MEDICAL OFFICER REVIEW Division Of Pulmonary and Allergy Drug Products (HFD-570)

APPLICATION: APPLICANT/SPONSOR: MEDICAL OFFICER: TEAM LEADER: DATE: Document Date November 21, 2007 NDA 21-433 Flovent HFA Carol H. Bosken, MD Lydia Gilbert-McClain, MD June 11 , 2008 CATEGORY: TRADE NAME: FORMULATION: Flovent HFA Fluticasone propionate in an HFA MDI ICS

ROUTE: Oral inhalation SUBMISSIONS REVIEWED IN THIS DOCUMENT CDER Stamp Date Submission Submission Type & Comments November 22, 2007 SLR_011 Prior approval labeling supplement

RECOMMENDED REGULATORY ACTION : Approval of Supplement

INTRODUCTION Flovent HFA was approved for the maintenance treatment of asthma in patients 12 years of age and older in May 2004: an efficacy supplement for the treatment of patients as young as 4 years of age was approved in February of 2006. Studies in patients less than 4 years of age, required under PREA, were deferred. The current submission is a pre-approval labeling supplement which is a partial response to the PREA commitment. It includes a PD/PK study in patients 6 to 11 months of age, a summary of in vitro tests of drug delivery using a spacer and face mask, and a draft label based on the new information. Proposed labeling changes also include information from Study FAS 30030 which was reviewed with SE5_004, the supplement to support the efficacy claim in children 4 to 11 years of age. A complete review of Study FAS106533 is attached, and the study and the in vitro experiments are summarized below.

REVIEW OF NEW STUDIES Study FAS106533 This was an open-label, cross-over trial conducted in subjects 6 to less than 12 months of age, who had experienced at least 2 wheezing episodes in the 6 months prior to enrolment, but were other wise healthy. They did not require treatment with corticosteroids. Eligible subjects were treated twice daily with a placebo HFA inhaler for 14 days and then all were switched to Flovent HFA 88 mcg BID (FP) for an additional 28 days. At the end of the run-in and on the last day of active treatment they had blood drawn for cortisol and FP. The primary outcome was the 12-hour weighted mean serum cortisol comparing the measurements obtained after placebo treatment and after 28 days of treatment with FP. Safety was assessed with adverse events. Twenty three subjects were included in the safety population. They had a mean age of 9.4 months, 5 were female and 52% were Caucasian. Ten (44%) were African American and 1

was of North African heritage. The mean weight was 9.3 kg. Seventeen patients had measurements for cortisol and FP during both treatment periods. The 12-hour weighted mean cortisol level was 184.58 and 191.61 nmol/L in the FP and placebo time periods, respectively (Table 1). The ratio of the geometric means (95% CI) was 0.96 (0.71, 1.31). The pre-set criterion for non-inferiority was met because the lower limit of the confidence interval was greater than 0.7.
Treatment FP HFA Placebo Comparison FP HFA/Placebo Table 1. Serum Cortisol (nmol/L) Geometric Mean 95% Confidence Interval 184.58 144.59, 235.64 191.65 153.66, 239.03 Ratio of Geometric Means 95% Confidence Interval Ratio 0.96 0.71, 1.31

The geometric mean value of the minimum serum cortisol was 91.56 and 103.25 nmol/L in the FP and placebo time periods, respectively. The ratio of the geometric means (95% CI) was 0.89 (0.58, 1.36). A total of 106 plasma samples were analyzed for FP. Of the 85 samples obtained after treatment with FP 34 (40%) were NQ in a bioassay with a lower limit of quantification of 5 pg/mL. In two subjects all of the samples were NQ. The mean Cmax (95% CI) was 24.6 (13.4, 45.0) pg/ mL, and the mean AUC (95% CI) was 75.0 (33.8, 166.3) pghr/mL. The Tmax (95% CI) was 1 (NQ, 4.0) hours. Cough, rhinorrhea, and nasal congestion were the most common adverse events reported in both treatment periods. All three of these events were reported more commonly during placebo than FP treatment. Only insomnia was reported more often during FP treatment (52%) than during placebo (39%). In summary, treatment of infants 6 to 11 months of age with FP 88 mcg BID had a very small effect on cortisol metabolism as assessed with the weighted 12-hour mean serum cortisol levels. Exposure was confirmed in all but two of the subjects with the detection of FP in the blood at some time after exposure. In vitro Evaluation of Drug Delivery with Face Mask and Spacer The in vitro evaluation was performed using the AeroChamber Plus and AeroChamber ZStat Plus spacers fitted with either a small of medium facemask. All of the products used, including the Flovent HFA Inhalation Aerosol fitter with Counter, are commercially available. The Z-Stat model of the spacer incorporates an antistatic agent in the plastic of the chamber. The devices were used in conjunction with a model face with soft tissues around the mouth so that the facemask would form an effective seal when applied with clinically appropriate force. Drug was delivered through the spacer and facemask and through the open mouth onto one of two measuring devices. An electret filter was located immediately behind the open lips to (b) (4) measure the total dose delivered or a was used to determine the aerodynamic particle size distribution (APSD). Tests were performed

