Label: XOPENEX HFA- levalbuterol tartrate aerosol, metered

8.1 PREGNANCY

Risk Summary

There are no adequate and well-controlled studies of XOPENEX HFA in pregnant women.   There are clinical considerations with the use of XOPENEX HFA in pregnant women [see Clinical Considerations]

Following oral administration of levalbuterol HCl to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day [approximately 750 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol tartrate for adults on a mg/m 2basis]; however, racemic albuterol sulfate was teratogenic in mice (cleft palate) and rabbits (cranioschisis) at doses slightly higher than the human therapeutic range ( see Data)

The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control

Labor or 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 beta 2-agonists, including racemic albuterol

Data

Animal Data

The oral administration of levalbuterol HCl to pregnant New Zealand White rabbits during the period of organogenesis found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 750 times the MRHDID of levalbuterol tartrate for adults on a mg/m 2basis). In a rat developmental study, a racemic albuterol sulfate (comprising approximately 50% levalbuterol)/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 160 times the MRHDID (on a mg/m 2basis at a maternal dose of 10.5 mg/kg)

However, other developmental studies with the racemic albuterol sulfate, did result in teratogenic effects in mice and rabbits at doses slightly higher than the human therapeutic range.  In a rabbit development study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 1500 times the MRHDID (on a mg/m 2basis at a maternal dose of 50 mg/kg).  In a mouse developmental study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately 2 times MRHDID for adults (on a mg/m 2basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 20 times MRHDID (on a mg/m 2basis at a maternal dose of 2.5 mg/kg/day).  Similar effects were not observed at approximately 0.2 times MRHDID of levalbuterol tartrate for adults on a mg/m 2basis (i.e., less than the therapeutic dose).  Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control)

8.2 Lactation

Risk Summary

There are no available data on the presence of levalbuterol in human milk, the effects on the breastfed child, or the effects on milk production

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XOPENEX HFA and any potential adverse effects on the breastfed child from XOPENEX HFA or from the underlying maternal condition

8.4 PEDIATRIC USE

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 (6)and Clinical Studies (14)]

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 Adverse Reactions (6.1)]

8.5 GERIATRIC USE

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

8.6 Renal Impairment

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

12.1 MECHANISM OF ACTION

Activation of beta 2-adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3', 5'-adenosine monophosphate (cyclic AMP).  The increase in cyclic AMP is associated with the activation of protein kinase A, which in turn, inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation.  Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles.  Increased cyclic AMP concentrations are also associated with the inhibition of the release of mediators from mast cells in the airways.  Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges.  While it is recognized that beta 2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are beta 2-adrenergic receptors.  The precise function of these receptors has not been established [see Warnings and Precautions (5)].  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

12.3 PHARMACOKINETICS

A population pharmacokinetic model was developed using plasma concentrations of (R)-albuterol obtained from 632 asthmatic patients aged 4 to 81 years in three large trials.  For adolescent and adult patients 12 years and older, following 90 mcg dose of XOPENEX HFA, yielded mean peak plasma concentrations (C max) and systemic exposure (AUC 0-6) of approximately 199 pg/mL and 695 pg•h/mL, respectively, compared to approximately 238 pg/mL and 798 pg•h/mL, respectively, following 180 mcg dose of Racemic Albuterol HFA metered-dose inhaler.  For pediatric patients from 4 to 11 years of age, following 90 mcg dose of XOPENEX HFA, yielded C maxand AUC 0-6of approximately 163 pg/mL and 579 pg•h/mL, respectively, compared to approximately 238 pg/mL and 828 pg•h/mL, respectively, following 180 mcg dose of Racemic Albuterol HFA metered-dose inhaler

These pharmacokinetic data indicate that mean exposure to (R)-albuterol was 13% to 16% less in adult and 30% to 32% less in pediatric patients given XOPENEX HFA as compared to those given a comparable dose of racemic albuterol.  When compared to adult patients, pediatric patients given 90 mcg of levalbuterol have a 17% lower mean exposure to (R)-albuterol

