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Open Access

Using intranasal corticosteroids

James Fowler and Leigh J Sowerby
CMAJ January 11, 2021 193 (2) E47; DOI: https://doi.org/10.1503/cmaj.201266
James Fowler
Department of Otolaryngology–Head and Neck Surgery, Western University, London, Ont.
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Leigh J Sowerby
Department of Otolaryngology–Head and Neck Surgery, Western University, London, Ont.
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  • RE: Intranasal corticosteroids may have systemic absorption and potential impact upon cortisol measures
    Leigh J Sowerby [MD MHM FRCSC] and James Fowler [MD]
    Posted on: 26 January 2021
  • Intranasal corticosteroids may have systemic absorption and potential impact upon cortisol measures
    Gregory A. Kline [MD], Christopher J. Symonds [MD] and Daniel T. Holmes [MD]
    Posted on: 22 January 2021
  • Posted on: (26 January 2021)
    Page navigation anchor for RE: Intranasal corticosteroids may have systemic absorption and potential impact upon cortisol measures
    RE: Intranasal corticosteroids may have systemic absorption and potential impact upon cortisol measures
    • Leigh J Sowerby [MD MHM FRCSC], Otolaryngologist - Head and Neck Surgeon, Western University
    • Other Contributors:
      • James Fowler, Otolaryngologist - Head and Neck Surgeon

    Thank you to Dr. Kline and his co-authors for their insightful comments regarding the potential risk of HPA axis suppression in certain scenarios with nasal corticosteroid (1). We agree that prescribers should be aware of possible medication interactions, in particular with CYP3A4 inhibitors. At the same time, prescribers should not shy away from prescribing these medications for the vast majority of patients with symptomatic nasal complaints as their safety profile is well established.

    We would like to comment on the systematic review citing a 4% incidence of biochemical adrenal insufficiency with nasal steroid use (2). Broersen references 8 papers regarding this, but on detailed review of this paper, we could only identify 5 papers with intranasal delivery of corticosteroid, the most recent being from 2004. This also included two papers that used corticosteroid drops rather than spray, which is well-known to deliver a higher dose of corticosteroid and is not available in Canada due to the risk of HPA axis suppression.

    A much more detailed review of side-effects with intranasal corticosteroid therapy in adults was published in December 2020 (3). This paper found 28 studies looking specifically at HPA suppression in adults. Of these, 23 reported no evidence of HPA axis suppression, and the 5 studies that did were with non-FDA approved methods of corticosteroid delivery (including 3 using drops). The same group published a similar systematic review in chi...

    Show More

    Thank you to Dr. Kline and his co-authors for their insightful comments regarding the potential risk of HPA axis suppression in certain scenarios with nasal corticosteroid (1). We agree that prescribers should be aware of possible medication interactions, in particular with CYP3A4 inhibitors. At the same time, prescribers should not shy away from prescribing these medications for the vast majority of patients with symptomatic nasal complaints as their safety profile is well established.

    We would like to comment on the systematic review citing a 4% incidence of biochemical adrenal insufficiency with nasal steroid use (2). Broersen references 8 papers regarding this, but on detailed review of this paper, we could only identify 5 papers with intranasal delivery of corticosteroid, the most recent being from 2004. This also included two papers that used corticosteroid drops rather than spray, which is well-known to deliver a higher dose of corticosteroid and is not available in Canada due to the risk of HPA axis suppression.

    A much more detailed review of side-effects with intranasal corticosteroid therapy in adults was published in December 2020 (3). This paper found 28 studies looking specifically at HPA suppression in adults. Of these, 23 reported no evidence of HPA axis suppression, and the 5 studies that did were with non-FDA approved methods of corticosteroid delivery (including 3 using drops). The same group published a similar systematic review in children (4), identifying 23 studies including information on HPA axis suppression. Of these studies, 17 demonstrated no evidence of HPA axis suppression. Five of the six that did note some suppression were using non-FDA approved intranasal corticosteroid drops.