immediately after washing the spacer and after the spacer had delivered 28 doses (the equivalent of one-weeks usage). The tests were performed at a flow rate of 4.9, 8.0, or 12.0 L/min and with a delay time of 0, 2, 5, and 10 seconds. In general, the results showed only small changes in total delivered dose as measured with the electret filter. Delivery was similar in the two spacers and, seven of 12 flow/delay time/size combinations showed slightly higher flow with a 10 second compared to 0 seconds delay while 5/12 showed greater delivery with zero delay. As measured with the Marple Impactor, both spacers had a peak delivery in the fine particle (FP) range. At a flow rate of 4.9 L/min the greatest delivery was in Stage 5 (0.77 3.1 m) and at 12 L/min the maximum delivery was in Stage 4 (2.0 3.1 m). Defining fine particle mass as Stage 4 and 5 when the drug was delivered at 4.9 L/min and Stage 3, 4, and 5 when the drug was delivered at 12 L/min, Table 2 shows a slight decrease in total delivery and increase in the FP percentage when the delay time is increased. Using the impactor as the measuring device, total delivery appeared to be slightly higher for the AeroChamber Z-Stat at 12 L/min and slightly lower at 4.9 L/min when compared to the AeroChamber without antistatic treatment.
Table 2. Summary of Drug Delivery (mcg/actuation) Under Varying in Vitro Conditions AeroChamber AeroChamber Z-stat Flow Rate Facemask Delay FP Total %FP FP Total %FP 0 11.9 16.3 73 9.8 14.1 70 4.9 L/min Small 2 11.0 15.0 73 10.9 14.9 73 10 9.4 12.3 76 8.2 10.8 76 0 14.0 17.9 78 14.8 19.3 77 12 L/min Medium 2 10.8 13.9 78 12.2 15.6 78 10 9.5 11.6 82 11.6 13.8 84

Attachment 2 contains a summary of total dose delivered in mcg/kg. Assuming that infants would use the small face mask and apply a low flow rate, while older children would used the medium size facemask and apply higher flow rates, the doses on a per kg basis vary little and are similar to the doses that a 70 kg man would receive after a single inhalation of 44 mcg Flovent without a spacer. Finally, tests were performed after washing the spacer and after 2 inhalations had been simulated without washing. Using the Aerochamber, the total emitted dose was 2 to 3 mcg less after washing, but using the AeroChamber Z-stat, the emitted dose was 1.6 mcg higher after washing if a flow rate of 4.9 L/min were applied to the system, but it was 5.4 mcg lower after washing if the flow rate was 12 L/min. In summary, Flovent, delivered through the Aerochamber Plus spacers does not appear to have the same problem with decreased delivery of drug with increasing delays that have been seen with other inhaled corticosteroids. It is, therefore, safe to allow use of Flovent with spacers in children who are too young to operate an unaltered MDI.

