Descriptive analysis of COVID-19-related spontaneous reports … · Diffuse alopecia occurred in a patient treated for COVID-19 without a history of autoimmune disorders and may be

Last updated: August 11, 2020

Descriptive analysis of COVID-19-related spontaneous reports from VigiBase: interim results Report from the WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre

Report date: 2020-08-12 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 committee1. 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.


Reports in VigiBase The methodology of search is, with one exception, the same in this tenth review, as in the ninth. Reports were screened for drugs given on a corona or COVID-19 indication, by relevant free-text terms and laboratory tests. Reports were considered for inclusion if they were received at the National Centres between 1 November 2019 and 2 August 2020 and were reported to VigiBase no later than 2 August 2020.* Reports were considered for inclusion when they reported as suspected/interacting drugs initially included in the Solidarity trial or drugs considered clinically relevant based on medical-expertise and reported to VigiBase on a Corona or COVID-19 indication, see Table 3. There is country-specific reporting delay after receipt of reports at National Centres and thus the reporting date to VigiBase should not be considered as proxy for reporting date to National Centres or the date of adverse events. See Figure 1 for a visualisation of the arrival dates at National Centres for this reviewing period. Assessment of causality in individual cases is for all COVID-19 drugs difficult due to the background disease, the limited data on the drugs as used in this disease and the relatively large proportion of multiple concomitant other COVID-19 treatments and has therefore in most cases not been performed.

Figure 1. Number of reports by dates received at national center (left), and cumulative number of reports in VigiBase at the dates of extractions for reports. The rightmost bar (right panel) shows the total number of reports received so far.

∗ If the arrival date at the National Center was not reported, the date of latest update at the National Center was used instead. Reports referred to as "new" during the current time interval may be reports with an initial entry into Vigibase during the time interval or an update of a report which had been previously received into the database prior to the current reporting period.


Overview of patient characteristics Since the last analysis, 598 new case reports have been identified using the selected search strategy (Table 1). Cumulatively, there have been a total of 4739 reports from six WHO regions with the large majority from the European region (50.1 %). 51.5 % of the reports were classified as “serious” (Table 2) but not all reporting standards include seriousness (e.g. INTDIS). Males accounted for 56.6 % of the reports and females for 38.5 %. Most of the reports describe at least one drug or substance originally included in the WHO Solidarity trial, i.e. hydroxychloroquine (in some regions replaced by chloroquine), azithromycin, remdesivir and lopinavir;ritonavir reported as either suspected or interacting. The search also identified additional reports describing other drugs used in the treatment of COVID-19 disease. Among these, tocilizumab, oseltamivir, enoxaparin and sarilumab were reported more than 100 times into the database and were included in the more detailed descriptive analysis. Overall reporting demographics are shown in Figure 2. In line with males being more affected by COVID-19 infection globally, all drugs except chloroquine and oseltamivir are distinctly more reported for men than women. Patient ages are similar between drugs, with oseltamivir appearing to have the lowest median age. A)

B)

Figure 2. Overall demographics of case safety reports sent into VigiBase in treatment of COVID-19. A) All reports. B) Reports by drug. The B) graphs rely on counts of reports which include each drug as suspected or interacting. Reports including several drugs will be counted once for each reported drug. Patient age boxes show medians and interquartile ranges.


Characteristics of the reports on WHO Solidarity trial drugs, and drugs reported more than 100 times into VigiBase Hydroxychloroquine alone or in combination with azithromycin There were 214 new reports for hydroxychloroquine during this time period, adding to a cumulative total of 2192 reports. The new reports included 117 men, 92 women and five with unknown sex. The new reports originated from Eastern Mediterranean Region (41), European Region (117), Region of the Americas (36) and Western Pacific Region (20). In the new reports the median age was 61 years (eight reports had age unreported). For the new reports, hydroxychloroquine was a single suspected drug in 95 cases. An overview of the cumulative reporting demography is shown in Figure 3.

Figure 3. Demography of VigiBase reports received cumulatively so far on hydroxychloroquine as suspected or interacting drug.

Adverse events The reports included 110 serious reactions. Of these, most concerned the MedDRA PT Electrocardiogram QT prolonged, followed by Off label use, COVID-19 treatment (indicating an indication ‘spill-over’) and Product use in unapproved indication or Intentional product use issue. Gastrointestinal symptoms, such as diarrhoea, nausea and vomiting continue to be among the most reported terms. Hepatic adverse events continue to be reported, particularly cholestasis, hepatocellular injury, hepatotoxicity, along with investigations that relate to increases of liver enzymes (gamma-glutamyl transferase, transaminases). During this iteration additional severe cutaneous adverse drug reactions (SCARs) were reported including acute generalised exanthematous pustulosis (four reports) and Stevens-Johnson’s syndrome, which was reported for the first time since the beginning of the routine monitoring. There were also three reports of erythema multiforme and serious reports of rashes (either unspecified or e.g. maculo-papular) were further present in the dataset. At least three of these were published2–4 and the authors seem suspect hydroxychloroquine to have been the primary cause of the reaction, although lopinavir;ritonavir was co-suspected in one. The report of Stevens-Johnson syndrome involved a patient treated for HIV infection with abacavir;dolutegravir;lamivudine, initiated two days after hydroxychloroquine and four after cobicistat ;darunavir;emtricitabine;tenofovir for COVID-19. While the time to onset of nine days since the start of hydroxychloroquine may suggest its role in the development of Stevens-Johnson syndrome, underlying disorders and co-suspected medicinal products cannot be ruled out.