    Given the comorbidity of asthma with chronic rhinosinusitis and/or allergic rhinitis, it is important to keep in mind the potential additive effect of both inhaled and intranasal corticosteroid in HPA axis suppression. Indeed, one of the cases cited by Kline was on concurrent inhaled corticosteroid (5). As such, we would recommend selecting a second generation nasal corticosteroid (ciclesonide hydrofluoroalkane, mometasone furoate or fluticasone propionate) for patients on inhaled corticosteroids, and to, on occasion, re-evaluate whether the current intranasal corticosteroid dose and therapy is still required for symptom control.

    Show Less
    Competing Interests: Leigh Sowerby reports receiving personal fees from Mylan, GSK and Sanofi, and grants from GSK, Roche and Astra­Zeneca, outside of the submitted work. No other competing interests were declared.

    References

    • 1. Kline GA, Symonds CJ, Holmes DT. Intranasal corticosteroids may have systemic absorption and potential impact upon cortisol measures. CMAJ 2021; doi:10.1503/cmaj.78162
    • 2. Broersen LHA, Pereira AM, Jørgensen JOL, Dekkers OM. Adrenal insufficiency in corticosteroids use: Systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100:2171–80.
    • 3. Donaldson AM, Choby G, Kim DH, Marks LA, Lal D. Intranasal Corticosteroid Therapy: Systematic Review and Meta-analysis of Reported Safety and Adverse Effects in Adults. Otolaryngol Head Neck Surg. 2020 Dec;163(6):1097-1108.
    • 4. Donaldson AM, Choby G, Kim DH, Marks LA, Lal D. Intranasal Corticosteroid Therapy: Systematic Review and Meta-analysis of Reported Safety and Adverse Effects in Children. Otolaryngology–Head and Neck Surgery. 2020;163(6):1087-1096.
    • 5. Veilleux O, Lee TC, McDonald EG. Rebound adrenal insufficiency after withdrawal of ritonavir in a 65-year-old man using inhaled budesonide. CMAJ. 2017;189(37):E1188-91.
  • Posted on: (22 January 2021)
    Page navigation anchor for Intranasal corticosteroids may have systemic absorption and potential impact upon cortisol measures
    Intranasal corticosteroids may have systemic absorption and potential impact upon cortisol measures
    • Gregory A. Kline [MD], Clinical Professor of Medicine/Endocrinology, University of Calgary
    • Other Contributors:
      • Christopher J. Symonds, Clinical Associate Professor of Medicine/Endocrinology
      • Daniel T. Holmes, Clinical Professor, Department of Pathology and Lab Medicine

    In their recent review of intranasal corticosteroids, the authors claim that there is no correlation with hypothalamic-pituitary-adrenal suppression(1). However, there are scenarios for which this is not always true and therefore, some additional details may be useful. In support of their claim, the authors have only cited a review article which, in turn, cites another review article and other small older studies. Most studies looking at this question have had major design flaws in their 1) very small numbers, 2) use of presently out-dated and less accurate cortisol assays, 3) collection of adrenal tests as an exploratory secondary endpoint, 4) lack of differentiation between different types, doses and durations of glucocorticoids and 5) lack of clinically relevant data.

    A 2015 systematic review and meta-analysis of primary data, using appropriate inclusion, exclusion and stratification criteria has shown that nearly 4% (0.5-28.9%) of intranasal steroid users can show adrenal suppression when defined biochemically(2). The risk is likely increased with longer duration of use and with higher doses but is likely less than what is seen with inhaled steroids, for asthma treatment. However, in combination with medications that inhibit cytochrome p450 3A4 (CYP3A4 inhibitors) which will slow systemic glucocorticoid metabolism, intranasal steroids may even cause Cushing’s syndrome(3)(4) with rebound adrenal insufficiency after discontinuation(5) emphasizing their poten...

