Xopenex (levalbuterol HCl) Inhalation Solution is a sterile,
clear, colorless, preservative-free solution of the hydrochloride salt of
levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol.
Levalbuterol HCl is a relatively selective beta2-adrenergic receptor agonist (see CLINICAL PHARMACOLOGY). The chemical name for
levalbuterol HCl is (R)-α1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol
hydrochloride, and its established chemical structure is as follows:
The molecular weight of levalbuterol HCl is 275.8, and its empirical formula
is C13H21NO3•HCl. It is a white to off-white, crystalline solid, with a
melting point of approximately 187°C and solubility of approximately 180 mg/mL
in water.
Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the
United States.
Xopenex (levalbuterol HCl) Inhalation Solution Concentrate supplied in 0.5 mL
unit-dose vials should be diluted with sterile normal saline before
administration by nebulization. Each 0.5 mL unit-dose vial contains 1.25 mg of
levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust
tonicity, and hydrochloric acid to adjust the pH to 4.0 (3.3 to 4.5).
Clinical Pharmacology:
Activation of beta2-adrenergic receptors
on airway smooth muscle leads to the activation of adenylcyclase and to an
increase in the intracellular concentration of cyclic-3′, 5′-adenosine
monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation
of protein kinase A, which inhibits the phosphorylation of myosin and lowers
intracellular ionic calcium concentrations, resulting in relaxation.
Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the
terminal bronchioles. Levalbuterol acts as a functional antagonist to relax the
airway irrespective of the spasmogen involved, thus protecting against all
bronchoconstrictor challenges. Increased cyclic AMP concentrations are also
associated with the inhibition of release of mediators from mast cells in the
airway.
While it is recognized that beta2-adrenergic receptors
are the predominant receptors on bronchial smooth muscle, data indicate that
there is a population of beta2-receptors in the human
heart that comprise between 10% and 50% of cardiac beta-adrenergic receptors.
The precise function of these receptors has not been established (see WARNINGS
). However, all
beta-adrenergic agonist drugs can produce a significant cardiovascular effect in
some patients, as measured by pulse rate, blood pressure, symptoms, and/or
electrocardiographic changes. Preclinical Studies Results from an in vitro study of
binding to human beta-adrenergic receptors demonstrated that levalbuterol has
approximately 2-fold greater binding affinity than racemic albuterol and
approximately 100-fold greater binding affinity than (S)-albuterol. In guinea
pig airways, levalbuterol HCl and racemic albuterol decreased the response to
spasmogens (e.g., acetylcholine and histamine), whereas (S)-albuterol was
ineffective. These results suggest that the bronchodilatory effects of racemic
albuterol are attributable to the (R)-enantiomer.
Intravenous studies in rats with racemic albuterol sulfate have demonstrated
that albuterol crosses the blood-brain barrier and reaches brain concentrations
amounting to approximately 5.0% of the plasma concentrations. In structures
outside the blood-brain barrier (pineal and pituitary glands), albuterol
concentrations were found to be 100 times those in the whole brain.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated
the occurrence of cardiac arrhythmias and sudden death (with histologic evidence
of myocardial necrosis) when beta-agonists and methylxanthines are administered
concurrently. The clinical significance of these findings is unknown. Pharmacokinetics (Adults and Adolescents ≥12 years
old) The inhalation pharmacokinetics of Xopenex Inhalation Solution
were investigated in a randomized cross-over study in 30 healthy adults
following administration of a single dose of 1.25 mg and a cumulative dose of 5
mg of Xopenex Inhalation Solution and a single dose of 2.5 mg and a cumulative
dose of 10 mg of racemic albuterol sulfate inhalation solution by nebulization
using a PARI LC Jet™ nebulizer with a Dura-Neb® 2000
compressor.
Following administration of a single 1.25 mg dose of Xopenex Inhalation
Solution, exposure to (R)-albuterol (AUC of 3.3 ng•hr/mL) was approximately
2-fold higher than following administration of a single 2.5 mg dose of racemic
albuterol inhalation solution (AUC of 1.7 ng•hr/mL) (see Table 1
). Following administration of a cumulative 5 mg
dose of Xopenex Inhalation Solution (1.25 mg given every 30 minutes for a total
of four doses) or a cumulative 10 mg dose of racemic albuterol inhalation
solution (2.5 mg given every 30 minutes for a total of four doses), Cmax and AUC of (R)-albuterol were comparable (see Table 1
).
Table 1: Mean (SD) Values for Pharmacokinetic Parameters in Healthy Adults
Single
Dose
Cumulative
Dose
Xopenex 1.25 mg
Racemic albuterolsulfate 2.5 mg
Xopenex 5 mg
Racemic albuterolsulfate 10mg
Cmax (ng/mL)Â (R)-albuterol
1.1 (0.45)
0.8 (0.41)**
4.5 (2.20)
4.2 (1.51)**
Tmax (h)γ (R)-albuterol
0.2 (0.17, 0.37)
0.2 (0.17. 1.50)
0.2 (-0.18*, 1.25)
0.2 (-0.28*, 1.00)
AUC (ng•h/mL) (R)-albuterol
3.3 (1.58)
1.7 (0.99)**
17.4 (8.56)
16.0 (7.12)**
T½ (h) (R)-albuterol
3.3 (2.48)
1.5 (0.61)
4.0 (1.05)
4.1 (0.97)
γ    Median (Min, Max) reported for Tmax.*   A negative Tmax indicates Cmax
occurred between first and last nebulizations.**Â Values reflect only (R)-albuterol and do not include (S)-albuterol.
