Included as part of the PRECAUTIONS section.
XOPENEX Inhalation Solution can produce paradoxical
bronchospasm, which may be life-threatening. If paradoxical bronchospasm
occurs, XOPENEX Inhalation Solution should be discontinued immediately and
alternative therapy instituted. It should be recognized that paradoxical
bronchospasm, when associated with inhaled formulations, frequently occurs with
the first use of a new vial.
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
XOPENEX Inhalation Solution 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, e.g., corticosteroids.
Use Of Anti-Inflammatory Agents
XOPENEX Inhalation Solution is not a substitute for
corticosteroids. The use of beta-adrenergic agonist alone may not be adequate
to control asthma in many patients. Early consideration should be given to
adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic
XOPENEX Inhalation Solution, like other beta-adrenergic
agonists, can produce clinically significant cardiovascular effects in some
patients, as measured by heart rate, blood pressure, and symptoms. Although
such effects are uncommon after administration of XOPENEX Inhalation Solution
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, XOPENEX Inhalation Solution, like all sympathomimetic
amines, should be used with caution in patients with cardiovascular disorders,
especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Do Not Exceed Recommended Dose
Do not exceed the recommended dose. Fatalities have been
reported in association with excessive use of inhaled sympathomimetic drugs in
patients with asthma. The exact cause of death is unknown, but cardiac arrest
following an unexpected development of a severe acute asthmatic crisis and
subsequent hypoxia is suspected.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after
administration of levalbuterol or racemic albuterol. Reactions have included
urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal
edema. The potential for hypersensitivity must be considered in the clinical
evaluation of patients who experience immediate hypersensitivity reactions
while receiving XOPENEX Inhalation Solution.
XOPENEX Inhalation Solution, like all sympathomimetic
amines, should be used with caution in patients with cardiovascular disorders,
especially coronary insufficiency, hypertension, and cardiac arrhythmias; 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 in
individual patients and could be expected to occur in some patients after the
use of any beta-adrenergic bronchodilator.
Changes in blood glucose may occur. Large doses of
intravenous racemic albuterol have been reported to aggravate preexisting
diabetes mellitus and ketoacidosis.
As with other beta-adrenergic agonist medications,
XOPENEX Inhalation Solution 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
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION
and Instructions for Using XOPENEX Inhalation Solution).
Patients should be given the following information:
Query patients about previously experienced
hypersensitivity to levalbuterol or racemic albuterol and counsel patients to
report any hypersensitivity reactions to their physician.
Frequency Of Use
Inform patients not to increase the dose or use XOPENEX
Inhalation Solution more frequently than recommended without consulting their
physician. If patients find that treatment with XOPENEX Inhalation Solution
becomes less effective for symptomatic relief, symptoms become worse, or they need
to use the product more frequently than usual, they should seek medical
Inform patients that XOPENEX Inhalation Solution can
produce paradoxical bronchospasm. Instruct patients to discontinue XOPENEX
Inhalation Solution if paradoxical bronchospasm occurs.
Concomitant Drug Use
Inform patients using XOPENEX Inhalation Solution, that
other inhaled drugs and asthma medications should be taken only as directed by
Common Adverse Reactions
Advise patients of the common adverse reactions of
treatment with XOPENEX Inhalation Solution including palpitations, chest pain,
fast heart rate, headache, dizziness, tremor and nervousness.
Advise patients who are pregnant or nursing to contact
their physician about the use of XOPENEX Inhalation Solution.
General Information On Storage And Use
Advise patients to store XOPENEX Inhalation Solution in
the foil pouch between 20°C to 25°C (68°F to 77°F) protected from light and
excessive heat. Do not use after the expiration date stamped on the container.