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 HFA 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 HFA to patients with renal impairment [see Use in Specific Populations(8.6)]

13.1 CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

Although there have been no carcinogenesis studies with levalbuterol tartrate, racemic albuterol sulfate has been evaluated for its carcinogenic potential

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 MRHDID) of levalbuterol tartrate for adults and approximately 15 times the MRHDID of levalbuterol tartrate for children on a mg/m 2basis).  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 MRHDID of levalbuterol tartrate for adults and approximately 1800 times the MRHDID of levalbuterol tartrate for children on a mg/m 2basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 500 times the MRHDID of levalbuterol tartrate for adults on a mg/m 2basis and approximately 240 times the MRHDID of levalbuterol tartrate for children on a mg/m 2basis)

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 vivomicronucleus test in mouse bone marrow.  Racemic albuterol sulfate was not clastogenic in an in vitrochromosomal 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 MRHDID of levalbuterol tartrate for adults on a mg/m 2basis)

13.2 ANIMAL PHARMACOLOGY & OR TOXICOLOGY

Propellant HFA-134a

In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (t max) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation. Based on studies in animals, the propellant HFA-134a had no detectable toxicological activity at amounts less than 380 times the maximum human exposure based on comparisons of AUC values. The toxicological effects observed at these very high doses included ataxia, tremors, dyspnea, or salivation, similar to effects produced by the structurally-related chlorofluorocarbons (CFCs) used in metered-dose inhalers, that were extensively used in the past

14.1 Bronchospasm Associated with Asthma

Adults and Adolescent Patients 12 Years of Age and Older

The efficacy and safety of XOPENEX HFA were established in two 8-week, multicenter, randomized, double-blind, active- and placebo-controlled trials in 748 adults and adolescents with asthma between the ages of 12 and 81 years.  In these two trials, XOPENEX HFA (403 patients) was compared to an HFA-134a placebo MDI (166 patients), and the trials included a marketed albuterol HFA-134a MDI (179 patients) as an active control.  Serial forced expiratory volume in 1 second (FEV 1) measurements demonstrated that 90 mcg (2 inhalations) of XOPENEX HFA produced significantly greater improvement in FEV 1over the pretreatment value than placebo.  The results from one of the trials are shown in Figure 1 as the mean percent change in FEV 1from test-day baseline at Day 1 (n=445) and Day 56 (n=387).  The results from the second trial were similar

Figure 1: Percent Change in FEV 1

from Test-Day Baseline in Adults and Adolescents Aged 12 to 81 Years at Day 1 and Day 56

For XOPENEX HFA on Day 1, the median time to onset of a 15% increase in FEV 1ranged from 5.5 to 10.2 minutes and the median time to peak effect ranged from 76 to 78 minutes.  In the responder population, on Day 1 the median duration of effect as measured by a 15% increase in FEV 1was 3 to 4 hours, with duration of effect in some patients of up to 6 hours

Pediatric Patients 4 to 11 Years of Age

The efficacy and safety of XOPENEX HFA in children were established in a 4-week, multicenter, randomized, double-blind, active- and placebo-controlled trial in 150 pediatric patients with asthma between the ages of 4 and 11 years.  In this trial, XOPENEX HFA (76 patients) was compared to a placebo HFA-134a MDI (35 patients), and the trial included a marketed albuterol HFA-134a MDI (39 patients) as an active control.  Serial FEV 1measurements demonstrated that 90 mcg (2 inhalations) of XOPENEX HFA produced significantly greater improvement in FEV 1over the pretreatment value than placebo and were consistent with the efficacy findings in the adult studies

For XOPENEX HFA, on Day 1 the median time to onset of a 15% increase in FEV 1was 4.5 minutes and the median time to peak effect was 77 minutes.  In the responder population, the median duration of effect as measured by a 15% increase in FEV 1was 3 hours, with a duration of effect in some pediatric patients of up to 6 hours