Fluticasone Propionate

Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.

Fluticasone Propionate and Salmeterol

In an embryofetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1,000; 30/0; 10/100; 30/1,000; and 100/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Omphalocele, increased embryofetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses in the presence of maternal toxicity when combining fluticasone propionate at a dose approximately equivalent to the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and salmeterol at a dose approximately 970 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed when combining fluticasone propionate at a dose approximately 0.3 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and salmeterol at a dose approximately 100 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 1,000 mcg/kg/day).

In an embryofetal development study with pregnant mice that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1,400; 40/0; 10/200; 40/1,400; or 150/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Cleft palate, fetal death, increased implantation loss, and delayed ossification were observed in mouse fetuses when combining fluticasone propionate at a dose approximately 0.7 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a dose approximately 490 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day). No developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 0.2 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 70 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 1,400 mcg/kg).

Fluticasone Propionate

In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately equivalent to the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat NOAEL was observed at approximately 0.3 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.2 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.07 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).

In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.25 times the MRHDID (on a mcg/m2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.05 times the MRHDID (on a mcg/m2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.012 times the MRHDID and higher (on a mcg/m2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.08 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.002 times the MRHDID (on a mcg/m2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

In a pre- and post-natal development study in pregnant rats dosed by the subcutaneous route from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.5 times the MRHDID (on a mcg/m2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

Salmeterol

In 3 embryofetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. In pregnant Dutch rabbits administered salmeterol doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1,000 mcg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at a salmeterol dose approximately 20 times the MRHDID (on an AUC basis at a maternal oral dose of 600 mcg/kg/day). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 2,000 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 10,000 mcg/kg/day).

In 2 embryofetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. Salmeterol produced no maternal toxicity or embryofetal effects at doses up to 973 times the MRHDID (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).

In a peri- and post-natal development study in pregnant rats dosed by the oral route from late gestation through delivery and lactation, salmeterol at a dose 973 times the MRHDID (on a mcg/m2 basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of survivors.

Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.

Cardiovascular Effects

Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) trials were conducted with healthy adult subjects: (1) a single-dose crossover trial using 2 inhalations of fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg given concurrently, or fluticasone propionate inhalation powder 500 mcg given alone, (2) a cumulative dose trial using 50 to 400 mcg of salmeterol inhalation powder given alone or as fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, (3) a repeat-dose trial for 11 days using 2 inhalations twice daily of fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, fluticasone propionate inhalation powder 250 mcg, or salmeterol inhalation powder 50 mcg, and (4) a single-dose trial using 5 inhalations of fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg, fluticasone propionate inhalation powder 100 mcg alone, or placebo. In these trials no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as fluticasone propionate and salmeterol inhalation powder, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in fluticasone propionate and salmeterol inhalation powder. The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in these trials.

Hypothalamic-Pituitary-Adrenal Axis Effects

No significant differences across treatments were observed in 24-hour urinary cortisol excretion and, where measured, 24-hour plasma cortisol AUC. The systemic pharmacodynamic effects of fluticasone propionate were not altered by the presence of salmeterol in fluticasone propionate and salmeterol inhalation powder in healthy subjects.

Cardiovascular Effects

In clinical trials with fluticasone propionate and salmeterol inhalation powder in adult and adolescent subjects aged 12 years and older with asthma, no significant differences were observed in the systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given alone or as fluticasone propionate and salmeterol inhalation powder. In 72 adult and adolescent subjects with asthma given either fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg or fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of therapy, and no clinically significant dysrhythmias were noted.

Hypothalamic-Pituitary-Adrenal Axis Effects

In a 28-week trial in adult and adolescent subjects with asthma, fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg twice daily was compared with the concurrent use of salmeterol inhalation powder 50 mcg plus fluticasone propionate inhalation powder 500 mcg from separate inhalers or fluticasone propionate inhalation powder 500 mcg alone. No significant differences across treatments were observed in serum cortisol AUC after 12 weeks of dosing or in 24-hour urinary cortisol excretion after 12 and 28 weeks.

In a 12-week trial in adult and adolescent subjects with asthma, fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg twice daily was compared with fluticasone propionate inhalation powder 250 mcg alone, salmeterol inhalation powder 50 mcg alone, and placebo. For most subjects, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation, remained intact with fluticasone propionate and salmeterol inhalation powder. One subject (3%) who received fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg had an abnormal response (peak serum cortisol less than 18 mcg/dL) after dosing, compared with 2 subjects (6%) who received placebo, 2 subjects (6%) who received fluticasone propionate 250 mcg, and no subjects who received salmeterol.

