Incidence of Suspected Serious Adverse Drug Reactions in Corona Virus Disease-19 Patients Detected by a Pharmacovigilance Program by Laboratory Signals in a Tertiary Hospital in Spain: Cautionary Data

Abstract

BACKGROUND: From March to April 2020, Spain was the center of the SARS-CoV-2 pandemic, particularly Madrid with approximately 30% of the cases in Spain. The aim of this study is to report the suspected serious adverse drug reactions (SADRs) in COVID-19 patients vs. non-COVID-19 patients detected by the prospective pharmacovigilance program based on automatic laboratory signals (ALSs) in the hospital (PPLSH) during that period. We also compared the results with the suspected SADRs detected during the same period for 2019. METHODS: All ALSs that reflected potential SADRs including neutropenia, pancytopenia, thrombocytopenia, anemia, eosinophilia, leukocytes in cerebrospinal fluid, hepatitis, pancreatitis, acute kidney injury, rhabdomyolysis, and hyponatremia were prospectively monitored in hospitalized patients during the study periods. We analyzed the incidence and the distribution of causative drugs for the COVID-19 patients. RESULTS: The incidence rate of SADRs detected in the COVID-19 patients was 760.63 (95% CI 707.89-816.01) per 10,000 patients, 4.75-fold higher than the SADR rate for non-COVID-19 patients (160.15 per 10,000 patients, 95% CI 137.09-186.80), and 5.84-fold higher than the SADR rate detected for the same period in 2019 (130.19 per 10,000 patients, 95% CI 109.53-154.36). The most frequently related drugs were tocilizumab (59.84%), dexketoprofen (13.93%), azithromycin (8.43%), lopinavir-ritonavir (7.35%), dexamethasone (7.62%), and chloroquine/hydroxychloroquine (6.91%). CONCLUSIONS: The incidence rate of SADRs detected by the PPSLH in patients with COVID-19 was 4.75-fold higher than that of the non-COVID-19 patients. Caution is recommended when using medications for COVID-19 patients, especially drugs that are hepatotoxic, myotoxic, and those that induce thromboembolic events.

Keywords: adverse (side) effects; adverse drug reaction; corona virus disease-19 (COVID-19); pharmacovigilance process; serious adverse drug reaction.

FIGURE 1

Methodology of the Pharmacovigilance Program From Laboratory Signals in Hospital. Abbreviations: ALS, automatic laboratory signal; EMR, electronic medical record; SADR, serious adverse reaction.

FIGURE 2

COVID-19 infection stages and treatments employed. Abbreviations: LMWH, low-molecular-weight heparin; Ig, immunoglobulin; IV Ig, intravenous immunoglobulin; IF β-1b, interferon beta-1b; SADRs, serious adverse drug reactions.

FIGURE 3

Sequence chart: Progression of parameters related to liver function in COVID-19 patients during hospitalization according to the treatment undergone. The X-axis indicates the value number (baseline, the last value before drug administration; value 1, first value after administration; values 2–19, values on days 1–20 after the first dose administration; values 20–39, results between days 21 and 60 of hospitalization). The Y-axis indicates the number of times above or below the limit of normality, as appropriate. The red circle indicates the points with statistical significance. ALL, all patients; AZ, azithromycin; BLN, below limit of normal; CEF, ceftriaxone; HQ, hydroxychloroquine; DEX, dexamethasone, L/r, lopinavir/ritonavir; MET, metamizole; PARA, paracetamol; ULN, upper limit of normality.

FIGURE 4

Sequence chart: Progression of parameters related to coagulation status in COVID-19 patients during hospitalization according to the treatment undergone. The X-axis indicates the value number (baseline, the last value before drug administration; value 1, first value after administration; values 2–19, values on days 1–20 after the first dose administration; values 20–39, results between days 21–60 of hospitalization). The Y-axis indicates the number of times above or below the limit of normality, as appropriate. The arrows indicate the change in the trend of normality. The red circles indicate the points with statistical significance. BLN, below limit of normal; DEX, dexamethasone; LMWH, low-molecular-weight heparins; OAC, oral anticoagulants; TOC, tocilizumab; ULN, upper limit of normal.