Included as part of the PRECAUTIONS section.
XOPENEX HFA can produce paradoxical bronchospasm, which
may be life-threatening. If paradoxical bronchospasm occurs, XOPENEX HFA 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 canister.
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 HFA 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.,
Use Of Anti-Inflammatory Agents
The use of a 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
XOPENEX HFA, 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 HFA at recommended doses, if they
occur, the drug may need to be discontinued. In addition, betaagonists 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 HFA,
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
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 racemic albuterol, as demonstrated by rare cases of
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 HFA.
XOPENEX HFA, 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
Large doses of intravenous racemic albuterol have been
reported to aggravate preexisting diabetes mellitus and ketoacidosis.
As with other beta-adrenergic agonist medications,
XOPENEX HFA 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
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Using XOPENEX HFA).
Patients should be given the following information:
Frequency of Use
The action of XOPENEX HFA should last for 4 to 6 hours.
Do not use XOPENEX HFA more frequently than recommended. Instruct patients to
not increase the dose or frequency of doses of XOPENEX HFA without consulting
their physician. If patients find that treatment with XOPENEX HFA becomes less
effective for symptomatic relief, symptoms become worse, or they need to use
the product more frequently than usual, they should seek medical attention
Priming, Cleaning and Storage
Priming: SHAKE WELL BEFORE USING. Patients should
be instructed that priming XOPENEX HFA is essential to ensure appropriate
levalbuterol content in each actuation. Patients should prime XOPENEX HFA
before using for the first time and in cases where the inhaler has not been
used for more than 3 days by releasing 4 test sprays into the air, away from
Cleaning: To ensure proper dosing and prevent
actuator orifice blockage, instruct patients to wash the actuator in warm water
and air-dry thoroughly at least once a week. Patients should be informed that
detailed cleaning instructions are included in the FDA-Approved Patient
Storage: Store canister between 20° and 25°C (68°
and 77°F). Protect from freezing temperatures and direct sunlight.
Inform patients that XOPENEX HFA can produce paradoxical
bronchospasm. Instruct patients to discontinue XOPENEX HFA if paradoxical
Concomitant Drug Use
While patients are using XOPENEX HFA, other inhaled drugs
and asthma medications should be taken only as directed by the physician.
Common Adverse Reactions
Common adverse effects of treatment with inhaled
beta-agonists include palpitations, chest pain, rapid heart rate, tremor, and
Patients who are pregnant or nursing should contact their
physicians about the use of XOPENEX HFA.
General Information on Use
Effective and safe use of XOPENEX HFA includes an
understanding of the way that it should be administered.
Shake the inhaler well immediately before each use.
Use XOPENEX HFA only with the actuator supplied with the
product. Discard the canister after 200 sprays have been used from the 15 g
canister or after 80 sprays have been used from the 8.4 g canister. Never
immerse the canister in water to determine how full the canister is (“float
In general, the technique for administering XOPENEX HFA
to children is similar to that for adults. Children should use XOPENEX HFA
under adult supervision, as instructed by the patient's physician [see FDA-approved
patient labeling – (PATIENT INFORMATION and Instructions for Using
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Although there have been no carcinogenesis studies with
levalbuterol tartrate, 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 30 times the MRDI) dose of
levalbuterol tartrate for adults and approximately 15 times the MRDI dose of
levalbuterol tartrate 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 3800 times the MRDI dose of levalbuterol tartrate for adults and
approximately 1800 times the MRDI dose of levalbuterol tartrate for children on
a mg/m² basis) and doses in the golden hamster study were up to 50
mg/kg/day (approximately 500 times the MRDI dose of levalbuterol tartrate for
adults on a mg/m² basis and approximately 240 times the MRDI dose of
levalbuterol tartrate 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 tartrate. Reproduction studies in rats using racemic albuterol
sulfate demonstrated no evidence of impaired fertility at oral doses up to 50
mg/kg/day (approximately 750 times the maximum recommended daily inhalation
dose of levalbuterol tartrate for adults on a mg/m² basis).