REVIEW OF PROPOSED LABEL CHANGES The primary additions to the label occur in the PD/PK section of Pediatric Use. Also included is a summary of the table included in Attachment II of this review, and edits to the Patient Use Information. The PK data included in the proposed label were considered to be insufficiently descriptive by the FDA clinical pharmacology reviewer because the geometric mean measured values in the children less than 4 years of age had a very large coefficient of variation (many values were below the level of quantitation [BLQ] and others were very high). Therefore, the ranges for Cmax and AUC were added to the label. The FDA-edited label also states explicitly that exposure was higher in children 6 12 months of age treated with the spacer than in children 4 11 years of age treated with the same dose without a spacer. Comparing the data obtained in Study FAS106533 (age 6 to < 12 months), FAS30030 (age 1 to <4 years), and data taken from the approved label (age 4 years and older) showed an inconsistent relationship between age and AUC, although the younger children had a relatively high exposure. The Cmax ranged between 15.1 pg/mL in the children 4 to 11, to 22 pg/m l in those 1 to <4, and 25 pg/mL in both the children 6 to <12 months and adults. The AUC was also similar in the very young and adults (75 and 76 pghr/mL) while the AUC was 28 pghr/mL in the children 4 to 11 and 141 pghr/mL in those 1 to <4 years. Some of this variability may be related to the method of administration. The children 4 to 11 years of age were treated without a spacer and mask whereas the younger children used the spacer. What ever the cause the data suggest that systemic exposure may be high in young children treated with 88 mcg fluticasone HFA using a spacer and mask. More data should probably be collected if the sponsor seeks a claim for treatment of children less than 4 years of age.
(b) (4) In the PD section, the proposed label stated that urinary cortisol excretion after 12 weeks of treatment with Advair HFA and placebo. The FDA reviewer edited the section to (b) (4) remove the statement and replace it with the measured median change from baseline in cortisol excretion in the two treatment groups in the children 1 to < 4 years of age. For the children 6 to < 12 months of age the geometric mean ratio of serum cortisol over 12 hours was reported. The FDA clinical pharmacology reviewer also noted that the study design of FAS106533 may not have been optimal for small children. All of the subjects were treated with placebo followed immediately by treatment with Flovent HFA. Because there was no concurrent control population, it is impossible to rule out a period effect. This issue is particularly important in small children because the serum cortisol circadian rhythm is not well established before 2 years of age and cortisol levels are highly dependent on wake-sleep patterns which may also be variable in this population.

The proposed table that summarized the in vitro medication delivery through Aero Chamber Plus holding chamber was similar in format to those included in other ICS labels and was not edited by the FDA reviewer. Numerous formatting edits were made to the Information for the Patient section by the OSE/DRISK reviewer. In addition, a list of possible adverse events was added.

Attachment I Study # FAS106533

A repeat-dose, open-label, 2-session study to assess the systemic exposure to, and pharmacodynamics of, fluticasone propionate HFA inhalation aerosol 88 mcg administered twice-daily for 28 days delivered via an MDI and valved holding chamber with infant face mask to subjects ages 6 months to <12 months who have experienced 2 or more wheezing episodes in the preceding 6 months. 1.1 Protocol 1.1.1 Administrative Dates: Location: August 22, 2006 April 13, 2007 7 Centers in the United States 1.1.2. Objective/Rationale The primary objective was to determine the effect of administration of FP HFA MDI 88 mcg BID on 12-hour serum cortisol in pediatric subjects, ages 6 months to < 12 months, who had experienced 2 or more wheezing episodes in the preceding 6 months. The secondary objectives were to determine the systemic exposure to FP and to determine the safety and tolerability following administration of FP HFA MDI 88 mcg BID. 1.1.3. Study Design The study was an open-label, repeat dose, single-sequence, two-session study. Eligible subjects were enrolled in a run-in period, during which time they took 2 inhalations of placebo HFA MDI twice daily for 14 days. At the end of the run-in they were switched to 2 inhalations of FP HFA 44 mcg BID which was continued for 28 days. PK and PD data were collected on day 14 (last day of run-in) and 42 (day 28 of active treatment). During both sessions, the parents/guardians maintained symptom diaries, and staff personnel made periodic telephone calls to assess adverse events. The primary endpoint was the 12-hour weighted mean serum cortisol. 1.1.4. Study Population Inclusion Criteria Male of female between ages of 6 and < 12 months 2 or more wheezing episodes in preceding 6 months, but otherwise healthy Corticosteroid independent Documented compliance with diary Ability to use face mask and spacer Written informed consent

Exclusion Criteria Weight less than 7 kg Treatment with any corticosteroid within 4 weeks of screening Treatment with any drug that inhibited or induced CYP3A4 within 4 weeks of screening In ability to complete study procedures or to cooperate for any reason

1.1.5. Study Procedures Treatment Subjects were randomized to one of the following regimens: Flovent HFA inhaler in the 44 mcg per actuation strength (2 inhalations BID). Placebo HFA 2 inhalations BID

The valved holding chamber AeroChamber Plus with face mask was used with the MDI to administer the drug. Pharmacodynamic and Pharmacokinetic Evaluation Approximated 2 mL samples for serum cortisol were collected at 0, 2, 4, 8, and 12 hours postdose following the morning dose on Day 14 and Day 42 (Day 28 of active treatment). On Day 14 one sample was obtained for FP measurement at 1 hour post-dose. If serum was obtained for FP measurement at the same blood-draw, the serum for cortisol was collected first. On day 42 (Day 28 of active treatment) samples were collected for FP measurement at every time point that cortisol was obtained except at 2 hours post-dose. In total 19 mL and 33 mL were drawn at session 1 and 2, respectively. The total blood volume removed was 52 mL. FP was analyzed using a validated HPLC method. The lower limit of quantification was 5 pg/mL. Safety Evaluation Adverse events were recorded in the diary and parents/guardians were encouraged to call the clinical center if they had questions or problems. In addition, study personnel called the parents/guardians on Day 3, 7, and 10 of the run-in and on Days 3, 7, 14, 24, and 28 to assess adverse events. There was also a follow-up phone call 24 hours after completion of treatment.

