WHO Regulatory Update: ADR reporting with use of drugs for the treatment of COVID-19 symptoms

No pharmaceutical products have yet been shown to be safe and effective for the treatment of COVID-19. However, a number of medicines have been suggested as potential investigational therapies, many of which are now being or will soon be studied in clinical trials, including the SOLIDARITY trial co-sponsored by WHO and participating countries. 

Uppsala Monitoring Centre (UMC) in its role as the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring receives reports of suspected adverse reactions to medicinal products from National Centres in countries participating in the WHO Programme for International Drug Monitoring. The information is stored in VigiBase, the WHO global database of individual case safety reports (ICSRs). UMC is engaged in sharing relevant aggregated data regarding ADR reporting with use of drugs for the treatment of COVID-19 symptoms. At present these reviews are only descriptive in nature. No signal detection or causality assessment has been carried out with these reports at the current time but is the aim of further analyses.

Report date: 2020-4-12

Summary: 

There was a large increase in the number of reports of suspected adverse drug reactions (ADRs) with the use of drugs used in the treatment of covid-19. Most reports were identified by searching for “coronavirus infection” as indication with the drugs currently being investigated in the Solidarity trial. Reports are from Europe, the Americas and the Western Pacific regions. The reported adverse events are largely in line with those listed in product labels or other available drug information. COVID-19 PV Report 2020-04-12

Report date: 2020-4-19

Summary:

Vigibase continues to receive Individual case safety reports for drugs used in the treatment of Covid-19. Most reports continue to come from the European Region, but geographical spread continues to increase as the first reports from the Western Mediterranean region are noted in this weekly review. The most commonly reported ADRs continue to be those included in available product labelling. Overall, QT prolongation and hepatic events are the most commonly reported serious events. Renal events and skin events, including one case of toxic epidermal necrolysis, have also been reported and are further described in this review.  COVID-19 PV Report 2020-04-19

Report date: 2020-5-4

Summary:

This fourth report is still mainly descriptive in nature and is dominated by the reporting on drugs in the WHO SOLIDARITY trial. Systematic signal detection and causality assessment have not been performed for COVID-19 reports at the current time. Drugs, where reactions have been reported into VigiBase (the WHO global database of Individual Case Safety Reports), are, in most cases, approved (for other indications) while remdesivir, prior to COVID-19, had been investigated but not licensed for use in Ebola disease. Clinical trials are being performed and communicated elsewhere for the drugs. Reports for the drugs are presented below with general characteristics and statistics accessible in separate tables for an easy overview. Reports have now been shared from five of the six WHO regions, with the largest number still originating from the WHO European Region. The most commonly reported adverse drug reactions (ADRs) continue to be those included in available product labelling or information; QT prolongation and hepatic events are the most commonly reported events.  COVID-19 PV Report 2020-05-04

Report date: 2020-5-19

Summary:

This fifth summary of global reporting of ADRs for drugs used to treat COVID-19 is mainly descriptive in nature. It includes reviews for the drugs in the WHO SOLIDARITY trial and other drugs used for a COVID-19 indication, and where the number of reports exceeds 100. Reports have now been shared from five of the six WHO regions, with the largest number still originating in the WHO European Region. The reported ADRs largely continue to be those included in available product labelling or information; QT prolongation and hepatic events are the most commonly reported events. Of note are the concomitant use of multiple interacting medications and the occurrence of individual cases of serious events such as DRESS, completed suicide and sudden death which will remain under surveillance in future reviews.  COVID-19 PV Report 2020-05-19

Report date: 2020-6-2

Summary:

This sixth report of global reporting of ADRs for drugs used to treat COVID-19 is mainly descriptive in nature. It includes reviews for the drugs in the WHO Solidarity trial and other drugs used in the context of COVID-19 where the number of reports exceeds 100. Reports have been received from five of the six WHO regions, with the largest number still originating from the WHO European Region. The reported ADRs largely continue to be those included in available product labelling or information; QT prolongation and hepatic events are the most commonly reported events. Of note is the concomitant use of multiple interacting medications (Table 4); an example from this review period is the series of reports detailing an interaction between lopinavir;ritonavir and direct oral anticoagulants (DOAC). Given the increasing attention to the endothelial pathology of the COVID-19 virus 1 and the treatment of COVID-19 patients with anticoagulant therapy, further investigation/clinical guidance on the concomitant use of lopinavir;ritonavir and DOAC may be required. The serious events identified in previous reviews, including DRESS (Drug Rash with Eosinophilia and Systemic Symptom), completed suicide and sudden death remain under surveillance.  COVID-19 PV Report 2020-06-02

Report date: 2020-6-17

Summary:

This seventh report of global reporting of ADRs for drugs used to treat COVID-19 is mainly descriptive in nature. It includes reviews for the drugs in the WHO Solidarity trial and other drugs used for a COVID-19 indication where the number of reports exceeds 100. Reports have so far been shared from five of the six WHO regions, with the largest number still originating in the WHO European Region. Additional cases of rhabdomyolysis secondary to the known, labelled interaction between lopinavir;ritonavir and atorvastatin have been received. Reactions of interest for remdesivir are renal and skin events which are not currently included on available product information from the US FDA or the EMA.  COVID-19 PV Report 2020-06-17