Pharmacokinetics (Children 6–11 years old) The pharmacokinetic parameters of (R)- and (S)-albuterol in
children with asthma were obtained using population pharmacokinetic analysis.
These data are presented in Table 2
.
For comparison, adult data obtained by conventional pharmacokinetic analysis
from a different study also are presented in Table 2
.
In children, AUC and Cmax of (R)-albuterol following
administration of 0.63 mg Xopenex Inhalation Solution were comparable to those
following administration of 1.25 mg racemic albuterol sulfate inhalation
solution.
When the same dose of 0.63 mg of Xopenex was given to children and adults,
the predicted Cmax of (R)–albuterol in children was
similar to that in adults (0.52 vs. 0.56 ng/mL), while predicted AUC in children
(2.55 ng•hr/mL) was about 1.5-fold higher than that in adults (1.65 ng•hr/mL).
These data support lower doses for children 6-11 years old compared with the
adult doses (see DOSAGE AND
ADMINISTRATION
).
Table 2: (R)-Albuterol Exposure in Adults and Pediatric Subjects (6-11 years)
Children
6-11 years
Adults
> 12 years
Treatment
Xopenex0.31 mg
Xopenex0.63 mg
Racemicalbuterol1.25 mg
Racemicalbuterol2.5 mg
Xopenex0.63 mg
Xopenex1.25 mg
AUC0-∞(ng•hr/mL) c
1.36
2.55
2.65
5.02
1.65 a
3.3 b
Cmax (ng/mL) d
0.303
0.521
0.553
1.08
0.56 a
1.1 b
a The values are predicted by assuming linear pharmacokineticsb The data obtained from Table 1
c Area under the plasma concentration curve from time 0 to infinityd Maximum plasma concentration
Metabolism and Elimination Information available in the published literature suggests that
the primary enzyme responsible for the metabolism of albuterol enantiomers in
humans is SULT1A3 (sulfotransferase). When racemic albuterol was administered
either intravenously or via inhalation after oral charcoal administration, there
was a 3- to 4-fold difference in the area under the concentration-time curves
between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol
concentrations being consistently higher. However, without charcoal
pretreatment, after either oral or inhalation administration the differences
were 8- to 24-fold, suggesting that (R)-albuterol is preferentially metabolized
in the gastrointestinal tract, presumably by SULT1A3.
The primary route of elimination of albuterol enantiomers is through renal
excretion (80% to 100%) of either the parent compound or the primary metabolite.
Less than 20% of the drug is detected in the feces. Following intravenous
administration of racemic albuterol, between 25% and 46% of the (R)-albuterol
fraction of the dose was excreted as unchanged (R)-albuterol in the urine. Special Populations Hepatic Impairment: The effect of hepatic
impairment on the pharmacokinetics of Xopenex Inhalation Solution has not been
evaluated. Renal Impairment: The effect of renal
impairment on the pharmacokinetics of racemic albuterol was evaluated in 5
subjects with creatinine clearance of 7 to 53 mL/min, and the results were
compared with those from healthy volunteers. Renal disease had no effect on the
half-life, but there was a 67% decline in racemic albuterol clearance. Caution
should be used when administering high doses of Xopenex Inhalation Solution to
patients with renal impairment. Pharmacodynamics (Adults and Adolescents ≥12 years
old) In a randomized, double-blind, placebo-controlled, cross-over
study, 20 adults with mild-to-moderate asthma received single doses of Xopenex
Inhalation Solution (0.31, 0.63, and 1.25Â mg) and racemic albuterol sulfate
inhalation solution (2.5 mg). All doses of active treatment produced a
significantly greater degree of bronchodilation (as measured by percent change
from pre-dose mean FEV1) than placebo, and there were no
significant differences between any of the active treatment arms. The
bronchodilator responses to 1.25 mg of Xopenex Inhalation Solution and 2.5 mg of
racemic albuterol sulfate inhalation solution were clinically comparable over
the 6-hour evaluation period, except for a slightly longer duration of action
(>15% increase in FEV1 from baseline) after
administration of 1.25 mg of Xopenex Inhalation Solution. Systemic
beta-adrenergic adverse effects were observed with all active doses and were
generally dose-related for (R)-albuterol. Xopenex Inhalation Solution at a dose
of 1.25 mg produced a slightly higher rate of systemic beta-adrenergic adverse
effects than the 2.5 mg dose of racemic albuterol sulfate inhalation
solution.
