Replacement of a usual medication with a remarkably effective medication might result in a dramatic improvement for a specific disease. However, an abrupt change in medication might bring about other challenges. Herein, we report the case of an 84-year-old man who developed severe hyponatremia after the abrupt discontinuation of prolonged ultra-high topical steroid use. At the time of visiting the emergency department, he had been treating chronic eczema with the medication dupilumab for three months. We initially considered this newly started medication as the cause of the problem. However, dupilumab has not been reported to be connected to any electrolyte or endocrine disorder (e.g., syndrome of inappropriate anti-diuretic hormone secretion), and severe hyponatremia did not improve by the administration of high volume of NaCl. Thus, we reconsidered alternative causes for this hyponatremia and checked the patient’s history of medication. He had been prescribed clobetasol propionate 0.05% by the dermatologist until one month before arriving at the emergency department. In addition, he had completely stopped using topical steroids for the last two weeks because his dermal condition had substantially improved. His cortisol level was low, substantiating a diagnosis of adrenal insufficiency. Hydrocortisone administration improved both hyponatremia and his symptoms. Therefore, when a patient with newly administered medication presents with new symptoms, we recommend that differential diagnosis include a medical review of the patient’s last three months of medication and the conditions of use including how the topical agents were used.