Report date: 2020-7-1

Summary:

This eighth report of global reporting of ADRs for drugs used to treat COVID-19 is mainly descriptive in nature. It includes reviews for the drugs in the WHO Solidarity trial to find an effective COVID-19 treatment and other drugs used for a COVID-19 indication where the number of reports in VigiBase exceeds 100. Reports have so far been shared from five of the six WHO regions, with the largest number still originating in the WHO European Region. On 17 June 2020, WHO announced that inclusion of new patients into the hydroxychloroquine (HCQ) arm of the Solidarity Trial was being stopped. The decision applies only to the conduct of the Solidarity trial and not to the use or evaluation of hydroxychloroquine in pre- or post-exposure prophylaxis in patients exposed to COVID-19. NEWS in this report are A) summaries of reports for sarilumab and enoxaparin which have been reported more than 100 times in to the VigiBase and B) visualising figures on the adverse drug reaction spectrum of each drug sorted per SOC and PT with information on whether the terms are disproportionally reported or not. These visualisations are presented for each of the drugs reviewed as in Figure 4. COVID-19 PV Report 2020-07-01

Report date: 2020-7-22

Summary:

This ninth report of global reporting of ADRs for drugs used to treat COVID-19 is mainly descriptive in nature. It includes reviews for the drugs in the WHO Solidarity trial to find an effective COVID-19 treatment and other drugs used for a COVID-19 indication where the number of reports in VigiBase exceeds 100. The reviews from this reporting period have largely found ADR consistent with those previously described in earlier reports. Reports have so far been shared from five of the six WHO regions, with the largest number still originating in the WHO European Region. July 6th 2020, WHO announced the discontinuation of the hydroxychloroquine (HCQ) and lopinavir;ritonavir arms of the Solidarity trial as per the recommendation from the international steering committee. The decision applies only to the conduct of the Solidarity trial in hospitalized patients and does not affect the possible evaluation in other studies of hydroxychloroquine or lopinavir;ritonavir in non-hospitalized patients or as pre- or post-exposure prophylaxis for COVID-19. COVID-19 PV Report 2020-07-22

Report date: 2020-8-12

Summary:

This tenth report of global reporting of ADRs for drugs used to treat COVID-19 is mainly descriptive in nature. It includes reviews for the drugs that were initially included in WHO Solidarity trial to find an effective COVID-19 treatment and other drugs used for a COVID-19 indication where the number of reports in VigiBase exceeds 100. The reviews from this reporting period have found ADRs that are largely consistent with those previously described in earlier reports. Reports have so far been shared from all WHO regions, with the largest number still originating in the WHO European Region with around half of the shared reports (table 2). On 6 July 2020, WHO announced the discontinuation of the hydroxychloroquine (HCQ) and lopinavir;ritonavir arms of the Solidarity trial as per the recommendation from the international steering committee. The decision applies only to the conduct of the Solidarity trial in hospitalized patients and does not affect the possible evaluation in other studies of hydroxychloroquine or lopinavir;ritonavir in non-hospitalized patients or as pre- or post-exposure prophylaxis for COVID-19. COVID-19 PV Report 2020-08-12

Report date: 2020-8-26

Summary:

This eleventh review of global reporting of ADRs for drugs used to treat COVID-19 is as before mainly descriptive in nature. It includes reviews for the drugs that were initially included in WHO Solidarity trial to find an effective COVID-19 treatment and other drugs used for a COVID-19 indication where the number of reports in VigiBase exceeds 100. Regarding remdesivir, a major increase in reports was seen in this review. Notable numbers of reports for several non-labelled ADR terms have been shared within the system, described in the remdesivir section of the document. Concerning the other drugs reviewed, ADR-patterns are consistent with those described in earlier reports and mostly within the labelling for the respective drugs. Reports have been shared from all WHO regions, with the largest number now originating in the WHO region of the Americas with 45% of the shared reports (Table 2). WHO has announced the discontinuation of the hydroxychloroquine (HCQ) and lopinavir;ritonavir arms of the Solidarity trial as per the recommendation from the international steering committee. The decision applies only to the conduct of the Solidarity trial in hospitalized patients and does not affect the possible evaluation in other studies of hydroxychloroquine or lopinavir;ritonavir in nonhospitalized patients or as pre- or post-exposure prophylaxis for COVID-19. COVID-19 PV Report 2020-08-26

Report date: 2020-9-23

Summary:

This twelfth review of global reporting of ADRs for drugs used to treat COVID-19 is presented now more than half a year into the pandemic. For a few drugs, clinical trial results point to some efficacy in the disease. Among these, remdesivir is so far the only antiviral drug while glucocorticoids and the heparin class drugs have positive effects on complications of the disease. Other drugs widely used during the first part of the pandemic have by now been reported as ineffective in the patient groups studied, while numerous other suggested treatments still lack reliable information on their respective efficacy in COVID-19. The review has been adapted to the current state of knowledge and focus is hence given to remdesivir, the glucocorticoids and the heparin class of drugs for automated and manual reviews following the pattern of previous reviews. In addition, the COVID-19 related reporting into VigiBase for another two substances, favipiravir and ivermectin, has now passed the threshold of 100. A full overview of the reporting for these drugs has also been included.  COVID-19 PV Report 2020-09-23