Expert consensus on off-label administration of drugs in COVID-19

Abstract

The challenges for clinical management of coronavirus disease 2019 (COVID-19) consist of the unfamiliarity of immunomodulator prescription, the difficulty in drug administration in special patient populations (e.g., patients with dysphagia or severe renal insufficiency) and limited medication accessibility. Off-label administration of some medications for COVID-19 has been documented. Here, we highlight several issues pertinent to the clinical application of COVID-19 medications by soliciting multidisciplinary experts. We aggregated the drug specifications from and outside mainland China, the guidelines for clinical management of COVID-19 and the evidence from high-quality research. Recommendations were formed through teleconference with the consensus conference method by taking into account the levels of effectiveness and recommendation, and the strength of evidence of the Thomson Micromedex. We have formulated 10 recommendations for off-label drug administration, including three recommendations for off-label modification of drug dosage form for oral or gastric tube feeding administration (dissolving nirmatrelvir-ritonavir tablets into suspension, solution preparation for monulpiravir capsules, and solution of dispersed baricitinib tablets), five recommendations for off-indication use (intravenous injection of tocilizumab or baricitinib for severe or critically ill patients with COVID-19, subcutaneous injection of tocilizumab for severe or critically ill patients with COVID-19 in case of inaccessible intravenous tocilizumab or baricitinib tablets, substitution with tofacitinib 10 mg twice daily in case of the inaccessibility of tocilizumab and baricitinib; Methylprednisolone or prednisone for severe or critically ill patients with COVID-19 to reduce all-cause mortality), and two recommendations for off-label use among the targeted populations (no titration of tocilizumab doses for COVID-19 patients with severe renal insufficiency, baricitinib 2 mg once every other day or 1 mg daily for severe or critically ill patients with severe renal insufficiency and eGFR 15-30 ml/(min·1.73m2)). This consensus document aims to provide the reference for rational use of medications among clinicians and the pharmacovigilance monitoring.