Potential for Cortisol Suppression With the Use of High Volume Nasal Mometasone Irrigations in Varying Dosages.
Phase: PHASE1
Conditions: Chronic Rhinosinusitis (Diagnosis)
Sponsor: Rush University Medical Center

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Protocol Title: Potential for Cortisol Suppression with the Use of High Volume Nasal 
                         Mometasone Irrigations in Varying Dosages
Principal Investigator: Bobby Tajudeen, MD
Address: Rush University Medical Center, Department of Otorhinolaryngology – Head
                and Neck Surgery, 1611 W. Harrison Street, Suite 550, Chicago, IL  60612
Protocol Version Date: April 20, 2018
Objective:
To determine incidence of cortisol suppression with the use of high volume nasal 
Mometasone irrigations in varying dosages.
Study Duration: 1 year 
Timeframe of study treatment and participation: 12 – 16 weeks 
Inclusion Criteria:
•
Age 18+
•
Diagnosis of Chronic Rhinosinusitis, with or without nasal polyposis
•
History of prior endosopic sinus surgery
o
Must include at least ethmoidectomy with maxillary antrostomy
Exclusion Criteria:
•
Exposure to systemic corticosteroids within one month of the date of enrollment 
in to the study.
•
Adrenal insufficiency 
•
Liver disease
•
Use of oral estrogens in women 
•
Morbid obesity (BMI > 38)
•
Concurrent pregnancy
•
Use of medications which may alter HPA axis(refer to Drugs that affect HPAA)
•
Ciliary dysmotility, cystic fibrosis, sarcoidosis, systemic vasculitis, IgG or IgA 
deficiency, known pituitary or adrenal disease
Intervention:
1. Pre study  variables to be collected
a. Demographic data including MRN, Name, Age, Sex, BMI 
b. Laboratory data including AM cortisol level and pregnancy testing. 
c. Imaging data 
d. Pertinent medical history related to sinus disease 
ORA: 17121505-IRB02   Date IRB Approved: 8/23/2018

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e. Concomitant medication H/o ( Avoid drug interactions – refer to the drug 
interactions section)
f.
Hx of arenal insufficiency and liver disease 
g. Asthma history
h. Allergy history
i.
ASA intolerance
j.
Smoking history
k. Lund-Mackay radiographic score
l.
Modified Lund-Mackay endoscopic score
i. Only if able to be used preoperative. May be a strictly postoperative 
scoring system.
m. Presence/absence of polyps
2. Enrolled pts will be randomized on first come first serve into one of the three 
Mometasone irrigation groups (15 subjects in each dose study group)  
a. 1mg, 2mg, 4mg BID nasal sinus irrigation dose (see pharmacokinetic 
calculations in rationale)
3. Patients will be followed and treated as standard care. No additional patient visits 
will be required as part of the research protocol.
4. AM cortisol testing will be performed at 12 – 16 weeks after 12 weeks of 
continuous topical irrigation use 
a. Testing will be performed between 6-10 am
i. This is the standard in the literature
ii.  RUMC lab hours 7am-5:30pm M-F
b. If patient requires steroid burst for medical reasons, testing schedule will 
be delayed 1 month from oral steroid use
5.  Subjects with abnormal blood cortisol levels after 12 weeks of continuous topical 
irrigation will have a repeat blood cortisol level tested and if abnormal will be 
follow up with an Endocrinologist.
Drugs which affect the HPAA:
•
Mifepristone
•
Cyproheptadine, ketanserin, ritanserin, metergoline
•
Bromocriptine, cabergoline
•
Reserpine
•
Valproic acid
•
Octreotide, lanreotide, pasireotide
•
Pioglitazone, rosiglitazone
•
Metyrapone, Trilostane, mitotane, aminoglutethimide, ketoconazole, fluconazole, 
etomidate
•
Sertraline, citalopram, Trazodone
•
Clonidine
•
MDMA, cocaine, amphetamine
•
Methadone, buprenorphine, naltrexone
ORA: 17121505-IRB02   Date IRB Approved: 8/23/2018