In a randomized, double-blind, placebo-controlled, cross-over study, 12
adults with mild-to-moderate asthma were challenged with inhaled methacholine
chloride 20 and 180 minutes following administration of a single dose of 2.5 mg
of racemic albuterol sulfate, 1.25Â mg of Xopenex, 1.25 mg of (S)-albuterol, or
placebo using a PARI LC Jetâ„¢ nebulizer. Racemic albuterol sulfate, Xopenex, and
(S)-albuterol had a protective effect against methacholine-induced
bronchoconstriction 20 minutes after administration, although the effect of
(S)-albuterol was minimal. At 180 minutes after administration, the
bronchoprotective effect of 1.25 mg of Xopenex was comparable to that of 2.5 mg
of racemic albuterol sulfate. At 180 minutes after administration, 1.25 mg of
(S)-albuterol had no bronchoprotective effect.
In a clinical study in adults with mild-to-moderate asthma, comparable
efficacy (as measured by change from baseline FEV1) and
safety (as measured by heart rate, blood pressure, ECG, serum potassium, and
tremor) were demonstrated after a cumulative dose of 5 mg of Xopenex Inhalation
Solution (four consecutive doses of 1.25 mg administered every 30Â minutes) and
10 mg of racemic albuterol sulfate inhalation solution (four consecutive doses
of 2.5 mg administered every 30 minutes).
Clinical Trials (Adults and Adolescents ≥12 years
old) The safety and efficacy of Xopenex Inhalation Solution were
evaluated in a 4-week, multicenter, randomized, double-blind,
placebo-controlled, parallel-group study in 362 adult and adolescent patients 12
years of age and older, with mild-to-moderate asthma (mean baseline FEV1 60% of predicted). Approximately half of the patients were
also receiving inhaled corticosteroids. Patients were randomized to receive
Xopenex 0.63 mg, Xopenex 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic
albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI
LC Plus™ nebulizer and a Dura-Neb® portable compressor.
Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered dose inhaler
(MDI) was used on an as-needed basis as the rescue medication. Efficacy, as measured by the mean percent change from baseline FEV1, was demonstrated for all active treatment regimens compared
with placebo on day 1 and day 29. On both day 1 (see Figure 1) and day 29 (see Figure 2), 1.25 mg of Xopenex demonstrated the
largest mean percent change from baseline FEV1 compared
with the other active treatments. A dose of 0.63 mg of Xopenex and 2.5 mg of
racemic albuterol sulfate produced a clinically comparable mean percent change
from baseline FEV1 on both day 1 and day 29. Figure 1: Mean Percent Change from Baseline FEV1 on Day
1, Adults and Adolescents ≥12 years old Figure 2: Mean Percent Change from Baseline FEV1 on Day 29, Adults and Adolescents ≥12 years old
The mean time to onset of a 15% increase in FEV1 over
baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17
minutes and 10 minutes, respectively, and the mean time to peak effect for both
doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration
of effect, as measured by a >15% increase from baseline FEV1, was approximately 5 hours after administration of 0.63 mg of
levalbuterol and approximately 6 hours after administration of 1.25 mg of
levalbuterol after 4 weeks of treatment. In some patients, the duration of
effect was as long as 8 hours. Clinical Trials (Children 6–11 years old) A multicenter, randomized, double-blind, placebo- and
active-controlled study was conducted in children with mild-to-moderate asthma
(mean baseline FEV1 73% of predicted) (n=316). Following
a 1-week placebo run-in, subjects were randomized to Xopenex (0.31 or 0.63 mg),
racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times
a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb® 3000 compressor.
Efficacy, as measured by mean peak percent change from baseline FEV1, was demonstrated for all active treatment regimens compared
with placebo on day 1 and day 21. Time profile FEV1
curves for day 1 and day 21 are shown in Figure 3 and Figure 4, respectively. The onset of effect (time
to a 15% increase in FEV1 over test-day baseline) and
duration of effect (maintenance of a >15% increase in FEV1 over test-day baseline) of levalbuterol were clinically
comparable to those of racemic albuterol. Figure 3: Mean Percent Change from Baseline FEV1 on Day
1, Children 6-11 Years of Age Figure 4: Mean Percent Change from Baseline FEV1 on Day
21, Children 6-11 Years of Age
Indications And Usage
Xopenex (levalbuterol HCl) Inhalation Solution is indicated for the treatment or
prevention of bronchospasm in adults, adolescents, and children 6 years of age
and older with reversible obstructive airway disease.
Contraindications:
Xopenex (levalbuterol HCl) Inhalation Solution is contraindicated in patients
with a history of hypersensitivity to levalbuterol HCl or racemic albuterol.
Warnings:
Paradoxical Bronchospasm: Like other inhaled
beta-adrenergic agonists, 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 canister or 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: 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, to the therapeutic regimen.
Cardiovascular Effects: Xopenex Inhalation
Solution, 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 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 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: 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 Inhalation Solution.
Precautions:
General Levalbuterol HCl, 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.
Large doses of intravenous racemic albuterol have been reported to aggravate
preexisting diabetes mellitus and ketoacidosis. As with other beta-adrenergic
agonist medications, levalbuterol 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. Information for Patients See illustrated Patient's Instructions
for Use.