In a repeat-dose, 3-way crossover trial, 1 inhalation twice daily of fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg, FLOVENT® DISKUS® 100 mcg (fluticasone propionate inhalation powder 100 mcg), or placebo was administered to 20 adult and adolescent subjects with asthma. After 28 days of treatment, geometric mean serum cortisol AUC over 12 hours showed no significant difference between fluticasone propionate and salmeterol inhalation powder and FLOVENT DISKUS or between either active treatment and placebo.

Hypothalamic-Pituitary-Adrenal Axis Effects

In a 12-week trial in subjects with asthma aged 4 to 11 years who were receiving ICS at trial entry, fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg twice daily was compared with fluticasone propionate inhalation powder 100 mcg administered twice daily via a dry powder inhaler. The values for 24-hour urinary cortisol excretion at trial entry and after 12 weeks of treatment were similar within each treatment group. After 12 weeks, 24-hour urinary cortisol excretion was also similar between the 2 groups.

Cardiovascular Effects

In clinical trials with fluticasone propionate and salmeterol inhalation powder in subjects with COPD, no significant differences were seen in pulse rate, blood pressure, potassium, and glucose between fluticasone propionate and salmeterol inhalation powder, the individual components of fluticasone propionate and salmeterol inhalation powder, and placebo. In a trial of fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, 8 subjects (2 [1.1%] in the group given fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, 1 [0.5%] in the fluticasone propionate 250 mcg group, 3 [1.7%] in the salmeterol group, and 2 [1.1%] in the placebo group) had QTc intervals >470 msec at least 1 time during the treatment period. Five (5) of these 8 subjects had a prolonged QTc interval at baseline.

In a 24-week trial, 130 subjects with COPD received continuous 24-hour electrocardiographic monitoring prior to the first dose and after 4 weeks of twice-daily treatment with either fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, fluticasone propionate inhalation powder 500 mcg, salmeterol inhalation powder 50 mcg, or placebo. No significant differences in ventricular or supraventricular arrhythmias and heart rate were observed among the groups treated with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, the individual components, or placebo. One (1) subject in the fluticasone propionate group experienced atrial flutter/atrial fibrillation, and 1 subject in the group given fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg experienced heart block. There were 3 cases of nonsustained ventricular tachycardia (1 each in the placebo, salmeterol, and fluticasone propionate 500 mcg treatment groups).

In 24-week clinical trials in subjects with COPD, the incidence of clinically significant ECG abnormalities (myocardial ischemia, ventricular hypertrophy, clinically significant conduction abnormalities, clinically significant arrhythmias) was lower for subjects who received salmeterol (1%, 9 of 688 subjects who received either salmeterol 50 mcg or fluticasone propionate and salmeterol inhalation powder) compared with placebo (3%, 10 of 370 subjects).

No significant differences with salmeterol 50 mcg alone or in combination with fluticasone propionate as fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg were observed on pulse rate and systolic and diastolic blood pressure in a subset of subjects with COPD who underwent 12-hour serial vital sign measurements after the first dose (n = 183) and after 12 weeks of therapy (n = 149). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar to those seen with placebo.

Hypothalamic-Pituitary-Adrenal Axis Effects

Short-cosyntropin stimulation testing was performed both at Day 1 and Endpoint in 101 subjects with COPD receiving twice-daily fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, fluticasone propionate inhalation powder 250 mcg, salmeterol inhalation powder 50 mcg, or placebo. For most subjects, the ability to increase cortisol production in response to stress, as assessed by short cosyntropin stimulation, remained intact with fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg. One (1) subject (3%) who received fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg had an abnormal stimulated cortisol response (peak cortisol < 14.5 mcg/dL assessed by high-performance liquid chromatography) after dosing, compared with 2 subjects (9%) who received fluticasone propionate 250 mcg, 2 subjects (7%) who received salmeterol 50 mcg, and 1 subject (4%) who received placebo following 24 weeks of treatment or early discontinuation from trial.

After 36 weeks of dosing, serum cortisol concentrations in a subset of subjects with COPD (n = 83) were 22% lower in subjects receiving fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg and 21% lower in subjects receiving fluticasone propionate 500 mcg than in subjects receiving placebo.

Hypothalamic-Pituitary-Adrenal Axis Effects

In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol < 18 mcg/dL assessed by radioimmunoassay) were noted both in subjects receiving fluticasone propionate and in subjects receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year trial carried out with a dry powder inhaler in 64 subjects with mild, persistent asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no subject receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol < 18 mcg/dL). With a peak cortisol threshold of < 35 mcg/dL, 1 subject receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another subject receiving fluticasone propionate (5%) had an abnormal response at 2 years. No subject on placebo had an abnormal response at 1 or 2 years.

