Retrospective analysis of smell and taste disturbances associated with dermatologic medications reported to the United States Food and Drug Administration and relevance to COVID-19 infections.

To the Editor: Smell and taste disturbances are more recently reported symptoms of the novel coronavirus disease 2019 (COVID-19). Many commonly used dermatologic medications can also cause smell/taste changes. With COVID-19 testing shortages in the United States, these medication adverse events warrant careful consideration. In this study, we analyzed the United States Food and Drug Administration Adverse Event Reporting Database (FAERS) for the most common dermatologic medications associated with smell/taste disturbances and their relevance to COVID-19 infections.

The FAERS database was searched for the most common medications causing smell/taste disturbances and then filtered for dermatologic drugs. The data were substantiated using 2 other databases and recorded. The National Institute of Health Clinical Studies Database was queried for clinical trial data, and PubMed was examined for case reports/series on smell/taste disturbances associated with these medications.

Taste disturbances were 6.11-times more common than smell disturbances, with 10,232 and 62,524, respectively, reported to FAERS during the study period (Tables I and II ). Adalimumab was the most common dermatologic medication associated with anosmia in FAERS (84 cases), which was not corroborated in clinical trials or in a PubMed search (Table I).

Table I

Top 10 dermatologic medications in the United States Food and Drug Administration Adverse Event Reporting Database (FAERS) associated with smell disturbances, with the corresponding clinical trial data and the number of cases reports or case series in PuMmed∗

Medication	Cases in FAERS (% of all anosmia/hyposmia/smell disturbance cases)	Rank of all medications associated with anosmia/hyposmia/smell disturbance	Clinical trial data	Case reports/cases series in PubMed, No.
Adalimumab (injection)	84 (0.82)	7 of 956	No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials	0
Etanercept (injection)	75 (0.73)	22 of 956	No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials	1
Terbinafine hydrochloride (oral)	68 (0.66)	24 of 956	No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials	0
Cetirizine hydrochloride (oral)	27 (0.26)	45 of 956	No anosmia/hyposmia reported in phase III clinical trials, anosmia/hyposmia were reported in phase IV trials	0
Vismodegib (oral)	16 (0.14)	96 of 956	No anosmia/hyposmia reported in phase III clinical trials, anosmia/hyposmia were reported in phase IV trials	0
Secukinumab (injection)	14 (0.14)	109 of 956	No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV Trials	0
Prednisolone (oral)	13 (0.13)	113 of 956	No anosmia/hyposmia reported in phase III clinical trials, anosmia/hyposmia were reported in phase IV trials	0
Spironolactone (oral)	12 (0.13)	125 of 956	No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials	0
Isotretinoin (oral)	11 (0.12)	145 of 956	No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials	1
Fluconazole (oral)	9 (0.09)	153 of 956	No anosmia/hyposmia reported in phase III clinical trials, No anosmia/hyposmia reported in phase IV trials	0

There were 10,232 cases of smell disturbances reported to FAERS, from January 1, 1997, to December 31, 2019, using the key words anosmia, hyposmia, and smell disturbance.

Table II

Top 10 dermatologic medications in the United States Food and Drug Administration Adverse Event Reporting Database (FAERS) associated with taste disturbances, with the corresponding clinical trial data and the number of cases reports or case series in PubMed∗

Medication	Cases in FAERS (% of all ageusia/dysgeusia/taste disturbance cases	Rank of all medications associated with ageusia/dysgeusia/taste disturbance	Clinical trial data	Case reports/cases series in PubMed, No.
Vismodegib (oral)	1054 (1.69)	11 of 2591	67% ageusia/dysgeusia reported in phase III clinical trials, ageusia/dysgeusia were reported in phase IV trials	2
Etanercept (injection)	937 (1.50)	14 of 2591	No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials	1
Terbinafine hydrochloride (oral)	920 (1.47)	15 of 2591	2.8% ageusia/dysgeusia reported in phase III clinical trials, ageusia/dysgeusia were reported in phase IV trials	9
Apremilast (oral)	223 (0.36)	71 of 2591	No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials	1
Methotrexate (oral)	176 (0.28)	105 of 2591	No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials	1
Secukinumab (injection)	151 (0.24)	296 of 2591	No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials	0
Spironolactone (oral)	68 (0.11)	376 of 2591	No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials	0
Isotretinoin (oral)	57 (0.09)	430 of 2591	No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials	2
Tacrolimus (23 topical, 20 oral)	43 (0.07)	689 of 2591	No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials	0
Mycophenolate sodium (oral)	42 (0.07)	691 of 2591	No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials	0

There were 62,524 cases of taste disturbances reported to FAERS from January 1, 1969, to December 31, 2019, using the key words ageusia, dysgeusia, and taste disturbance.

Apremilast and methotrexate were associated with 223 and 176 cases of taste disturbances, respectively (Table II). An 83-year-old woman reported bitter taste after 4 weeks of apremilast treatment, which resolved 3 months after discontinuation. A 22-year-old woman presented with reproducible dysgeusia 5 to 6 hours after methotrexate ingestion, with resolution 24 to 36 hours after folic acid administration.

We found that 60% of the listed dermatologic medications caused both smell and taste disturbances (Tables I and II). Vismodegib is well known for causing taste disturbances, reported in 67% of patients in phase III clinical trials, and smell disturbances were reported in a phase IV trial. For terbinafine, taste disturbances were reported in 2.8% of phase III clinical trial patients, and taste/smell changes were described in 17 patients from an Italian adverse event reporting database. There are 2 case reports of smell/taste changes with isotretinoin treatment for acne, in a 23-year-old woman after 4 weeks of therapy and in a 36-year-old woman after 20 weeks of treatment, with resolution 6 months after discontinuation. , Although there are no clinical trial data describing smell/taste disturbances with etanercept, these changes were reported in a 31-year-old woman after several months of etanercept therapy for ankylosing spondylitis.

This study is subject to several limitations. FAERS data are collected from patients, physicians, and pharmaceutical companies, without confirmation of adverse events or dosage information. Although many of these dermatologic medications are associated with smell/taste disturbances, there is no proof of causation.

In conclusion, smell and taste disturbances are reported in approximately one-third of patients with COVID-19 and also with medications frequently used in dermatology. Taste disturbances are about 6 times more common than smell disturbances, and most dermatologic medications listed cause both changes. Therefore, dermatologists should be familiar with these lists and review both current medication lists in patients presenting with anosmia or dysgeusia and counsel patients of the possibility of smell/taste disturbances when initiating new treatments.