The action of Xopenex (levalbuterol HCl) Inhalation Solution may last up to 8
hours. Xopenex Inhalation Solution should not be used more frequently than
recommended. Do not increase the dose or frequency of dosing of Xopenex
Inhalation Solution without consulting your physician. If you find that
treatment with Xopenex Inhalation Solution 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 taking Xopenex Inhalation Solution, 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,
headache, dizziness, and tremor or nervousness. If you are pregnant or nursing,
contact your physician about the use of Xopenex Inhalation Solution.
Effective and safe use of Xopenex Inhalation Solution requires consideration
of the following information in addition to that provided under Patient's
Instructions for Use:
Xopenex Inhalation Solution single-use low-density polyethylene (LDPE) vials
should be protected from light and excessive heat. Store in the protective foil
pouch between 20°C and 25°C (68°F and 77°F) [see USP Controlled Room
Temperature]. Do not use after the expiration date stamped on the container.
Open the foil pouch just prior to administration. Once the foil pouch is opened,
the contents of the vial should be used immediately. Discard any vial if the
solution is not colorless. Xopenex (levalbuterol HCl) Inhalation Solution
Concentrate should be diluted with sterile normal saline before administration
by nebulization.
The drug compatibility (physical and chemical), efficacy, and safety of
Xopenex Inhalation Solution when mixed with other drugs in a nebulizer have not
been established. Drug Interactions Other short-acting sympathomimetic aerosol bronchodilators or
epinephrine should be used with caution with levalbuterol. If additional
adrenergic drugs are to be administered by any route, they should be used with
caution to avoid deleterious cardiovascular effects.
Beta-blockers: Beta-adrenergic receptor
blocking agents not only block the pulmonary effect of beta-agonists such as
Xopenex (levalbuterol HCl) Inhalation Solution, but may also produce severe
bronchospasm in asthmatic patients. Therefore, patients with asthma should not
normally be treated with beta-blockers. However, under certain circumstances,
e.g., prophylaxis after myocardial infarction, there may be no acceptable
alternatives to the use of beta-adrenergic blocking agents in patients with
asthma. In this setting, cardioselective beta-blockers could be considered,
although they should be administered with caution.
Diuretics: The ECG changes and/or hypokalemia
that may result from the administration of non-potassium sparing diuretics (such
as loop or thiazide diuretics) can be acutely worsened by beta-agonists,
especially when the recommended dose of the beta-agonist is exceeded. Although
the clinical significance of these effects is not known, caution is advised in
the coadministration of beta-agonists with non-potassium sparing diuretics.
Digoxin: Mean decreases of 16% and 22% in serum
digoxin levels were demonstrated after single-dose intravenous and oral
administration of racemic albuterol, respectively, to normal volunteers who had
received digoxin for 10 days. The clinical significance of these findings for
patients with obstructive airway disease who are receiving levalbuterol HCl and
digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to
carefully evaluate the serum digoxin levels in patients who are currently
receiving digoxin and Xopenex Inhalation Solution.
Monoamine Oxidase Inhibitors or Tricyclic
Antidepressants: Xopenex Inhalation Solution should be administered with
extreme caution to patients being treated with monoamine oxidase inhibitors or
tricyclic antidepressants, or within 2 weeks of discontinuation of such agents,
because the action of levalbuterol HCl on the vascular system may be
potentiated.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility No carcinogenesis or impairment of fertility studies have been
carried out with levalbuterol HCl alone. However, racemic albuterol sulfate has
been evaluated for its carcinogenic potential and ability to impair
fertility.
In a 2-year study in Sprague-Dawley rats, racemic albuterol sulfate caused a
significant dose-related increase in the incidence of benign leiomyomas of the
mesovarium at and above dietary doses of 2 mg/kg (approximately 2 times the
maximum recommended daily inhalation dose of levalbuterol HCl for adults and
children on a mg/m2 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, racemic albuterol
sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg
(approximately 260 times the maximum recommended daily inhalation dose of
levalbuterol HCl for adults and children on a mg/m2
basis). In a 22-month study in the Golden hamster, racemic albuterol sulfate
showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg
(approximately 35 times the maximum recommended daily inhalation dose of
levalbuterol HCl for adults and children on a mg/m2
basis).
Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian
Forward Gene Mutation Assay. Although levalbuterol HCl has not been tested for
clastogenicity, racemic albuterol sulfate was not clastogenic in a human
peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay.
Reproduction studies in rats using racemic albuterol sulfate demonstrated no
evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 55
times the maximum recommended daily inhalation dose of levalbuterol HCl for
adults on a mg/m2 basis). Teratogenic Effects — Pregnancy Category C A reproduction study in New Zealand White rabbits demonstrated
that levalbuterol HCl was not teratogenic when administered orally at doses up
to 25 mg/kg (approximately 110 times the maximum recommended daily inhalation
dose of levalbuterol HCl for adults on a mg/m2 basis).