Hypothalamic-Pituitary-Adrenal Axis Effects

After 4 weeks of dosing, the steady-state fluticasone propionate pharmacokinetics and serum cortisol levels were described in a subset of subjects with COPD (n = 86) randomized to twice-daily fluticasone propionate inhalation powder via a dry powder inhaler 500 mcg, fluticasone propionate inhalation powder 250 mcg, or placebo. Serial serum cortisol concentrations were measured across a 12-hour dosing interval. Serum cortisol concentrations following 250 mcg and 500 mcg twice-daily dosing were 10% and 21% lower than placebo, respectively, indicating a dose-dependent increase in systemic exposure to fluticasone propionate.

Cardiovascular Effects

Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium [see Warnings and Precautions (5.12, 5.18)]. The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50 mcg doses of salmeterol inhalation powder (N = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted.

Healthy Subjects

Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed.

Following administration of fluticasone propionate and salmeterol inhalation powder to healthy adult subjects, peak plasma concentrations of fluticasone propionate were achieved in 1 to 2 hours. In a single-dose crossover trial, a higher-than-recommended dose of fluticasone propionate and salmeterol inhalation powder was administered to 14 healthy adult subjects. Two (2) inhalations of the following treatments were administered: fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg given concurrently, and fluticasone propionate inhalation powder 500 mcg alone. Mean peak plasma concentrations of fluticasone propionate averaged 107, 94, and 120 pg/mL, respectively, indicating no significant changes in systemic exposures of fluticasone propionate.

In 15 healthy subjects, systemic exposure to fluticasone propionate from 4 inhalations of ADVAIR® HFA 230/21 (fluticasone propionate 230 mcg and salmeterol 21 mcg) Inhalation Aerosol (920/84 mcg) and 2 inhalations of fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg (1,000 mcg/100 mcg) was similar between the 2 inhalers (i.e., 799 versus 832 pg•h/mL, respectively), but approximately half the systemic exposure from 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg (880 mcg, AUC = 1,543 pg•h/mL). Similar results were observed for peak fluticasone propionate plasma concentrations (186 and 182 pg/mL from ADVAIR HFA and fluticasone propionate and salmeterol inhalation powder, respectively, and 307 pg/mL from the fluticasone propionate CFC inhalation aerosol). Absolute bioavailability of fluticasone propionate was 5.3% and 5.5% following administration of ADVAIR HFA and fluticasone propionate and salmeterol inhalation powder, respectively.

Subjects with Asthma and COPD

Peak steady-state fluticasone propionate plasma concentrations in adult subjects with asthma (N = 11) ranged from undetectable to 266 pg/mL after a 500 mcg twice-daily dose of fluticasone propionate inhalation powder using a dry powder inhaler. The mean fluticasone propionate plasma concentration was 110 pg/mL.

Full pharmacokinetic profiles were obtained from 9 female and 16 male subjects with asthma given fluticasone propionate inhalation powder 500 mcg twice daily using a dry powder inhaler and from 14 female and 43 male subjects with COPD given 250 or 500 mcg twice daily. No overall differences in fluticasone propionate pharmacokinetics were observed.

Peak steady-state fluticasone propionate plasma concentrations in subjects with COPD averaged 53 pg/mL (range: 19.3 to 159.3 pg/mL) after treatment with 250 mcg twice daily (n = 30) and 84 pg/mL (range: 24.3 to 197.1 pg/mL) after treatment with 500 mcg twice daily (n = 27) via a fluticasone propionate dry powder inhaler. In another trial in subjects with COPD, peak steady-state fluticasone propionate plasma concentrations averaged 115 pg/mL (range: 52.6 to 366.0 pg/mL) after treatment with 500 mcg twice daily via a fluticasone propionate dry powder inhaler (n = 15) and 105 pg/mL (range: 22.5 to 299.0 pg/mL) via fluticasone propionate and salmeterol inhalation powder (n = 24).

Healthy Subjects

Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect.

Following administration of fluticasone propionate and salmeterol inhalation powder to healthy adult subjects, peak plasma concentrations of salmeterol were achieved in about 5 minutes.

In 15 healthy subjects receiving ADVAIR HFA 230/21 Inhalation Aerosol (920/84 mcg) and fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg (1,000 mcg/100 mcg), systemic exposure to salmeterol was higher (317 versus 169 pg•h/mL) and peak salmeterol concentrations were lower (196 versus 223 pg/mL) following ADVAIR HFA compared with fluticasone propionate and salmeterol inhalation powder, although pharmacodynamic results were comparable.