    Show More

    In their recent review of intranasal corticosteroids, the authors claim that there is no correlation with hypothalamic-pituitary-adrenal suppression(1). However, there are scenarios for which this is not always true and therefore, some additional details may be useful. In support of their claim, the authors have only cited a review article which, in turn, cites another review article and other small older studies. Most studies looking at this question have had major design flaws in their 1) very small numbers, 2) use of presently out-dated and less accurate cortisol assays, 3) collection of adrenal tests as an exploratory secondary endpoint, 4) lack of differentiation between different types, doses and durations of glucocorticoids and 5) lack of clinically relevant data.

    A 2015 systematic review and meta-analysis of primary data, using appropriate inclusion, exclusion and stratification criteria has shown that nearly 4% (0.5-28.9%) of intranasal steroid users can show adrenal suppression when defined biochemically(2). The risk is likely increased with longer duration of use and with higher doses but is likely less than what is seen with inhaled steroids, for asthma treatment. However, in combination with medications that inhibit cytochrome p450 3A4 (CYP3A4 inhibitors) which will slow systemic glucocorticoid metabolism, intranasal steroids may even cause Cushing’s syndrome(3)(4) with rebound adrenal insufficiency after discontinuation(5) emphasizing their potential for systemic absorption.

    While adverse clinical sequelae may be uncommon, it is particularly worth noting that in modern lab medicine, use of more specific cortisol immunoassays or mass spectrometry can show a very low basal cortisol level when measured in a patient using intranasal or inhaled steroids particularly in patients receiving highly active antiretroviral therapy or azole antifungals. It is a common mistake to interpret this as “adrenal insufficiency” in need of replacement therapy; rather it is simply evidence that the synthetic glucocorticoid does indeed have systemic absorption and may be suppressing the basal HPA axis. Based upon a low serum cortisol measured while the patient is actively using exogenous glucocorticoids in any form, one cannot determine whether this leads to suppression, delayed recovery or clinical adrenal insufficiency after glucocorticoid discontinuation. Intranasal steroids may have systemic absorption with impact upon the native HPA axis and therefore the decision of when or how to stop such medications should keep this in mind, particularly among persons treated with CYP3A4 inhibitors.

    Show Less
    Competing Interests: None declared.

    References

    • James Fowler, Leigh J Sowerby. Using intranasal corticosteroids. CMAJ 2021;193:E47-E47.
    • Broersen LHA, Pereira AM, Jørgensen JOL, Dekkers OM. Adrenal insufficiency in corticosteroids use: Systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100:2171–80.
    • Hillebrand-Haverkort ME, Prummel MF, Ten Veen JH. Ritonavir-induced Cushing’s syndrome in a patient treated with nasal fluticasone [15]. AIDS. 1999;13:1803.
    • Chen F, Kearney T, Robinson S, Daley-Yates PT, Waldron S, Churchill DR. Cushing’s syndrome and severe adrenal suppression in patients treated with ritonavir and inhaled nasal fluticasone [3]. Sex Transm Infect. 1999;75:274.
    • Veilleux O, Lee TC, McDonald EG. Rebound adrenal insuficiency afer withdrawal of ritonavir in a 65-year-old man using inhaled budesonide. CMAJ. 2017;189(37):E1188-91.
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Canadian Medical Association Journal: 193 (2)
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Using intranasal corticosteroids
James Fowler, Leigh J Sowerby
CMAJ Jan 2021, 193 (2) E47; DOI: 10.1503/cmaj.201266

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Using intranasal corticosteroids
James Fowler, Leigh J Sowerby
CMAJ Jan 2021, 193 (2) E47; DOI: 10.1503/cmaj.201266
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    • Intranasal corticosteroids can be used as primary or adjunct therapy for many inflammatory conditions within the nasal cavity
    • There are 9 intranasal corticosteroids approved in Canada, all with similar efficacy
    • Intranasal corticosteroids are safe, but local adverse effects are common
    • Correct administration of intranasal corticosteroids is crucial for desired therapeutic effect
    • Fewer intranasal corticosteroids are available for children and pregnant women
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