However, racemic albuterol sulfate has been shown to be teratogenic in mice and
rabbits. A study in CD-1 mice given racemic albuterol sulfate subcutaneously
showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less
than the maximum recommended daily inhalation dose of levalbuterol HCl for
adults on a mg/m2 basis) and in 10 of 108 (9.3%) fetuses
at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation
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 (less than the maximum recommended daily inhalation
dose of levalbuterol HCl for adults on a mg/m2 basis).
Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated
subcutaneously with 2.5Â mg/kg of isoproterenol (positive control).
A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of
19 (37%) fetuses when racemic albuterol sulfate was administered orally at a
dose of 50Â mg/kg (approximately 110 times the maximum recommended daily
inhalation 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.
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 marketing experience of racemic albuterol, various congenital
anomalies, including cleft palate and limb defects, have been rarely reported in
the offspring of patients being treated with racemic albuterol. Some of the
mothers were taking multiple medications during their pregnancies. No consistent
pattern of defects can be discerned, and a relationship between racemic
albuterol use and congenital anomalies has not been established. Use in 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. Tocolysis Levalbuterol HCl 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. Nursing Mothers Plasma levels of levalbuterol after inhalation of therapeutic
doses are very low in humans, but 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. Pediatrics The safety and efficacy of Xopenex (levalbuterol HCl) Inhalation
Solution have been established in pediatric patients 6 years of age and older in
one adequate and well-controlled clinical trial (see CLINICAL PHARMACOLOGY; Pharmacokinetics
and Clinical Trials
). Use of Xopenex in
children is also supported by evidence from adequate and well-controlled studies
of Xopenex in adults, considering that the pathophysiology and the drug's
exposure level and effects in pediatric and adult patients are substantially
similar. Safety and effectiveness of Xopenex in pediatric patients below the age
of 6 years have not been established. Geriatrics Data on the use of Xopenex in patients 65 years of age and older
are very limited. A very small number of patients 65 years of age and older were
treated with Xopenex Inhalation Solution in a 4-week clinical study (see CLINICAL PHARMACOLOGY; Clinical
Trials
) (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. There are insufficient data to determine if the safety and efficacy
of Xopenex Inhalation Solution are different in patients less than 65 years of age and
patients 65 years of age and older. 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
).
Adverse Reactions (adults And Adolescents 12 Years Old):
Adverse events reported in ≥2% of patients receiving Xopenex
Inhalation Solution or racemic albuterol and more frequently than in patients
receiving placebo in a 4-week, controlled clinical trial are uled in Table 3.
Table 3: Adverse Events Reported in a 4-Week, Controlled Clinical Trial
in Adults and Adolescents ≥12 years old
Percent of
Patients
Body System    Preferred Term
Placebo(n=75)
Xopenex1.25 mg(n=73)
Xopenex0.63 mg(n=72)
Racemic albuterol2.5
mg(n=74)
Body as a Whole
    Allergic reaction
1.3
0
0
2.7
    Flu syndrome
0
1.4
4.2
2.7
    Accidental injury
0
2.7
0
0
    Pain
1.3
1.4
2.8
2.7
    Back pain
0
0
0
2.7
Cardiovascular System
    Tachycardia
0
2.7
2.8
2.7
    Migraine
0
2.7
0
0
Digestive System
    Dyspepsia
1.3
2.7
1.4
1.4
Musculoskeletal System
    Leg cramps
1.3
2.7
0
1.4
Central Nervous System
    Dizziness
1.3
2.7
1.4
0
    Hypertonia
0
0
0
2.7
    Nervousness
0
9.6
2.8
8.1
    Tremor
0
6.8
0
2.7
    Anxiety
0
2.7
0
0
Respiratory System
    Cough increased
2.7
4.1
1.4
2.7
    Infection viral
9.3
12.3
6.9
12.2
    Rhinitis
2.7
2.7
11.1
6.8
    Sinusitis
2.7
1.4
4.2
2.7
    Turbinate edema
0
1.4
2.8
0
The incidence of certain systemic beta-adrenergic adverse effects (e.g.,
tremor, nervousness) was slightly less in the Xopenex 0.63 mg group compared
with the other active treatment groups. The clinical significance of these small
differences is unknown.
Changes in heart rate 15 minutes after drug administration and in plasma
glucose and potassium 1 hour after drug administration on day 1 and day 29 were
clinically comparable in the Xopenex 1.25 mg and racemic albuterol 2.5 mg groups
(see Table 4). Changes in heart rate
and plasma glucose were slightly less in the Xopenex 0.63 mg group compared with
the other active treatment groups (see Table
4). The clinical significance of these small differences is unknown.
After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were
generally diminished compared with day 1 in all active treatment groups.
Table 4: Mean Changes from Baseline Heart Rate at 15 Minutes and
Glucose and Potassium at 1 Hour after First Dose (Day 1) in Adults and
Adolescents ≥12 years old
Treatment
Mean Changes (day
1)
Heart Rate(bpm)
Glucose(mg/dL)
Potassium(mEq/L)
Xopenex 0.63 mg, n=72
2.4
4.6
–0.2
Xopenex 1.25 mg, n=73
6.9
10.3
–0.3
Racemic albuterol 2.5 mg, n=74
5.7
8.2
–0.3
Placebo, n=75
–2.8
–0.2
–0.2
No other clinically relevant laboratory abnormalities related to
administration of Xopenex Inhalation Solution were observed in this study.