Subjects with Asthma

Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended dosages (50 mcg of salmeterol inhalation powder twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses.

Ritonavir

Ketoconazole

Salmeterol

In a placebo-controlled, crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

Fluticasone Propionate

In a multiple-dose drug interaction trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

Salmeterol

In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P<0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium.

Trial 1: Clinical Trial with Fluticasone Propionate and Salmeterol Inhalation Powder 100 mcg/50 mcg

This placebo-controlled, 12-week, U.S. trial compared fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg with its individual components, fluticasone propionate 100 mcg and salmeterol 50 mcg. The trial was stratified according to baseline asthma maintenance therapy; subjects were using either ICS (n = 250) (daily doses of beclomethasone dipropionate 252 to 420 mcg; flunisolide 1,000 mcg; fluticasone propionate inhalation aerosol 176 mcg; or triamcinolone acetonide 600 to 1,000 mcg) or salmeterol (n = 106). Baseline FEV1 measurements were similar across treatments: fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg, 2.17 L; fluticasone propionate 100 mcg, 2.11 L; salmeterol, 2.13 L; and placebo, 2.15 L.

Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled trial. Worsening asthma was defined as a clinically important decrease in FEV1 or PEF, increase in use of VENTOLIN® (albuterol, USP) Inhalation Aerosol, increase in night awakenings due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. As shown in Table 4, statistically significantly fewer subjects receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo.

The FEV1 results are displayed in Figure 1. Because this trial used predetermined criteria for worsening asthma, which caused more subjects in the placebo group to be withdrawn, FEV1 results at Endpoint (last available FEV1 result) are also provided. Subjects receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg had significantly greater improvements in FEV1 (0.51 L, 25%) compared with fluticasone propionate 100 mcg (0.28 L, 15%), salmeterol (0.11 L, 5%), and placebo (0.01 L, 1%). These improvements in FEV1 with fluticasone propionate and salmeterol inhalation powder were achieved regardless of baseline asthma maintenance therapy (ICS or salmeterol).

Figure 1. Mean Percent Change from Baseline in FEV1 in Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)

The effect of fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg on morning and evening PEF endpoints is shown in Table 5.

The subjective impact of asthma on subjects’ perception of health was evaluated through use of an instrument called the Asthma Quality of Life Questionnaire (AQLQ) (based on a 7 point scale where 1 = maximum impairment and 7 = none). Subjects receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg had clinically meaningful improvements in overall asthma-specific quality of life as defined by a difference between groups of ≥0.5 points in change from baseline AQLQ scores (difference in AQLQ score of 1.25 compared with placebo).

Trial 2: Clinical Trial with Fluticasone Propionate and Salmeterol Inhalation Powder 250 mcg/50 mcg

This placebo-controlled, 12-week, U.S. trial compared fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg with its individual components, fluticasone propionate 250 mcg and salmeterol 50 mcg, in 349 subjects with asthma using ICS (daily doses of beclomethasone dipropionate 462 to 672 mcg; flunisolide 1,250 to 2,000 mcg; fluticasone propionate inhalation aerosol 440 mcg; or triamcinolone acetonide 1,100 to 1,600 mcg). Baseline FEV1 measurements were similar across treatments: fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, 2.23 L; fluticasone propionate 250 mcg, 2.12 L; salmeterol, 2.20 L; and placebo, 2.19 L.

Efficacy results in this trial were similar to those observed in Trial 1. Subjects receiving fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg had significantly greater improvements in FEV1 (0.48 L, 23%) compared with fluticasone propionate 250 mcg (0.25 L, 13%), salmeterol (0.05 L, 4%), and placebo (decrease of 0.11 L, decrease of 5%). Statistically significantly fewer subjects receiving fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg were withdrawn from this trial for worsening asthma (4%) compared with fluticasone propionate (22%), salmeterol (38%), and placebo (62%). In addition, fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg was superior to fluticasone propionate, salmeterol, and placebo for improvements in morning and evening PEF. Subjects receiving fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg also had clinically meaningful improvements in overall asthma-specific quality of life as described in Trial 1 (difference in AQLQ score of 1.29 compared with placebo).

Trial 3: Clinical Trial with Fluticasone Propionate and Salmeterol Inhalation Powder 500 mcg/50 mcg

This 28-week, non-U.S. trial compared fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg with fluticasone propionate 500 mcg alone and concurrent therapy (salmeterol 50 mcg plus fluticasone propionate 500 mcg administered from separate inhalers) twice daily in 503 subjects with asthma using ICS (daily doses of beclomethasone dipropionate 1,260 to 1,680 mcg; budesonide 1,500 to 2,000 mcg; flunisolide 1,500 to 2,000 mcg; or fluticasone propionate inhalation aerosol 660 to 880 mcg [750 to 1,000 mcg inhalation powder]). The primary efficacy parameter, morning PEF, was collected daily for the first 12 weeks of the trial. The primary purpose of weeks 13 to 28 was to collect safety data.

