CONTRAINDICATIONS
Albuterol formulations are contraindicated in patients with a history of hypersensitivity to
any of its components.
WARNINGS
Syrup
Immediate hypersensitivity reactions may occur after administration of albuterol, as
demonstrated by rare cases of anaphylaxis, angioedema, oropharyngeal edema,
bronchospasm, urticaria and rash.
Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with
the administration of albuterol sulfate syrup in children.
Immediate-Release Tablets
Paradoxical Bronchospasm: Albuterol can produce paradoxical bronchospasm, which
may be life threatening. If paradoxical bronchospasm occurs, albuterol should be
discontinued immediately and alternative therapy instituted.
Cardiovascular Effects: Albuterol, 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 albuterol 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
QTc interval, and ST segment depression. The clinical significance of these findings is
unknown. Therefore, albuterol like all sympathomimetic amines, should be used with
caution in patients with cardiovascular disorders, especially coronary insufficiency,
cardiac arrhythmias, and hypertension.
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 albuterol than
usual, 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 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).
Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur
after administration of albuterol, as demonstrated by rare cases or urticaria, angiodema,
rash, bronchospasm, and oropharyngeal edema. Albuterol, like other beta-adrenergic
agonists, can produce a significant cardiovascular effect in some patients, as measured by
pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.
Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with
the administration of oral albuterol sulfate in children.
PRECAUTIONS
General
Syrup: Although albuterol usually has minimal effects on the beta1-adrenoceptors of the
cardiovascular system at the recommended dosage, occasionally the usual cardiovascular
and CNS stimulatory effects common to all sympathomimetic agents have been seen with
patients treated with albuterol necessitating discontinuation.
Syrup, Tablets and Extended-Release Tablets: Albuterol, as with all sympathomimetic
amines, should be used with caution in patients with cardiovascular disorders, including
(Extended-Release Tablets Only: ischemic heart disease, (Syrup and
Immediate-Release Tablets Only: coronary insufficiency), hypertension, or cardiac
arrhythmias, in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus;
and in patients who are unusually responsive to sympathomimetic amines. Tablets:
Clinically significant changes in systolic and diastolic blood pressure have been seen in
individual patients 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 through intracellular shunting, which has the
potential to produce adverse cardiovascular effects. The decrease is usually transient, not
requiring supplementation.
Information for the Patient
Syrup: The action of albuterol syrup may last up to 6 hours and therefore it should not be
taken more frequently than recommended. Do not increase the dose or frequency of
medication without medical consultation. If symptoms get worse, medical consultation
should be sought promptly. If pregnant or nursing, consult with your physician.
Immediate-Release Tablets: The action of albuterol immediate-release tablets may last
up to 8 hours or longer. Albuterol should not be taken more frequently than
recommended. Do not increase the dose or frequency of albuterol tablets without
consulting your physician. If you find that treatment with albuterol becomes less effective
for symptomatic relief, your symptoms get worse, and/or you need to take the product
more frequently than usual, you should seek medical attention immediately. While you are
taking albuterol, other asthma medications and inhaled drugs should be taken only as
directed by your physician. Common adverse effects include palpitations, chest pain,
rapid heart rate, and tremor or nervousness. If you are pregnant or nursing, contact your
physician about use of albuterol. Effective and safe use of albuterol includes an
understanding of the way that it should be administered.
Extended-Release Tablets: Patients being treated with albuterol extended-release 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.
Albuterol extended-release tablets should not be chewed, crushed or mixed in food.
Albuterol extended-release tablets should not be taken more frequently than
recommended. Do not increase the dose or frequency of 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 your
physician.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Extended-Release Tablets and Syrup
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 (or in syrup,
2, 9, and 46 times the maximum human [child weighing 21 kg] 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.
Immediate-Release Tablets
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 dietary
doses of 2.0, 10, and 50 mg/kg (approximately ˝, 3, and 15 times, respectively, the
maximum recommended daily oral dose for adults on a mg/m2 basis or 2/5, 2, and 10
times, respectively, the maximum recommended daily oral dose for children on a mg/m2
basis. In another study this effect was blocked by the coadministration of propranolol, a
non-selective beta-adrenergic antagonist.