In the clinical trials, a slightly greater number of serious adverse events,
discontinuations due to adverse events, and clinically significant ECG changes
were reported in patients who received Xopenex 1.25 mg compared with the other
active treatment groups.
The following adverse events, considered potentially related to Xopenex,
occurred in less than 2% of the 292 subjects who received Xopenex and more
frequently than in patients who received placebo in any clinical trial:
anxiety, hypesthesia of the hand, insomnia,
paresthesia, tremor
Special Senses:
eye itch
The following events, considered potentially related to Xopenex, occurred in
less than 2% of the treated subjects but at a frequency less than in patients
who received placebo: asthma exacerbation, cough increased, wheezing, sweating,
and vomiting.
ADVERSE REACTIONS (Adults and Adolescents ≥12 years
old): Adverse events reported in ≥2% of patients receiving Xopenex
Inhalation Solution or racemic albuterol and more frequently than in patients
receiving placebo in a 4-week, controlled clinical trial are uled in Table 3.
Table 3: Adverse Events Reported in a 4-Week, Controlled Clinical Trial
in Adults and Adolescents ≥12 years old
Percent of
Patients
Body System    Preferred Term
Placebo(n=75)
Xopenex1.25 mg(n=73)
Xopenex0.63 mg(n=72)
Racemic albuterol2.5
mg(n=74)
Body as a Whole
    Allergic reaction
1.3
0
0
2.7
    Flu syndrome
0
1.4
4.2
2.7
    Accidental injury
0
2.7
0
0
    Pain
1.3
1.4
2.8
2.7
    Back pain
0
0
0
2.7
Cardiovascular System
    Tachycardia
0
2.7
2.8
2.7
    Migraine
0
2.7
0
0
Digestive System
    Dyspepsia
1.3
2.7
1.4
1.4
Musculoskeletal System
    Leg cramps
1.3
2.7
0
1.4
Central Nervous System
    Dizziness
1.3
2.7
1.4
0
    Hypertonia
0
0
0
2.7
    Nervousness
0
9.6
2.8
8.1
    Tremor
0
6.8
0
2.7
    Anxiety
0
2.7
0
0
Respiratory System
    Cough increased
2.7
4.1
1.4
2.7
    Infection viral
9.3
12.3
6.9
12.2
    Rhinitis
2.7
2.7
11.1
6.8
    Sinusitis
2.7
1.4
4.2
2.7
    Turbinate edema
0
1.4
2.8
0
The incidence of certain systemic beta-adrenergic adverse effects (e.g.,
tremor, nervousness) was slightly less in the Xopenex 0.63 mg group compared
with the other active treatment groups. The clinical significance of these small
differences is unknown.
Changes in heart rate 15 minutes after drug administration and in plasma
glucose and potassium 1 hour after drug administration on day 1 and day 29 were
clinically comparable in the Xopenex 1.25 mg and racemic albuterol 2.5 mg groups
(see Table 4). Changes in heart rate
and plasma glucose were slightly less in the Xopenex 0.63 mg group compared with
the other active treatment groups (see Table
4). The clinical significance of these small differences is unknown.
After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were
generally diminished compared with day 1 in all active treatment groups.
Table 4: Mean Changes from Baseline Heart Rate at 15 Minutes and
Glucose and Potassium at 1 Hour after First Dose (Day 1) in Adults and
Adolescents ≥12 years old
Treatment
Mean Changes (day
1)
Heart Rate(bpm)
Glucose(mg/dL)
Potassium(mEq/L)
Xopenex 0.63 mg, n=72
2.4
4.6
–0.2
Xopenex 1.25 mg, n=73
6.9
10.3
–0.3
Racemic albuterol 2.5 mg, n=74
5.7
8.2
–0.3
Placebo, n=75
–2.8
–0.2
–0.2
No other clinically relevant laboratory abnormalities related to
administration of Xopenex Inhalation Solution were observed in this study.
In the clinical trials, a slightly greater number of serious adverse events,
discontinuations due to adverse events, and clinically significant ECG changes
were reported in patients who received Xopenex 1.25 mg compared with the other
active treatment groups.
The following adverse events, considered potentially related to Xopenex,
occurred in less than 2% of the 292 subjects who received Xopenex and more
frequently than in patients who received placebo in any clinical trial:
anxiety, hypesthesia of the hand, insomnia,
paresthesia, tremor
Special Senses:
eye itch
The following events, considered potentially related to Xopenex, occurred in
less than 2% of the treated subjects but at a frequency less than in patients
who received placebo: asthma exacerbation, cough increased, wheezing, sweating,
and vomiting.
ADVERSE REACTIONS (Children 6-11 years old):
Adverse events reported in ≥2% of patients in any treatment group
and more frequently than in patients receiving placebo in a 3-week, controlled
clinical trial are uled in Table
5.