Baseline PEF measurements were similar across treatments: fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, 359 L/min; fluticasone propionate 500 mcg, 351 L/min; and concurrent therapy, 345 L/min. Morning PEF improved significantly with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg compared with fluticasone propionate 500 mcg over the 12-week treatment period. Improvements in morning PEF observed with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg were similar to improvements observed with concurrent therapy.

Pediatric Subjects

In a 12-week U.S. trial, fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg twice daily was compared with fluticasone propionate inhalation powder 100 mcg twice daily in 203 children with asthma aged 4 to 11 years. At trial entry, the children were symptomatic on low doses of ICS (beclomethasone dipropionate 252 to 336 mcg/day; budesonide 200 to 400 mcg/day; flunisolide 1,000 mcg/day; triamcinolone acetonide 600 to 1,000 mcg/day; or fluticasone propionate 88 to 250 mcg/day). The primary objective of this trial was to determine the safety of fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg compared with fluticasone propionate inhalation powder 100 mcg in this age group; however, the trial also included secondary efficacy measures of pulmonary function. Morning predose FEV1 was obtained at baseline and Endpoint (last available FEV1 result) in children aged 6 to 11 years. In subjects receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg, FEV1 increased from 1.70 L at baseline (n = 79) to 1.88 L at Endpoint (n = 69) compared with an increase from 1.65 L at baseline (n = 83) to 1.77 L at Endpoint (n = 75) in subjects receiving fluticasone propionate 100 mcg.

The findings of this trial, along with extrapolation of efficacy data from subjects aged 12 years and older, support the overall conclusion that fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg is efficacious in the treatment of asthma in subjects aged 4 to 11 years.

Safety and Efficacy Trials Comparing Fluticasone Propionate and Salmeterol Inhalation Powder with Fluticasone Propionate

Serious Asthma-Related Events

Two 26-week, randomized, double-blind, parallel-group, active comparator trials were conducted to compare the safety and efficacy of fluticasone propionate and salmeterol inhalation powder with fluticasone propionate inhalation powder in adult and adolescent subjects (Trial 4, NCT01475721) and in pediatric subjects aged 4 to 11 years (Trial 5, NCT01462344). The primary safety objective of both trials was to evaluate whether the addition of salmeterol xinafoate to fluticasone propionate therapy (fluticasone propionate and salmeterol inhalation powder) was non-inferior to ICS fluticasone propionate in terms of the risk of a serious asthma-related event (hospitalization, endotracheal intubation, and death). The trials were designed to rule out pre-defined risk margins for serious asthma-related events of 2.0 for Trial 4 and 2.7 for Trial 5. A blinded adjudication committee determined whether events were asthma related.

Trial 4 enrolled subjects with moderate to severe persistent asthma with a history of asthma-related hospitalization or at least 1 asthma exacerbation in the previous year treated with systemic corticosteroids. A total of 11,679 adult and adolescent subjects [5,834 receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg, fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, or fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg and 5,845 receiving fluticasone propionate inhalation powder (100, 250, or 500 mcg)] were included. Trial 5 enrolled subjects with a diagnosis of asthma and a history of at least 1 asthma exacerbation in the previous year treated with systemic corticosteroid. A total of 6,208 subjects aged 4 to 11 years [3,107 receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg or fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg and 3,101 receiving fluticasone propionate inhalation powder (100 or 250 mcg)] were included. In both trials, subjects with life-threatening asthma were excluded. In Trials 4 and 5, fluticasone propionate and salmeterol inhalation powder was non-inferior to fluticasone propionate in terms of time to first serious asthma-related events based on the pre-specified risk margins, with estimated hazard ratios of 1.03 (95% CI: 0.64, 1.66) and 1.29 (95% CI: 0.73, 2.27), respectively (Table 6).

Effect on Exacerbation

Trials 4 and 5 included time to first exacerbation as a secondary endpoint, where exacerbation was defined as a deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. In Trials 4 and 5, the hazard ratio for the time to first asthma exacerbation for fluticasone propionate and salmeterol inhalation powder relative to fluticasone propionate inhalation powder was 0.79 (95% CI: 0.70, 0.89) and 0.86 (95% CI: 0.73, 1.01), respectively. The difference in exacerbations was primarily driven by a reduction in those requiring systemic corticosteroids only.