1.1.6. Statistical Analysis Plan Sample Size A sample size of 16 subjects was chosen as this would provide a reasonable estimate of the effect of FP on the HPA-axis using serum cortisol 12-hour weighted mean cortisol comparing FP and placebo. Non-inferiority was to be demonstrated if the lower limit of the two-sided 95% CI for the ratio of the geometric mean for the two treatments was greater than 0.7.

Based on a standard deviation of 0.40 for the logAUC, 16 subjects would provide a 91% power to demonstrate non-inferiority. Study Populations The Safety Population included all subjects who received at least one dose of placebo in Session #1 (Run-in). The PD population included all subjects in the Safety Population who had serum cortisol results for Day 14 or Day 42 with the exception of subjects who had a detectable FP level on Day 14 (end of session #1). The PK Concentration Population included all patients in the Safety Population who had PK results for Day 14 or Day 42. The PK Parameter Population included all subjects in the PK Concentration Population who had derived PK parameters for Day 42 (Day 28 of active treatment). Changes in Conduct of Study The original protocol required 4 out of 5 possible samples to be available for analysis for the subject to be included in the analysis. Due to the young age of the subjects, serum sampling was difficulty, and the final analysis includes all samples. PD & PK Analysis The primary analysis variable was the 12-hour weighted mean serum cortisol: the primary comparison was between values obtained after 28 days of FP treatment compared with values obtained after 14 days of placebo. Cmin was also compared at the 28-day FP and 14-day placebo time points. For all treatment comparisons a geometric mean plot was made of serum cortisol concentrations over time. A repeated measures analysis with treatment time and a treatment by time interaction was performed.
(b) (4) Serum FP analysis was carried out by . The non-compartmental analysis was performed using the analysis program WinNonlin Professional Edition version 4.0.1.

1.2. Results 1.2.1. Study Population Disposition Twenty-three subjects were enrolled and received at least one dose of placebo. Twenty-one subjects received at least one dose of FP. Eighteen (78%) subjects completed the study. One subject in the FP group withdrew due to varicella infection, three (2 placebo and 1 FP) were withdrawn by parent or lost to follow-up, and 1 FP subject was withdrawn due to failure to obtain venous access for PK/PD sampling. The safety population includes all subjects who received at least one dose of study medication (23 placebo and 21 FP). The PD population (21 placebo and 20 FP) included all subjects in the safety population with serum cortisol results for session 1 or session 2. The PK population (21 placebo and 17 FP) included all subjects in the safety population with serum

FP measurements for session 1 or session 2. The 17 subjects with measurements of FP on day 28 made up the PK parameter population. Reviewer: Seventeen subjects had paired (both placebo and FP) analyses for cortisol and 16 subjects had results for FP at both time points. Only one subject was excluded due to detectable FP in the placebo sample. Demographics The mean age of the population was 9.4 months (range 6 to 11 months) and 5 (22%) were female. Twelve (52%) of the subjects were White/Caucasian and 10 (44%) were African American. One was of North African/Arabic heritage. The mean (SD) weight was 9.3 (1.0) kg. Other than wheezing episodes, the subjects were healthy. Seventy-four percent of the subjects took concomitant medications during placebo treatment and 86% during FP treatment. The most common medication was paracetamol (35% placebo and 43% FP) followed by lidocaine, dextromthorphan, ibuprofen and salbutamol.

1.2.2. Efficacy Results Pharmacodynamic Results The 12-hour weighted mean cortisol level was 184.58 and 191.61 nmol/L in the FP and placebo time periods, respectively (Table 3). The ratio of the geometric means (95% CI) was 0.96 (0.71, 1.31). The criterion for non-inferiority was met because the lower limit of the confidence interval was greater than 0.7.
Treatment FP HFA Placebo Comparison FP HFA/Placebo Table 3. Serum Cortisol (nmol/L) Geometric Mean 95% Confidence Interval 184.58 144.59, 235.64 191.65 153.66, 239.03 Ratio of Geometric Means 95% Confidence Interval Ratio 0.96 0.71, 1.31