Table 5: Most Frequently Reported Adverse Events (≥2% in Any Treatment
Group) and Those Reported More Frequently Than in Placebo during the
Double-Blind Period (ITT Population, 6-11 Years Old)
Percent of Patients
Body System   Preferred Term
Placebo(n=59)
Xopenex0.31 mg(n=66)
Xopenex0.63 mg(n=67)
Racemic albuterol1.25
mg(n=64)
Racemic albuterol2.5
mg(n=60)
Body as a Whole
   Abdominal pain
3.4
0
1.5
3.1
6.7
   Accidental injury
3.4
6.1
4.5
3.1
5.0
   Asthenia
0
3.0
3.0
1.6
1.7
   Fever
5.1
9.1
3.0
1.6
6.7
   Headache
8.5
7.6
11.9
9.4
3.3
   Pain
3.4
3.0
1.5
4.7
6.7
   Viral Infection
5.1
7.6
9.0
4.7
8.3
Digestive System
   Diarrhea
0
1.5
6.0
1.6
0
Hemic and Lymphatic
   Lymphadenopathy
0
3.0
0
1.6
0
Musculoskeletal System
   Myalgia
0
0
1.5
1.6
3.3
Respiratory System
   Asthma
5.1
9.1
9.0
6.3
10.0
   Pharyngitis
6.8
3.0
10.4
0
6.7
   Rhinitis
1.7
6.1
10.4
3.1
5.0
Skin and Appendages
   Eczema
0
0
0
0
3.3
   Rash
0
0
7.5
1.6
0
   Urticaria
0
0
3.0
0
0
Special Senses
   Otitis Media
1.7
0
0
0
3.3
Note:Â Subjects may have more than one adverse event per body system and preferred term.
Changes in heart rate, plasma glucose, and serum potassium are shown in Table 6. The clinical significance of these
small differences is unknown.
Table 6: Mean Changes from Baseline Heart Rate at 30 Minutes and
Glucose and Potassium at 1 Hour after First Dose (Day 1) and Last Dose (Day 21)
in Children 6-11 years old
Treatment
Mean Changes (Day
1)
Heart Rate(bpm)
Glucose(mg/dL)
Potassium(mEq/L)
Xopenex 0.31 mg, n=66
0.8
4.9
–0.31
Xopenex 0.63 mg, n=67
6.7
5.2
–0.36
Racemic albuterol 1.25 mg, n=64
6.4
8.0
–0.27
Racemic albuterol 2.5 mg, n=60
10.9
10.8
–0.56
Placebo, n=59
–1.8
0.6
–0.05
Mean Changes (Day
21)
Treatment
Heart Rate(bpm)
Glucose(mg/dL)
Potassium(mEq/L)
Xopenex 0.31 mg, n= 60
0
2.6
–0.32
Xopenex 0.63 mg, n=66
3.8
5.8
–0.34
Racemic albuterol 1.25 mg, n= 62
5.8
1.7
–0.18
Racemic albuterol 2.5 mg, n= 54
5.7
11.8
–0.26
Placebo, n= 55
–1.7
1.1
–0.04
POSTMARKETING ADVERSE REACTIONS: In addition to the adverse events reported in clinical trials,
the following adverse events have been observed in postapproval use of Xopenex
Inhalation Solution. These events have been chosen for inclusion due to their
seriousness, their frequency of reporting, or their likely beta-mediated
mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation,
supraventricular tachycardia, extrasystoles), asthma, chest pain, cough
increased, dyspnea, nausea, nervousness, rash, tachycardia, tremor, urticaria.
Because these events have been reported spontaneously from a population of
unknown size, estimates of frequency cannot be made.
Overdosage
The expected symptoms with overdosage are those of excessive
beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of
the symptoms uled under ADVERSE
REACTIONS, e.g., seizures, angina, hypertension or hypotension,
tachycardia with rates up to 200 beats/min., arrhythmias, nervousness, headache,
tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and
sleeplessness. Hypokalemia also may occur. As with all sympathomimetic
medications, cardiac arrest and even death may be associated with the abuse of
Xopenex Inhalation Solution. Treatment consists of discontinuation of Xopenex
Inhalation Solution 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 Xopenex
Inhalation Solution.
The intravenous median lethal dose of levalbuterol HCl in mice is
approximately 66 mg/kg (approximately 70 times the maximum recommended daily
inhalation dose of levalbuterol HCl for adults and children on a mg/m2 basis). The inhalation median lethal dose has not been
determined in animals.
Dosage And Administration
Children 6–11 years old: The recommended
dosage of Xopenex (levalbuterol HCl) Inhalation Solution for patients 6–11 years
old is 0.31 mg administered three times a day, by nebulization. Routine dosing
should not exceed 0.63 mg three times a day. Adults and Adolescents≥12 years old: The recommended starting dosage of Xopenex
(levalbuterol HCl) Inhalation Solution for patients 12 years of age and older is
0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.
Patients 12 years of age and older with more severe asthma or patients who do
not respond adequately to a dose of 0.63 mg of Xopenex Inhalation Solution may
benefit from a dosage of 1.25 mg three times a day.
