Evaluation of Time to Onset and Outcome of Cardiac Adverse Events Associated with Nilotinib using Post-Marketing Surveillance.

INTRODUCTION: Cardiac adverse events (CAEs) have become a concern as serious adverse events (AEs) of nilotinib administration. No reports have described the incidence of CAEs associated with nilotinib in Japanese patients. Thus, we conducted this study to evaluate the risk of nilotinib-induced CAEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHODS: We analysed data for the period between April 2004 and March 2022. Data on CAEs were extracted, and relative risk of AEs was estimated using the reporting odds ratio. RESULTS: We analysed 2,021,907 reports and identified 3,545 reports of AEs caused by nilotinib. Of these, 511 reports involved CAEs. Signals were detected for 19 CAEs. Of these, electrocardiogram QT prolonged was the most frequently reported (30.9%). Fatal outcomes were observed in eight AEs: cardiac failure, atrial fibrillation, acute myocardial infarction, pericardial effusion, myocardial infarction, cardiac arrest, pericarditis, and cardiac tamponade. Of these, acute myocardial infarction, myocardial infarction, pericarditis, and cardiac tamponade exhibited mortality rates >10%. A histogram of median times to onset showed nilotinib-associated AEs occurring 3-485 days after nilotinib administration. CONCLUSION: We focused on CAEs caused by nilotinib as post-marketing AEs. Some cases resulted in serious outcomes. Patients should be monitored for signs of onset of these AEs not only at the start of administration but for a long period of time.

Evaluation of Cardiac Adverse Events with Ponatinib Using a Spontaneous Reporting Database.

INTRODUCTION: The efficacy of ponatinib was demonstrated in patients resistant or intolerant to prior BCR-ABL tyrosine kinase inhibitors. However, cardiac adverse events (CAEs) have become a concern as a serious side effect of ponatinib administration. No reports have described the incidence of CAEs associated with ponatinib in Japanese patients. Thus, this study aimed to determine the risk of ponatinib-induced CAEs, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHODS: We analyzed data for the period between April 2004 and March 2021. Data on CAEs were extracted, and relative risk of AEs was estimated using the reporting odds ratio. RESULTS: We analyzed 1,772,494 reports and identified 1,152 reports of AEs caused by ponatinib. Of these, 163 CAEs were reportedly associated with ponatinib. Signals were detected for thirteen CAEs: hypertension, cardiac failure, acute cardiac failure, atrial fibrillation, increased blood pressure, coronary artery stenosis, myocardial infarction, angina pectoris, pulmonary hypertension, prolonged QT on electrocardiography, cardiomyopathy, cardiac dysfunction, and acute myocardial infarction. Among these, hypertension was the most frequently reported AE (27.6%). A histogram of times to onset showed occurrence from 4.5 to 150.5 days. DISCUSSION/CONCLUSION: Hypertension, cardiac failure, coronary artery stenosis, and myocardial infarction could potentially result in serious outcomes and some cases occurred earlier or even more than 1 year after starting administration. Patients should be monitored for signs of the onset of these AEs not only at the start of ponatinib administration but also over the longer term.

Evaluation of Lung Toxicity Related to the Treatment With Alectinib Using a Pharmacovigilance Database.

BACKGROUND/AIM: The anaplastic lymphoma kinase (ALK) inhibitor alectinib is recommended as a first-line treatment for ALK lung cancer. Interstitial lung disease is the most common adverse event leading to discontinuation of alectinib. The purpose of this study was to use the Japanese Adverse Drug Event Report database for the evaluation of incidence trends and timing of alectinib toxicity in the lungs. PATIENTS AND METHODS: Adverse drug reactions (ADRs) by alectinib were extracted between April 2004 and March 2021. Data related to lung toxicity ADRs were analyzed, and the relative risk was estimated using the reporting odds ratio (ROR) and 95% confidence interval (CI). The time of onset of the lung toxicity signs was noted. RESULTS: We obtained 524 reports of ADRs associated with alectinib. Of these, 157 were lung toxicity, including interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema. The RORs for these signs were 10.28 (95%CI=8.38-12.60), 9.19 (5.58-15.13), 7.40 (3.67-14.88), and 7.01 (3.13-15.69), respectively. The median onset times (quartiles, 25-75%) of interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema associated with alectinib treatment were 92 (36-195), 57 (51-129), 228 (62-431), and 83 (22-96) days, respectively. CONCLUSION: Among the lung toxicity signs, interstitial lung disease had the highest ROR, suggesting a strong causal relationship with alectinib treatment. Interstitial lung disease most frequently developed within 60 days after the start of treatment. These results will be useful for monitoring adverse events associated with the use of alectinib.