FLOVENT HFA (Page 4 of 7)

8.4 Pediatric Use

The safety and effectiveness of FLOVENT HFA in pediatric patients aged 4 years and older have been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Use of FLOVENT HFA in patients aged 4 to 11 years is supported by evidence from adequate and well-controlled trials in adults and adolescents aged 12 years and older, pharmacokinetic trials in patients aged 4 to 11 years, established efficacy of fluticasone propionate formulated as FLOVENT DISKUS (fluticasone propionate inhalation powder) and FLOVENT ROTADISK (fluticasone propionate inhalation powder) in patients aged 4 to 11 years, and supportive findings with FLOVENT HFA in a trial conducted in subjects aged 4 to 11 years.

The safety and effectiveness of FLOVENT HFA in pediatric patients younger than 4 years have not been established.

Effects on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including ICS. The effects of long-term treatment of children and adolescents with ICS, including fluticasone propionate, on final adult height are not known.

Controlled clinical trials have shown that ICS may cause a reduction in growth in pediatric patients. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT HFA, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT HFA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

Since a cross trial comparison in adult and adolescent subjects (aged 12 years and older) indicated that systemic exposure of inhaled fluticasone propionate from FLOVENT HFA would be higher than exposure from FLOVENT ROTADISK, results from a trial to assess the potential growth effects of FLOVENT ROTADISK in pediatric subjects (aged 4 to 11 years) are provided.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S. in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical relevance of these growth data is not certain.

Pediatric Patients Younger than 4 Years

Pharmacokinetics: [see Clinical Pharmacology (12.3)].

Pharmacodynamics: A 12-week, double-blind, placebo-controlled, parallel-group trial was conducted in children with asthma aged 1 to younger than 4 years. Twelve-hour overnight urinary cortisol excretion after a 12-week treatment period with 88 mcg of FLOVENT HFA twice daily (n = 73) and with placebo (n = 42) were calculated. The mean and median change from baseline in urine cortisol over 12 hours were -0.7 and 0.0 mcg for FLOVENT HFA and 0.3 and -0.2 mcg for placebo, respectively.

In a 1-way crossover trial in children aged 6 to younger than 12 months with reactive airways disease (N = 21), serum cortisol was measured over a 12-hour dosing period. Subjects received placebo treatment for a 2-week period followed by a 4-week treatment period with 88 mcg of FLOVENT HFA twice daily with an AeroChamber Plus Valved Holding Chamber (VHC) with mask. The geometric mean ratio of serum cortisol over 12 hours [AUC_{(0-12 h)} ] following FLOVENT HFA (n = 16) versus placebo (n = 18) was 0.95 (95% CI: 0.72, 1.27).

Safety: FLOVENT HFA administered as 88 mcg twice daily was evaluated for safety in 239 pediatric subjects aged 1 to younger than 4 years in a 12-week, double-blind, placebo-controlled trial. Treatments were administered with an AeroChamber Plus VHC with mask. The following events occurred with a frequency >3% and more frequently in subjects receiving FLOVENT HFA than in subjects receiving placebo, regardless of causality assessment: pyrexia, nasopharyngitis, upper respiratory tract infection, vomiting, otitis media, diarrhea, bronchitis, pharyngitis, and viral infection.

FLOVENT HFA administered as 88 mcg twice daily was evaluated for safety in 23 pediatric subjects aged 6 to 12 months in an open-label placebo-controlled trial. Treatments were administered with an AeroChamber Plus VHC with mask for 2 weeks with placebo followed by 4 weeks with active drug. There was no discernable difference in the types of adverse events reported between subjects receiving placebo compared with the active drug.

In Vitro Testing of Dose Delivery with Holding Chambers: In vitro dose characterization studies were performed to evaluate the delivery of FLOVENT HFA via holding chambers with attached masks. The studies were conducted with 2 different holding chambers (AeroChamber Plus VHC and AeroChamber Z-STAT Plus VHC) with masks (small and medium size) at inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively. The mean delivered dose of fluticasone propionate through the holding chambers with masks was lower than the 44 mcg of fluticasone propionate delivered directly from the actuator mouthpiece. The results were similar through both holding chambers (see Table 2 for data for the AeroChamber Plus VHC). The fine particle fraction (approximately 1 to 5 μm) across the flow rates used in these studies was 70% to 84% of the delivered dose, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for FLOVENT HFA delivered without a holding chamber typically represents 42% to 55% of the delivered dose measured at the standard flow rate of 28.3 L/min. These data suggest that, on a per kilogram basis, young children receive a comparable dose of fluticasone propionate when delivered via a holding chamber and mask as adults do without their use.

Table 2. In Vitro Medication Delivery through AeroChamber Plus Valved Holding Chamber with a Mask

a Centers for Disease Control growth charts, 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. b A single inhalation of FLOVENT HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 44 mcg, or 0.6 mcg/kg.
Age	Mask	Flow Rate (L/min)	Holding Time (seconds)	Mean Medication Delivery through AeroChamber Plus VHC (mcg/actuation)	Body Weight 50th Percentile (kg)a	Medication Delivered per Actuation (mcg/kg)b
6 to 12 Months	Small	4.9	0	8.3	7.5-9.9	0.8-1.1
			2	6.7		0.7-0.9
			5	7.5		0.8-1.0
			10	7.5		0.8-1.0
2 to 5 Years	Small	8.0	0	7.3	12.3-18.0	0.4-0.6
			2	6.8		0.4-0.6
			5	6.7		0.4-0.5
			10	7.7		0.4-0.6
2 to 5 Years	Medium	8.0	0	7.8	12.3-18.0	0.4-0.6
			2	7.7		0.4-0.6
			5	8.1		0.5-0.7
			10	9.0		0.5-0.7
>5 Years	Medium	12.0	0	12.3	18.0	0.7
			2	11.8		0.7
			5	12.0		0.7
			10	10.1		0.6