Store unused vials in the protective foil pouch. Once the foil pouch is opened,
use the vials within 2 weeks. Use vials removed from the pouch, immediately, or
protect from light and use within 1 week. Discard any vial if the solution is
Advise patients not to mix XOPENEX Inhalation Solution
with other drugs in a nebulizer.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Although there have been no carcinogenesis studies with
levalbuterol HCl, racemic albuterol sulfate has been evaluated for its
In a 2-year study in Sprague-Dawley rats, dietary
administration of racemic albuterol sulfate resulted in a significant
dose-related increase in the incidence of benign leiomyomas of the mesovarium
at doses of 2 mg/kg/day and greater (approximately 4 times the MRDI dose of
levalbuterol HCl for adults and approximately 5 times the MRDI dose of
levalbuterol HCl for children on a mg/m² basis). In an 18- month study in CD-1
mice and a 22-month study in the golden hamster, dietary administration of
racemic albuterol sulfate showed no evidence of tumorigenicity. Dietary doses
in CD-1 mice were up to 500 mg/kg/day (approximately 540 times the MRDI dose of
levalbuterol HCl for adults and approximately 630 times the MRDI dose of
levalbuterol HCl for children on a mg/m² basis) and doses in the golden hamster
study were up to 50 mg/kg/day (approximately 90 times the MRDI dose of
levalbuterol HCl for adults on a mg/m² basis and approximately 105 times the
MRDI dose of levalbuterol HCl for children on a mg/m² basis).
Levalbuterol HCl was not mutagenic in the Ames test or
the CHO/HPRT Mammalian Forward Gene Mutation Assay. Levalbuterol HCl was not
clastogenic in the in vivo micronucleus test in mouse bone marrow. Racemic
albuterol sulfate was not clastogenic in an in vitro chromosomal aberration
assay in CHO cell cultures.
No fertility studies have been conducted with
levalbuterol hydrochloride. Reproduction studies in rats using racemic
albuterol sulfate demonstrated no evidence of impaired fertility at oral doses
up to 50 mg/kg/day (approximately 108 times the maximum recommended daily
inhalation dose of levalbuterol HCl for adults on a mg/m² basis).
Use In Specific Populations
Pregnancy Category C.
There are no adequate and well-controlled studies of
XOPENEX Inhalation Solution in pregnant women. Because animal reproduction
studies are not always predictive of human response, XOPENEX Inhalation
Solution 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
newborns of women treated with racemic albuterol which contains the levalbuterol
isomer (active drug substance of XOPENEX Inhalation Solution). However, since
multiple medications were taken during some of the pregnancies and there was no
consistent pattern of anomalies, it was not possible to establish a
relationship between racemic albuterol use and the occurrence of these congenital
In animal studies, oral administration of levalbuterol
HCl to pregnant New Zealand White rabbits found no evidence of teratogenicity
at doses up to 25 mg/kg/day (approximately 108 times the maximum recommended
daily inhalation [MRDI] dose of levalbuterol HCl for adults on a mg/m² basis).
However, other studies demonstrated that racemic
albuterol sulfate was teratogenic in mice and rabbits at doses comparable to
the human therapeutic range. Pregnant mice administered racemic albuterol sulfate
subcutaneously had a dose-related increased incidence of cleft palate in their
fetuses (4.5% of fetuses at 0.25 mg/kg/day or greater, corresponding to
approximately 0.3 times the MRDI dose, 9.3% of fetuses at 2.5 mg/kg/day,
approximately 3 times the MRDI dose of levalbuterol HCl for adults on a mg/m²
basis). The drug did not induce cleft palate formation when administered
subcutaneously at a dose of 0.025 mg/ kg/day (approximately 0.03 times the MRDI
dose of levalbuterol HCl for adults on a mg/m² basis). In addition, oral
administration of racemic albuterol sulfate to pregnant rabbits resulted in an
increased incidence of cranioschisis in fetuses (approximately 215 times the
MRDI dose of levalbuterol HCl for adults on a mg/m² basis).
A study in which pregnant rats were dosed with
radiolabeled racemic albuterol sulfate demonstrated that drug-related material
is transferred from the maternal circulation to the fetus.
Labor And Delivery
Because of the potential for beta-adrenergic agonists to
interfere with uterine contractility, the use of XOPENEX Inhalation Solution
for the treatment of bronchospasm during labor should be restricted to those
patients in whom the benefits clearly outweigh the risk.
XOPENEX Inhalation Solution has not been approved for the
management of preterm labor. The benefit:risk ratio when levalbuterol HCl 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 racemic albuterol.
Plasma concentrations of levalbuterol after inhalation of
therapeutic doses are very low in humans. It is not known whether levalbuterol
is excreted in human milk.