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•
Olanzapine, quetiapine, imipramine, desimipramine, clomipramine, mirtazapine
•
Medroxyprogresterone, megestrol, Raloxifene
Drug Interactions 
•
Avoid combination with Desmopressin 
•
Monitor therapy while on 
A. CYP3A4 Inhibitors (Strong) Interacting Members Atazanavir; Boceprevir; 
Clarithromycin; Cobicistat; Darunavir; Idelalisib; Indinavir; Itraconazole; 
Ketoconazole (Systemic); Lopinavir; MiFEPRIStone; Nefazodone; Nelfinavir; 
Ombitasvir, Paritaprevir, and Ritonavir; Ombitasvir, Paritaprevir, Ritonavir, 
and Dasabuvir; Posaconazole; Ritonavir; Saquinavir; Telaprevir; 
Telithromycin; Voriconazole 
B. Ceritinib.
C. Ritodrine
Mometasone Study Rationale
The addition of budesonide 0.5 mg/2 ml respules to nasal irrigations has become 
common practice in the treatment of chronic rhinosinusitis1-2.  The dose of budesonide 
0.5 mg/2 ml was chosen as a result of convenience, as budesonide respules are 
commercially available as an inhalation in the treatment of asthma.  Mometasone is an 
alternative to budesonide with improved pharmacokinetics resulting in increased local 
efficacy and lower systemic absorption, however, data is limited in its use as a topical 
irrigation formulation.  
There is relevant literature available discussing the pharmacokinetic profile of 
budesonide and mometasone used intranasally.  Following intranasal administration a 
drug may enter systemic circulation through direct local absorption in the nasal mucosa 
or oral absorption of any swallowed medication3.  The intranasal bioavailability of 
budesonide and mometasone through nasal mucosa have been measured at 34% and 
<0.1% respectively4.  If a drug enters systemic circulation through the nasal mucosa, the 
medication is subject to plasma protein binding.  When a medication is protein bound it 
is not bioactive and thus reduces the potential for systemic adverse effects. 
 Approximately 85-90% of budesonide is bound to plasma proteins after entering 
systemic circulation5.  Alternatively, mometasone is 99% protein bound at clinically 
relevant concentrations6.  Therefore, budesonide is bioactive at 10-15 times the 
concentration of mometasone in the serum due to plasma protein binding.
A portion of the drug may also be cleared from the sinuses into the throat and 
swallowed, making it available for gastrointestinal absorption.  Medications absorbed 
through the gastrointestinal tract are subject to first pass hepatic metabolism which 
largely determines the amount of medication which reaches systemic circulation. 
 Approximately 90% of swallowed budesonide is metabolized by the liver during first 
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pass metabolism7.  On the other hand, when mometasone is swallowed and undergoes 
first pass metabolism, 99% of the drug is eliminated leaving only 1% of the drug to enter 
the circulation7.           
A desired pharmacokinetic property of intranasal steroids is high lipophilicity. 
 Higher lipophilicity leads to increased intranasal absorption as well as prolonged 
retention in the nasal tissue3.  Longer retention of the steroid in nasal tissue results in 
increased exposure to the glucocorticoid receptor8.  The relative lipophilicity of 
budesonide and mometasone are 3,980 and 50,000 respectively6,9.  Thus, mometasone 
has twelve times higher lipophilicity than budesonide.            
In order to determine the proper dose of mometasone, it is important to take into 
account the volume of nasal irrigation that will remain in the sinus cavity. In patients who 
have undergone endoscopic sinus surgery, after performing a nasal irrigation with a 240 
ml saline filled Neilmed bottle, the result is 1.2% to 5% of the solution remaining in the 
sinuses10.  Therefore, the maximum  amount of fluid left in the sinuses after a 240 ml 
nasal irrigation is 5% of the total volume or 12 ml.  Applying this data one may estimate 
the maximum absorption of mometasone added to a 240 ml saline filled Neilmed bottle 
for irrigation.  
•
Mometasone 1 mg capsule dissolved in 240 mg
o
1 mg/ 240 ml = 0.00416 mg/ml or 4.16 mcg/ml

Max volume that can be retained in sinuses is 12 ml

12 ml x 4.16 mcg/ml = 50 mcg

Medication dosed twice daily, therefore total daily dose = 100 mcg
•
Mometasone 2 mg capsule dissolved in 240 mg
o
2 mg/ 240 ml = 0.00833 mg/ml or 8.33 mcg/ml

Max volume that can be retained in sinuses is 12 ml

12 ml x 8.33 mcg/ml = 100 mcg

Medication dosed twice daily, therefore total daily dose = 200 mcg
•
Mometasone 4 mg capsule dissolved in 240 mg
o
4 mg/ 240 ml = 0.0166 mg/ml or 16.6 mcg/ml