Patients receiving the highest dose of Xopenex Inhalation Solution should be
monitored closely for adverse systemic effects, and the risks of such effects
should be balanced against the potential for improved efficacy.
The use of Xopenex Inhalation Solution 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 inhalation solution.
If a previously effective dosage regimen fails to provide the expected
relief, medical advice should be sought immediately, since this is often a sign
of seriously worsening asthma that would require reassessment of therapy.
The drug compatibility (physical and chemical), efficacy, and safety of
Xopenex Inhalation Solution when mixed with other drugs in a nebulizer have not
been established.
The safety and efficacy of Xopenex Inhalation Solution have been established
in clinical trials when administered using the PARI LC Jetâ„¢ and PARI LC Plusâ„¢
nebulizers, and the PARI Master® Dura-Neb® 2000 and Dura-Neb® 3000 compressors.
The safety and efficacy of Xopenex Inhalation Solution when administered using
other nebulizer systems have not been established.
How Supplied:
Xopenex (levalbuterol HCl) Inhalation Solution Concentrate (foil pouch label color red) is supplied in 0.5 mL
unit-dose, low-density polyethylene (LDPE) vials, and is a clear, colorless,
sterile, preservative-free, aqueous solution. Each vial contains 1.25 mg of
levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 30
(NDC 54868-6021-0) individually pouched vials.
Xopenex (levalbuterol HCl) Inhalation Solution is also available in 3 mL
vials in three different strengths of levalbuterol: 0.63 mg (NDC 54868-4409-0), and 1.25 mg (NDC 54868-5459-0).
Caution:
Federal law (U.S.) prohibits dispensing without prescription.
Store Xopenex (levalbuterol HCl) Inhalation Solution Concentrate in the
protective foil pouch at 20-25°C (68-77°F) [see USP Controlled Room
Temperature]. Protect from light and excessive heat. Open the foil pouch just
prior to administration. Once the foil pouch is opened, the contents of the vial
should be used immediately. Discard any vial if the solution is not colorless.
Xopenex (levalbuterol HCl) Inhalation Solution Concentrate should be diluted
with sterile normal saline before administration by nebulization.
Manufactured for:
Sepracor Inc.
Marlborough,
MA 01752 USAby Cardinal Health, Woodstock, IL 60098 USAFor customer
service, call 1-888-394-7377.To report adverse events, call
1-877-737-7226.For medical information, call 1-800-739-0565.
July 2005400438-R1
Patient's Instructions For Use
PHARMACIST — DETACH HERE AND GIVE INSTRUCTIONS TO
PATIENT
--------------------------------------------------------------------------------------------------------------- PATIENT'S INSTRUCTIONS FOR USE Xopenex®(levalbuterol HCl) Inhalation Solution Concentrate; 1.25 mg*;0.5
mL Unit-Dose Vials
*Potency expressed as levalbuterol
Read complete instructions carefully before using. For the 0.5 mL Concentrate only: Open the foil pouch by tearing on the serrated edge along the seam of the pouch.
Remove one unit-dose vial for immediate use. Keep the rest of the unused
unit-dose vials in the foil pouch to protect them from light.
2.
Carefully twist open the top of the unit-dose vial (Figure
1) and squeeze the entire contents into the nebulizer reservoir.
3. Add 2.5 mL (or the amount as directed by your physician)of sterile normal saline
solution. Gently swirl the nebulizer to mix the contents. 4. Connect the nebulizer reservoir to the mouthpiece or face mask (Figure 2).
5. Connect the nebulizer to the compressor.
6. Sit in a comfortable, upright position. Place the mouthpiece in your mouth
(Figure 3) (or put on the face mask) and turn on the
compressor. 7. Breathe as calmly, deeply, and evenly as possible until no more mist is formed
in the nebulizer reservoir (about 5 to 15 minutes). At this point, the treatment
is finished.
8. Clean the nebulizer (see manufacturer's instructions).
Note: Xopenex (levalbuterol HCl) Inhalation Solution should be used in a
nebulizer only under the direction of a physician. More frequent administration
or higher doses are not recommended without first discussing with your doctor.
This solution should not be injected or administered orally. Protect from light
and excessive heat. Store in the protective foil pouch at 20-25°C (68-77°F) [see
USP Controlled Room Temperature]. Open the foil pouch just prior to
administration. Once the foil pouch is opened, the contents of the vial should
be used immediately. Discard any vial if the solution is not colorless. Xopenex
(levalbuterol HCl) Inhalation Solution Concentrate should be diluted with
sterile normal saline before administration by nebulization.
The safety and effectiveness of Xopenex Inhalation Solution have not been
determined when one or more drugs are mixed with it in a nebulizer. Check with
your doctor before mixing any medications in your nebulizer.
Manufactured for:
Sepracor Inc.
Marlborough, MA
01752 USAby Cardinal Health, Woodstock, IL 60098 USAFor customer
service, call 1-888-394-7377.To report adverse events, call
1-877-737-7226.For medical information, call 1-800-739-0565.
July 2005400438-R1
Principal Display Panel
DISCLAIMER:
"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."
"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
PillSync may earn a commission via links on our site
