Co-administration of Nefazodone, a CYP3A4 inhibitor, and Fluticasone Proprionate Induces Secondary Adrenal Insufficiency

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 1-16-Adrenal Insufficiency
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-3
Jesslyn Lu*1, Marco Marcelli2 and Madhuri Vasudevan3
1Baylor College of Medicine, Houston, TX, 2Baylor Coll of Med VAMC, Houston, TX, 3Michael E. DeBakey VA Medical Center, Houston, TX
Background: Nefazodone, an antidepressant medication, inhibits the cytochrome P450 3A4 pathway, responsible for metabolism of exogenous corticosteroids.  Coadministration of nefazodone with triamcinolone acetonide, a topical steroid, can cause adrenal insufficiency.  Fluticasone propionate, a high potency inhaled corticosteroid, suppresses the hypothalamic pituitary adrenal (HPA) axis, when used chronically.  The combined effect of intermittent intranasal fluticasone use and nefazodone on HPA axis is unknown. 

Case: 64 yo man with history of depression, allergic rhinitis and ten year history of syncope of unclear etiology, presented for endocrine evaluation of episodic sympathomimetic symptoms, concerning for hypoglycemia. He is a nondiabetic on no oral hypoglycemic agents.  72-hour continuous glucose monitor revealed normoglycemia.  Biochemistry revealed normal plasma metanephrines and thyroid function studies, negative anti-adrenal antibody and random serum cortisol of 6 mg/dL.  Patient failed a 250 microgram cosyntropin stimulation test with baseline cortisol 1.1 mg/dL, ACTH 5.8 ng/mL and peak cortisol of 11.1mg/dL.  Additional pituitary biochemical work-up and magnetic resonance imaging were unremarkable. Medication review revealed 10-year history of nefazodone for depression and intermittent intranasal fluticasone for allergic rhinitis.  Time course of co-administetered therapies coincided with onset of symptoms.  Physiologic steroid replacement therapy with hydrocortisone resolved syncopal and sympathomimetic symptoms. 

Interpretation: Timely clearance of corticosteroid medications, whether systemic, topical or inhaled, requires an intact cytochrome P450 3A4 pathway.  Medications, such as nefazodone which inhibit the P450 3A4 pathway, reduce clearance of exogenous steroids, resulting in supraphysicologic corticosteroid levels and consequent suppression of the HPA axis.  Among inhaled corticosteroids, fluticasone has a high risk for HPA suppression due to longer plasma elimination half life, greater tissue binding, and prolonged receptor binding, which accentuates its greater glucocorticoid potency, particularly when used chronically. 

Conclusion:  This is the first known case describing adrenal insufficiency in a patient co-treated with nefazodone and fluticasone.  Co-treatment with cytochrome P450 3A4 inhibitors, such as nefazodone, and fluticasone can suppress the HPA axis and predispose to secondary adrenal insufficiency.  Intermittent use or withdrawal from fluticasone can unmask endogenous cortisol insufficiency and result in life-threatening adrenal crisis.  Greater patient and physician awareness of the risks associated with combined medication profiles should be instituted, with endocrinologic monitoring of HPA axis, as long as the patient remains on fluticasone and nefazodone.

Nothing to Disclose: JL, MM, MV

*Please take note of The Endocrine Society's News Embargo Policy at