Max volume that can be retained in sinuses is 12 ml

12 ml x 16.6 mcg/ml = 200 mcg

Medication dosed twice daily, therefore total daily dose = 400 mcg
Mometasone nasal spray is currently FDA approved at a dose of 2 sprays (100 
mcg) in each nostril twice daily for the treatment of nasal polyps.  Total daily dose is 400 
mcg11.  Therefore even at a dose of mometasone 4 mg used in a 240 ml nasal irrigation, 
the total daily dose is equivalent to that of the mometasone nasal spray.    
There is current relevant data to assess the safety of mometasone administered 
intranasally.  A review of 20 clinical trials with more than 6,000 patients worldwide at 
doses up to 20 times the recommended daily dose found no detectable effect of 
mometasone on the hypothalamic-pituitary-adrenal axis (HPA)12.  Additionally, 
mometasone at high doses, did not cause atrophy to the nasal mucosa12.  Intranasal 
mometasone at a dose of 1600 mcg, which is 4 times the recommended dose 
administered daily to human volunteers for 29 days showed no incidence of adverse 
ORA: 17121505-IRB02   Date IRB Approved: 8/23/2018

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effects11.  The effects of oral mometasone on HPA axis function has also been studied. 
 Oral mometasone was administered at doses of 2, 4, and 8 mg to 24 healthy male 
volunteers with no significant change in plasma or urinary cortisol from placebo13.  
   
References:
1.
Smith, K. A., French, G., Mechor, B., & Rudmik, L. (2016, March). Safety of longterm 
highvolume sinonasal budesonide irrigations for chronic rhinosinusitis. In International forum of 
allergy & rhinology (Vol. 6, No. 3, pp. 228-232).
2.
Soudry, E., Wang, J., Vaezeafshar, R., Katznelson, L., & Hwang, P. H. (2016, June). Safety 
analysis of longterm budesonide nasal irrigations in patients with chronic rhinosinusitis post 
endoscopic sinus surgery. In International forum of allergy & rhinology (Vol. 6, No. 6, pp. 568-
572).
3.
Derendorf, H., & Meltzer, E. O. (2008). Molecular and clinical pharmacology of intranasal 
corticosteroids: clinical and therapeutic implications. Allergy, 63(10), 1292-1300.
4.
Sastre, J., & Mosges, R. (2012). 1 Local and Systemic Safety of Intranasal Corticosteroids. 
Journal of Investigational Allergology and Clinical Immunology, 22(1), 1.
5.
Pulmicort(R) [package insert]. Wilmington, DE: AstraZeneca; 2000.
6. Hochhaus, G. (2008). Pharmacokinetic/pharmacodynamic profile of mometasone furoate nasal 
spray: potential effects on clinical safety and efficacy. Clinical therapeutics, 30(1), 1-13.
7.
Lipworth, B. J., & Jackson, C. M. (2000). Safety of inhaled and intranasal corticosteroids. Drug 
Safety, 23(1), 11-33.
8.
Corren, J. (1999). Intranasal corticosteroids for allergic rhinitis: how do different agents 
compare?. Journal of allergy and clinical immunology, 104(4), s144-s149.
9.
Brattsand, R. What factors determine anti-inflammatory activity and selectivity of inhaled 
steroids? Eur. Respir. Rev. 1997, 7, 356– 361.
10. Harvey, R. J., Debnath, N., Srubiski, A., Bleier, B., & Schlosser, R. J. (2009). Fluid residuals and 
drug exposure in nasal irrigation. Otolaryngology—Head and Neck Surgery, 141(6), 757-761.
11. Nasonex(R) [package insert]. Whitehouse Station, NJ: Merk & CO.,INC; 1997.
12. Davies, R. J., & Nelson, H. S. (1997). Once-daily mometasone furoate nasal spray: efficacy and 
safety of a new intranasal glucocorticoid for allergic rhinitis. Clinical therapeutics, 19(1), 27-38.
13. Brannan, M. D., Seiberling, M., Cutler, D. L., Cuss, F. M., & Affrime, M. B. (1996, January). Lack 
of systemic activity with intranasal mometasone furoate. In JOURNAL OF ALLERGY AND 
CLINICAL IMMUNOLOGY (Vol. 97, No. 1, pp. 62-62). 11830 WESTLINE INDUSTRIAL DR, ST 
LOUIS, MO 63146-3318: MOSBY-YEAR BOOK INC.
Parameter
Budesonide
Mometasone
Systemic bioavailability through nasal mucosa
34%
<0.1%
Drug remaining after first pass metabolism 
10%
1%
Plasma protein binding
85-90%
99%
Relative lipophilicity
3980
50,000
ORA: 17121505-IRB02   Date IRB Approved: 8/23/2018