Because of the potential for tumorigenicity shown for
racemic albuterol in animal studies and the lack of experience with the use of
XOPENEX Inhalation Solution by nursing mothers, 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. Caution should be exercised when
XOPENEX Inhalation Solution is administered to a nursing woman.
Pediatric Patients 6 Years Of Age And Older
The safety and efficacy of XOPENEX Inhalation Solution
have been established in pediatric patients 6 years of age and older in an
adequate and well-controlled clinical trial [see ADVERSE REACTIONS and Clinical
Pediatric Patients Less Than 6 Years Of Age
XOPENEX Inhalation Solution is not indicated for
pediatric patients less than 6 years of age.
Clinical trials with XOPENEX Inhalation Solution in this
age group failed to meet the primary efficacy endpoint and demonstrated an
increased number of asthma-related adverse reactions following chronic XOPENEX
XOPENEX Inhalation Solution was studied in 379 pediatric
patients less than 6 years of age with asthma or reactive airway disease - (291
patients 2 to 5 years of age, and 88 patients from birth to less than 2 years
of age). Efficacy and safety data for XOPENEX Inhalation Solution in this age
group are primarily available from one 3-week, multicenter, randomized,
double-blind, active and placebo- controlled study (Study 1) in 211 pediatric
patients between the ages of 2 and 5 years, of whom 119 received XOPENEX
Inhalation Solution. Over the 3 week treatment period, there were no
significant treatment differences in the Pediatric Asthma Questionnaire (PAQ)
total score between groups receiving XOPENEX Inhalation Solution 0.31 mg,
XOPENEX Inhalation Solution 0.63 mg, racemic albuterol, and placebo. Additional
safety data following chronic dosing is available from a 4-week, multicenter,
randomized, modified-blind, placebo-controlled study (Study 2) of 196 patients
between the ages of birth and 3 years, of whom 63 received open-label XOPENEX
Inhalation Solution. In these two studies, treatment-emergent asthma
exacerbations or asthma-related adverse reactions and treatment discontinuations
due to asthma occurred at a higher frequency in XOPENEX Inhalation-treated
subjects compared to control (Table 5). Other adverse reactions were consistent
with those observed in the clinical trial population of patients 6 years of age
and older [see ADVERSE REACTIONS].
Table 5: Asthma-related Adverse Reactions in 3- and
4-Week Clinical Trials in Children Birth to <6 Years of Age
|Treatment Discontinuations due to Asthma
|Asthma-related Adverse Reactions**
|XOPENEX 0.31 mg, n=58
|XOPENEX 0.63 mg, n=51
|Racemic albuterol, n=52
|XOPENEX 0.31 mg, n=63
|Levalbuterol HFA inhalation aerosol, n=65
|*Asthma exacerbation defined as worsening of asthma
symptoms or pulmonary function that required any of the following: emergency
department visit, hospitalization, therapeutic intervention with oral or
parenteral steroids, unscheduled clinic visit to treat acute asthma symptoms
**Includes the following Preferred Terms (whether considered by the
investigator to be related or unrelated to drug): asthma, cough, hypoxia,
status asthmaticus, tachypnea
Clinical studies of XOPENEX Inhalation Solution did not
include sufficient numbers of subjects aged 65 years and older to determine
whether they respond differently from younger subjects. Only 5 patients 65
years of age and older were treated with XOPENEX Inhalation Solution in a
4-week clinical study [see CLINICAL PHARMACOLOGY and Clinical Studies]
(n=2 for 0.63 mg and n=3 for 1.25 mg). In these patients, bronchodilation was
observed after the first dose on day 1 and after 4 weeks of treatment. In general,
patients 65 years of age and older should be started at a dose of 0.63 mg of
XOPENEX Inhalation Solution. If clinically warranted due to insufficient
bronchodilator response, the dose of XOPENEX Inhalation Solution may be
increased in elderly patients as tolerated, in conjunction with frequent
clinical and laboratory monitoring, to the maximum recommended daily dose [see
DOSAGE AND ADMINISTRATION].
Albuterol is known to be substantially excreted by the
kidney, and the risk of toxic reactions may be greater in patients with
impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.