The mean values for serum cortisol at each time point are shown in figure 1.
Figure 1. Serum cortisol after 28 days of treatment with FP or 14 days of treatment with Placebo

The geometric mean value of the minimum serum cortisol was 91.56 and 103.25 nmol/L in the FP and placebo time periods, respectively (Table 4). The ratio of the geometric means (95% CI) was 0.89 (0.58, 1.36).
Table 4. Minimum Serum Cortisol After 14 Days of Placebo Treatment or 28 Days of treatment with FP. Treatment Geometric Mean 95% Confidence Interval FP HFA 91.56 64.00, 131.01 Placebo 103.25 74.47, 143.15 Comparison Ratio of Geometric Means 95% Confidence Interval Ratio FP HFA/Placebo 0.89 0.58, 1.36

Pharmacokinetic Results A total of 106 plasma samples were analyzed for FP. Of the 85 samples obtained after treatment with FP 34 (40%) were NQ in a bioassay with a lower limit of quantification of 5 pg/mL. In two subjects all of the samples were NQ. The mean Cmax (95% CI) was 24.6 (13.4, 45.0) pg/ mL, and the mean AUC (95% CI was 75.0 (33.8, 166.3) pghr/mL. The Tmax (95% CI) was 1 (NC, 4.0) hours. The measured PK values are summarized in Table 5.
Table 5. Serum Fluticasone Levels (pg/mL) Number Time N Imputed Mean 17 4 20.8 Pre-dose 17 6 28.8 1 hr 14 5 19.4 4 hr 16 8 11.6 8 hr 15 11 5.1 12 hr

Median 19 18 10 3 0

Range 0, 83 0, 106 0, 58 0, 47 0, 27

There was no relationship between the maximum concentration of FP and the minimum concentration of cortisol (Figure 2). In part this was due to the large coefficient of variation for the FP measurements (172%) which in turn was related to the large number of NQ samples. Reviewer: as noted by the FDA clinical pharmacology reviewer, the range of values for Cmax and AUC was quite broad. The Cmax varied from BLQ to 106 pg/mL and the AUC ranged from Not Calculable to 671.74 pghr/mL.
Figure 2. Minimum Cortisol compared to Maximum FP

1.2.3. Safety

Exposure Twenty three subjects received placebo for a mean of 15.7 (range = 12 to 24) days. Twentyone subjects received FP HFA for a mean of 29 (range=26 to 33) days. Adverse Events During 2 weeks of placebo treatment 22 (96%) of the subjects reported an AE and during 28 weeks of FP treatment 19 (90%) reported at least 1 AE. The most common in both treatment periods was cough (74 and 67% in the placebo and FP treatment periods, respectively) and rhinorrhea (65 and 62% in the placebo and FP treatment periods, respectively). Nasal congestion was reported during 52% of the subjects during placebo treatment but only 29% of the subjects during treatment with FP. By comparison, 39 and 52% of the subjects complained of insomnia during treatment with placebo and FP, respectively. Wheezing, pyrexia and dyspnea were all slightly more common in the placebo time period. Serious Adverse Events and Events Leading to Withdrawal There were no deaths or serious adverse events during FP treatment. One FP subject withdrew due to the onset of varicella. One placebo subject developed pyelonephritis that was classified as severe, but he was not withdrawn from the study. Laboratory Results There was no laboratory examination other than that reported in the PK / PD section.
1.3. Summary and Discussion

In this study, 23 infants age 6 to 11 months were treated with Fluticasone HFA MDI 88 mcg BID. Serum measurements of cortisol and fluticasone were obtained after 14 days of placebo and again after 28 days of fluticasone treatment. The weighted 12-hour mean value of cortisol was only slightly lower during fluticasone that placebo treatment. Ratio FP/placebo 0.96 (95% CI: 0.71, 1.31). The lower limit of the confidence limit was greater than 0.70 and thus met the pre-specified criterion of non-inferiority. Measurement of FP confirmed exposure in all but two of the subjects. The study design, because of a lack of concurrent control subjects makes the results less than definitive because of the possibility of a period effect. However, there is not evidence in this data of an undue effect of inhaled fluticasone on the HPA-axis,

Attachment II

Centers for Disease Control growth chars, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50th percentile weight for boys and girls at the ages indicated.
A

single inhalation of FLOVENT HFA in a 70-kg adult without use of a spacer device and facemask delivers approximately 44 mcg, or 0.6 mcg/kg.

--------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------/s/ --------------------Carol Bosken 6/11/2008 08:47:07 AM MEDICAL OFFICER

Lydia McClain 6/11/2008 11:55:13 AM MEDICAL OFFICER I concur