TABLE IX.B.2.c-4.

Studies evaluating adverse effects of intranasal corticosteroids

Study	Year	LOE	Study design	Study groups	Clinical endpoint	Conclusion
Ahmadi et al.1319	2015	1a	SR	19 studies of INCS reporting original ocular endpoints (10 RCTs, 1 case-control, 8 case series) included.	IOP, lens opacity, glaucoma or cataract incidence.	None of the 10 RCTs reporting IOP demonstrated changes vs control. None of the 6 RCTs reporting cataract or lens opacity demonstrated changes vs control.
Mener et al.1320	2015	1a	SR with meta-analysis	8 RCTs (n = 755) investigating INCS for AR in children 3-12 years.	Interval change in growth. Knemometry (n = 342 participants, duration 2–4 weeks). Stadiometry (n = 413 participants, duration 12 months).	Knemometry studies: Mean growth lower among children using INCS. Stadiometry studies: No significant growth difference in INCS vs placebo. Limitations: Difficulty in predicting longer-term or catch-up growth.
Verkerk et al.1305	2015	1a	SR	34 studies (11 RCTs, 5 cohorts, 20 case series) included. INCS use with or without control group.	Histopathology of nasal mucosa. Mucosal atrophy reported in 17 studies.	The concept of nasal mucosal atrophy is poorly defined. No histological evidence for deleterious effects from INCS use on human nasal mucosa.
Hampel et al.1317	2015	1b	RDBPCT	PAR, children 6–11 years. BDP 800 μg daily (n = 67) vs placebo (n = 32) for 6 weeks.	Change in 24-hour serum cortisol from baseline.	Serum cortisol values remained stable in both groups. Concentration-time profiles similar for the placebo and BDP groups at baseline and week 6.
Meltzer et al.1302	2009	1b	Subanalysis of 3 RDBPCTs, focusing on the 6-11 age group	SAR: 2-week U.S. study. PAR: 12-week global study. HPA axis safety: 6-week U.S. study. FF 55 μg vs FF 110 μg vs placebo daily (n = 948).	Different endpoints, which included: adverse event monitoring, nasal examinations, ophthalmic examinations, 24-hour urinary cortisol excretions, and serum cortisol concentrations.	Epistaxis 4% in both active and placebo groups. No differences between groups for IOP, and no posterior subcapsular cataracts. No difference in HPA measures between groups.
Ratner et al.1304	2009	1b	Multicenter, randomized, controlled trial	PAR, children 6–11 years (n = 255). MFNS 100 μg vs BDP 168 μg daily for 12 months.	Symptom control and safety.	There was appropriate symptom control in both groups. Adverse events were mild. Incidence of epistaxis was 12.7% with MFNS and 9.4% for BDP.
Tripathy et al.1316	2009	1b	Double-blind, randomized parallel-group study	PAR, children 2–11 years (n = 112). FF 110 μg vs placebo daily for 6 weeks.	24-hour serum and urinary cortisol. FF plasma measurements.	FF was non-inferior to placebo with respect to 24-hour serum cortisol. Urinary cortisol excretion over 24 hour at baseline and end of treatment similar between treatment groups.
Weinstein et al.1315	2009	1b	RDBPCT, multicenter, parallel-group	PAR, children 2–5 years (n = 474). TAA 110 μg vs placebo daily for 4 weeks.	Adverse events, morning serum cortisol levels, and growth as measured using office stadiometry.	Adverse event rates comparable between groups. No significant change from baseline in serum cortisol levels after cosyntropin infusion. Distribution by stature-for-age percentile remained stable.
Maspero et al.1301	2008	1b	Double-blind, placebo-controlled study	PAR, children 2–11 years (n = 558). FF 110 μg vs FF 55 μg vs placebo daily for 12 weeks.	Nasal symptom scores for efficacy. Nasal and ophthalmic examinations, and HPA assessments for safety.	Epistaxis 6% in all groups. There were no significant ophthalmic or HPA related side effects in the treated subjects. The lower dose of FF reduced nasal symptoms.
Patel et al.1314	2008	1b	RDBPCT, parallel-group	PAR, 12–65 years (n = 112). FF 110 μg daily for 6 weeks vs prednisone 10 mg daily for last 7 days of study vs placebo.	Change in 24-hour serum cortisol and 24-hour urinary free cortisol, total 24-hour urinary free cortisol, 6-beta hydroxycortisol excretion, and plasma concentration of FF.	Ratio from baseline in serum cortisol weighted mean: FF noninferior to placebo, prednisone significantly reduced the ratio. 24-hour urinary cortisol excretion was similar in the FF and placebo groups. Plasma levels of FF were undetectable after 6 weeks of treatment.
Chervinsky et al.1313	2007	1b	RDBPCT	PAR patients ≥12 years (n = 663). Ciclesonide 200 μg vs placebo daily for up to 52 weeks.	Adverse events, exam findings, 24-hour urinary free cortisol, morning plasma cortisol, IOP, lens opacification.	No clinically relevant differences observed between the ciclesonide and placebo groups.
Kim et al.1312	2007	1b	Two separate phase 3, double-blind, parallel-group, placebo-controlled trials	PAR, children 2–5 years. Safety, tolerability, and efficacy of intranasal ciclesonide 200 μg once daily. First study: 6 weeks. Second study: 12 weeks.	Cortisol levels were measured at the beginning and end of each study. The systemic exposure of ciclesonide and its active metabolite measured at treatment end in the 6-week study.	Changes in plasma or urine cortisol levels showed no difference in active vs placebo group. Serum concentrations were below the lower limit of quantification, suggesting that systemic exposure to ciclesonide was low.
Rosenblut et al.1303	2007	1b	RDBPCT, parallel-group	PAR (n = 806). FF 110 μg vs placebo daily for 12 months.	Adverse events, 24-hour urinary cortisol excretion, nasal and ophthalmic examinations, electrocardiograms and clinical laboratory tests.	Incidence of adverse events similar to placebo, except epistaxis (active 20%, placebo 8%). No clinically meaningful differences in ophthalmic parameters or urine cortisol excretion.
Galant et al.1311	2003	1b	RDBPCT	AR, children 2-3 years (n = 65). FP 200 μg vs placebo daily for 6 weeks.	12-hour urinary free cortisol concentration at baseline and after 6 weeks of treatment.	FP group equivalent to placebo group in mean change from baseline of 12-hour urinary free cortisol at treatment end.

AR = allergic rhinitis; BDP; beclomethasone dipropionate; FF = fluticasone furoate; FP = fluticasone propionate; HPA; hypothalamic pituitary axis; INCS = intranasal corticosteroid; IOP = intraocular pressure; LOE = level of evidence; MFNS = mometasone furoate nasal spray; PAR = perennial allergic rhinitis; RCT = randomized controlled trial; RDBPCT = randomized double-blind placebo-controlled trial; SAR = seasonal allergic rhinitis; SR = systematic review; TAA = triamcinolone acetonide.