Using MetaNurse and KNHIS–NSC, this study investigated certain drugs with the potential for causing drug-induced ototoxicity [13–17]. To our knowledge, this is the first study to evaluate the possibility of ototoxicity with the use of cimetidine, hydroxyzine, and sucralfate. We used MetaNurse as a post-marketing pharmacovigilance tool based on EHR and the South Korean nationwide population insurance data. We initially selected several candidate drugs for ototoxicity, and then conducted a retrospective cohort study to evaluate the risk of bilateral hearing loss in patients who were prescribed the candidate drugs. External validation was performed to verify the novel findings using the spontaneous reports FAERS database.
Ototoxicity is a pharmacological adverse reaction affecting the inner ear or auditory nerve, characterized by cochlear or vestibular dysfunction [1, 2]. To date, aminoglycoside antibiotics and platinum-based chemotherapy, mainly cisplatin, are the most important ototoxic drugs that are commonly used in clinical practice [10]. These medications play an important role in modern medicine although they cause harmful effects and lead to significant patient morbidity. Thus, the early detection of ototoxicity through prospective monitoring is very important because it allows the consideration of treatment modifications to minimize or prevent permanent hearing loss and balance impairment [18–20]. However, some pharmacotherapy associated with the development of ototoxicity could remain undetected for a long time because physicians do not recognize the need for drug concentration monitoring for these drugs. Therefore, studies are needed to explore possible ototoxic ADR based on EHR [13, 21–23].
In this study, we detected capsaicin, cimetidine, epinephrine, hydroxyzine, and sucralfate as possible candidate ototoxic drugs using the MetaNurse algorithm, which is based on nurse statements because nurses reportedly play a more important role in discovering and spontaneously reporting ADR than doctors and pharmacists [24–27]. However, on a limitation is that the result of the MetaNurse algorithm extracts the candidate drug list as the result of analysis for one hospital. To overcome this issue, we further verified candidate drugs obtained from the MetaNurse algorithm through a nationwide cohort sample because this dataset could accurately represent the characterization of South Koreans. In the analysis of KNHIS–NSC data, we used the diagnostic codes of bilateral hearing loss (H90.0, H90.3, and H90.6). There is no diagnostic code for ototoxicity and, therefore, we used the diagnostic code for bilateral hearing loss, which is the commonest phenotype of ototoxicity. Interestingly, we observed an increased incidence of bilateral hearing loss in patients who received cimetidine, hydroxyzine, and sucralfate when compared with those in the propensity score-matched comparator group developed based on sociodemographic factors, comorbidities, and enrollment year. After the analysis of KNHIS–NSC data, external validation was performed and showed that the values of PRR and ROR in hydroxyzine and sucralfate were positive indicators of ototoxicity because their 95% CI values were statistically significant; however, there was no significance in the PRR and ROR of cimetidine. Collectively, this means that these novel study findings, which indicate that hydroxyzine and sucralfate have a potential ototoxic effect, may be reliable.
Hydroxyzine is a histamine receptor (H1) antagonist that has been widely used to treat allergic skin reactions, such as pruritus and urticaria, and it is also used as an anti-emetic and anti‐cholinergic medication. Additionally, hydroxyzine can reduce central nervous system activity. Thus, in psychiatric disorders, hydroxyzine has been used widely as a sedative to relieve anxiety and tension in generalized anxiety disorder since the 1980s [28, 29]. The commonest side effect of hydroxyzine is dry mouth because of the anticholinergic effect. Drowsiness and involuntary motor activity could also occur when patients take considerably higher than recommended doses. Drug allergic reactions, headaches, and hallucinations are rarely reported in post-marketing surveillance data, but we could not find any information on hydroxyzine-induced ototoxicity. Sucralfate has been commonly used to treat and prevent duodenal or stress ulcers because it adheres to damaged ulcer tissue and protects against acid and enzyme damage, leading to better healing. Treatment with other medications, such as antibiotics, may be needed to treat and prevent the ulcer recurrence caused by some types of bacteria (e.g., H. pylori) [30]. Sucralfate can sometimes cause some side effects, including constipation, hives, rash, itching, difficulty in breathing or swallowing, and angioedema. Post-marketing surveillance reports revealed hypersensitivity reactions and hyperglycemia as side effects, but there were no reports of sucralfate-related ototoxicity.
This study has several limitations. First, to date, mechanisms of drug-induced ototoxicity with hydroxyzine and sucralfate have not been defined previously. Thus, further mechanistic studies are needed to determine their ototoxic effects. Second, we used bilateral hearing loss as a diagnostic code; however, in some cases, bilateral hearing loss may have developed due to non-ototoxicity-related causes. However, ototoxicity is the commonest cause of bilateral hearing loss, which suggests that this issue may be an acceptable limitation. Third, data on the degree of hearing impairment were not available in the registry (KNHIS–NSC); therefore, we could not ascertain the degree of hearing difficulty effected by the candidate drug and whether that side effect was transient or permanent. Finally, we could not access other health data, including body mass index, lipid profile, and information on behavioral risk factors, such as smoking or alcohol consumption. Therefore, these possible confounding factors could not be controlled in the study analyses.
This study investigated the detection of unknown ototoxic drugs among widely used drugs using MetaNurse and the KNHIS–NSC. We found that patients who were prescribed cimetidine, hydroxyzine, and sucralfate had a significant risk of bilateral hearing loss events. Additionally, the possibility of ototoxicity with hydroxyzine and sucralfate drugs was confirmed by an external validation based on FAERS. This study provides new insight into the potential risk of ototoxic ADR with hydroxyzine and sucralfate. Further studies are needed to elucidate the underlying pathophysiological mechanisms mediating the drug-related ototoxicity identified for these three drugs.