In an 18–month study in CD-1 mice, albuterol sulfate showed no evidence of
tumorigenicity at dietary doses of up to 500 mg/kg (approximately 65 times the maximum
recommended daily oral dose for adults on a mg/m2 basis or approximately 50 times the
maximum recommended daily oral dose for children on a mg/m2 basis). In a 22–month
study in the Golden hamster, albuterol sulfate showed no evidence of tumorigenicity at
dietary doses of up to 50 mg/kg (approximately 8 times the maximum recommended
daily oral dose for adults on a mg/m2 basis or approximately 7 times the maximum
recommended daily oral dose for children on a mg/m2 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 at
intraperitoneal doses of up to 200 mg/kg.
Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses
up to 50 mg/kg (approximately 15 times the maximum recommended daily oral dose for
adults on a mg/m 2 basis).
Pregnancy, 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 [in syrup 0.2 times the
maximum human [child weighing 21 kg] 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 study in CD-1 mice at
subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg (approximately 3/1000, 3/100,
and 3/10 times, respectively, the maximum recommended daily oral dose for adults on a
mg/m2 basis) 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. The drug did not induce cleft palate formation
at the lowest dose, at 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%)
fetuses from females treated with 2.5 mg/kg isoproterenol (positive control) subcutaneous
(approximately 3/10 times the maximum recommended daily oral dose for adults on a
mg/m2 basis. A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of
19 (37%) fetuses at 50 mg/kg, corresponding to 78 times the maximum human oral dose
of albuterol (in syrup, 46 times the maximum human [child weighing 21 kg] oral dose of
albuterol sulfate).
During worldwide marketing experience, various congenital anomalies, including cleft
palate and limb defects, have been rarely reported in the offspring of patients being
treated with albuterol. Some of the mothers were taking multiple medications during their
pregnancies. No consistent pattern of defects can be discerned, and a relationship
between albuterol use and congenital anomalies cannot be established.
Labor and Delivery
Syrup and Extended-Release Tablets: Oral albuterol has been shown to delay preterm
labor in some reports. There are presently no well-controlled studies that demonstrate
that it will stop preterm labor or prevent labor at term. Therefore, cautious use of
albuterol is required in pregnant patients when given for relief of bronchospasm so as to
avoid interference with uterine contractility. Use in such patients should be restricted to
those patients in whom the benefits clearly outweigh the risks.
Immediate-Release Tablets: Because of the potential for beta-agonist interference with
uterine contractility, use of albuterol 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
ration 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 beta2—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
Syrup: Safety and effectiveness in children below the age of 2 years have not yet been
adequately demonstrated.
Immediate-Release Tablets: Safety and effectiveness in children below the age of 6
years for albuterol have not been established.
Extended-Release Tablets: The safety and effectiveness of albuterol extended-release
tablets have been established in pediatric patients 6 years of age and older. Use of
albuterol extended-release tablets in these age groups is supported by evidence from
adequate and well-controlled studies of albuterol extended-release tablets in adults; the
likelihood that the disease course, pathophysiology, and the drug's effect in pediatric and
adult patients are substantially similar; the established safety and effectiveness of albuterol
immediate-release tablets in pediatric patients 6 years of age and older; and one clinical
trial that provides evidence of the safety of albuterol extended-release tablets in pediatric
patients aged 6 to 12 years. The recommended dose of albuterol extended-release
tablets for the pediatric population is based upon the recommended pediatric dosing of
albuterol immediate-release tablets and pharmacokinetic studies in adults showing
albuterol extended-release tablets to have similar peak albuterol levels (i.e., Cmax) and
exposures (i.e., AUC) as albuterol immediate-release tablets administered every 6 hours
at one-half of the albuterol extended-release tablets dose. Safety and effectiveness in
children below the age of 6 years have not been established for albuterol
extended-release tablets.