and children on a mg/m basis). The inhalation median lethal dose has not been determined in animals.
Proventil (Albuterol) Dosage And Administration
The usual dosage for adults and children 12 years of age and older is 2 inhalations repeated every 4 to 6 hours; in some patients, 1 inhalation every 4 hours may be sufficient. More frequent administration or a larger number of inhalations is not recommended. For maintenance therapy or prevention of exacerbation of bronchospasm, 2 inhalations, 4 times a day should be sufficient.
The use of Proventil (Albuterol) Inhalation Aerosol 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 inhaler. Safe usage for periods extending over several years has been documented.
If a previously effective dosage regimen fails to provide the usual response, 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, eg, corticosteroids.
The usual dosage for adults and children 12 years and older is 2 inhalations, 15 minutes prior to exercise. For treatment, see above.
As with all other inhalation aerosol medications, patients should make sure that the canister is firmly seated in the plastic mouthpiece before each use and the product is primed at specific times. Patients should prime Proventil (Albuterol) Inhalation Aerosol by actuating into the air, away from the eyes and face, 4 times before using for the first time and 2 times when the aerosol has not been used for a period of at least 4 days.
Proventil (Albuterol) How Supplied
Proventil (Albuterol) Inhalation Aerosol, 17.0 g canister contains 200 metered inhalations, box of one (NDC 0085-0614-02). Each actuation delivers 100 mcg of albuterol from the valve and 90 mcg of albuterol from the mouthpiece. Each canister is supplied with a yellow plastic actuator with orange dust cap, and Patient's Instructions.
Proventil (Albuterol) Inhalation Aerosol REFILL canister, 17.0 g, contains 200 metered inhalations, with Patient's Instructions; box of one (NDC 0085-0614-03).
The correct amount of medication in each inhalation cannot be assured after 200 actuations from the 17.0 g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used.
Proventil (Albuterol) Inhalation Aerosol canister should be used only with the actuator provided. The yellow actuator should not be used with other aerosol medication canisters.
A notice similar to the above WARNING has been placed in the "Patient's Instructions for Use" portion of this package insert under the Environmental Protection Agency's (EPA's) regulations. The patient's warning states that the patient should consult his or her physician if there are questions about alternatives.
Proventil (Albuterol)
Proventil (Albuterol)
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