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of
XOPENEX HFA in pregnant women. Because animal reproduction studies are not
always predictive of human response, XOPENEX HFA should be used during
pregnancy only if the potential benefit justifies the potential risk to the
Rare instances of congenital anomalies, including cleft
palate and limb defects, were reported in newborns of women treated with
racemic albuterol in which the levalbuterol isomer (active drug substance of
XOPENEX HFA) is present. However, since multiple medications were taken during
their 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 anomalies.
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 750 times the maximum recommended
daily inhalation dose of levalbuterol tartrate for adults on a mg/m² basis).
However, other studies demonstrated that racemic
albuterol sulfate was teratogenic in mice and rabbits at doses slightly higher
than the human therapeutic range. Pregnant mice administered racemic albuterol
sulfate subcutaneously resulted in 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 2 times MRDI dose, 9.3% of fetuses at 2.5
mg/kg/day, approximately 20 times MRDI dose of levalbuterol tartrate 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
0.2 times MRDI dose of levalbuterol tartrate 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 1500 times the MRDI dose of levalbuterol tartrate 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 HFA for the treatment
of bronchospasm during labor should be restricted to those patients in whom the
benefits clearly outweigh the risk.
XOPENEX HFA has not been approved for the management of
preterm labor. The benefit:risk ratio when levalbuterol tartrate 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 HFA 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
HFA is administered to a nursing woman.
Pediatric Patients 4 Years of Age and Older
The safety and efficacy of XOPENEX HFA have been
established in pediatric patients 4 years of age and older in an adequate and
well-controlled clinical trial [see ADVERSE REACTIONS and Clinical
Pediatric Patients less than 4 Years of Age
XOPENEX HFA is not indicated for pediatric patients less
than 4 years of age. A clinical trial in pediatric patients below the age of 4
years showed no statistical significant difference between treatment groups in
the primary efficacy endpoint. There was an increased incidence of
asthma-related adverse reactions reported in pediatric patients below the age
of 4 years treated with XOPENEX HFA compared to placebo.
XOPENEX HFA was evaluated in one 4-week, multicenter,
randomized, modified-blind, placebo-controlled, parallel group trial of 196
pediatric patients ages birth to < 4 years of age with asthma or reactive
airway disease (68 patients birth to < 2 years of age and 128 patients 2 to
< 4 years of age). XOPENEX HFA 45 mcg (N=23), XOPENEX HFA 90 mcg (N=42),
levalbuterol inhalation solution 0.31 mg (N=63), and placebo HFA (N=68) were
administered three times daily. XOPENEX HFA or placebo HFA was delivered with
the Monaghan AeroChamber MAX™ Valved Holding Chamber with mask. The primary
efficacy endpoint was the mean change in Pediatric Asthma Caregiver Assessment
(PACA) total score from baseline over the 4 week treatment period. There was no
statistical difference in the change in PACA total score between Xopenex HFA
and placebo. Regarding safety, an increased number of treatment-emergent
asthma-related adverse reactions were reported in XOPENEX HFA-treated patients.
Eight subjects reported asthma-related adverse reactions for Xopenex HFA
compared to 3 subjects for placebo. There was one subject that discontinued
treatment due to asthma in the Xopenex HFA group compared to zero subjects in
the placebo group (Table 3). Other adverse reactions were consistent with those
observed in the clinical trial population of patients 4 years of age and older [see
Table 3: Asthma-related Adverse Reactions in a 4-Week
Clinical Trial in Children Birth to < 4 Years of Age*
||XOPENEX HFA 45-90 mcg
|Levalbuterol inhalation solution 0.31 mg
|Asthma-related adverse reactions*, n (%)
|Treatment discontinuations due to asthma, n (%)
|*This table 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 HFA
did not include sufficient numbers of subjects aged 65 and older to determine
whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant diseases or other drug therapy.
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.