There were at least eight new reports of drug-drug interactions, all of which were serious. Of these, two were duplicates, yielding six cases in total. Four were published case reports or studies5–7 One describes two patients who experienced QT interval prolongation after an interaction between hydroxychloroquine and azithromycin. A second does not appear to describe a drug-drug interaction in the full text of the publication and another illustrates the withdrawal of calcineurin inhibitors to prevent an interaction with ritonavir. The last published case report describes a possible interaction between the addition of a regimen of hydroxychloroquine, azithromycin and lopinavir;ritonavir to a pre-existing treatment with venlafaxine, vortioxetine and trazodone, leading to QT prolongation. The event subsumed upon discontinuation of venlafaxine and did not re-occur upon introduction of a lower dose of the anti-depressive regimen. Among the unpublished reports two indicated a suspected interaction between azithromycin and hydroxychloroquine which led to QT prolongation, as per the reporters’ clinical judgments expressed in the narratives. One new fatal report of the MedDRA PTs acute kidney injury has been added to VigiBase, containing hydroxychloroquine and azithromycin. The patient recovered from the adverse reaction and the cause of death was due to underlying disorders. Of the MedDRA PTs that were never entered in VigiBase, four were of note: acute myocardial infarction, diffuse alopecia, shock hypoglycaemic and counterfeit product administered. The first may be a result of the cardiac toxicity of hydroxychloroquine, which was the only suspected medicinal product in the report. Diffuse alopecia occurred in a patient treated for COVID-19 without a history of autoimmune disorders and may be considered as a known adverse effect of hydroxychloroquine. However, the European SmPC only includes ‘alopecia’ which resolves upon discontinuation, while the present report’s outcome was ‘Not recovered’ at the time of reporting.8 As for shock hypoglycaemic, this reaction occurred with a co-administration of zinc for the treatment of COVID-19 at double the dose following an administration error in hospital settings which led to renal and hepatic toxicity. Finally, as pertains the administration of a counterfeit product: this was a non-serious report from the Region of the Americas, which led to diarrhoea. It seems unclear how the product was determined to be counterfeit, based on the narrative of the report.

Figure 4. Cumulative report counts for hydroxychloroquine in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.


Chloroquine During this reviewing period 43 new reports in which chloroquine was reported as suspecting or interacting drugs were reviewed. These concerned 25 male and 18 female patients; median age of patients described in the new reports was 59 years (two reports had age unreported). The new reports originated from Eastern Mediterranean Region (five), European Region (two), Region of the Americas (seven) and Western Pacific Region (29). An overview of the cumulative reporting demography is shown in Figure 5.

Figure 5. Demographics of VigiBase reports received cumulatively so far for chloroquine as suspected or interacting drug.

Adverse events The profile of chloroquine continues to be in line with the previous iterations and included in the labelling9, with cardiac (Electrocardiogram QT prolonged), gastrointestinal (Diarrhoea, vomiting, abdominal pain upper), psychiatric (Insomnia, Hallucination) and eye disorders (Vision blurred) composing the majority of the reports in VigiBase.

Reports including MedDRA PTs never reported to VigiBase include: Cardiac disorder, ventricular asystole, drug interaction, intentional product use issue, interleukin level increased and renal injury (each reported once). Both drug interaction and interleukin level increased were reported with medicinal products included in this report (tocilizumab, remdesivir respectively).

Figure 6. Cumulative report counts for chloroquine in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.


Azithromycin Azithromycin is to a high extent reported from the Eastern Mediterranean region. The 124 new reports including azithromycin are largely reviewed in the sections of hydroxychloroquine or lopinavir;ritonavir as it is mostly reported in combination with these drugs. Statistics regarding co-medications used with azithromycin are presented in Table 4. Azithromycin reported as the single drug for COVID-19: ADRs reported are dominated by gastrointestinal reactions, most commonly diarrhoea, nausea, abdominal pain and including one (the first in this context) case of pseudomembranous colitis which resolved on withdrawal. Among the other most reported reactions this period were QT-prolongation and different hepatic function disorders. All these reactions are labelled for the drug.10 The symptoms where noted, resolved on withdrawal of the drug. An overview of the cumulative reporting demography is shown in Figure 7.

Figure 7. Demography of VigiBase reports received cumulatively so far on azithromycin as suspected or interacting drug.

Figure 8. Cumulative report counts for azithromycin in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.


Lopinavir;ritonavir During this reviewing period 147 new reports in which lopinavir;ritonavir were reported as suspecting or interacting drugs were reviewed. These concerned 91 male and 51 female patients; median age of patients described in the new reports was 53 years (two reports had age unreported). The new reports originated from Eastern Mediterranean Region (six), European Region (51), Region of the Americas (68) and Western Pacific Region (22). An overview of the cumulative reporting demography is shown in Figure 9.

Figure 9. Demographics of VigiBase reports received cumulatively so far for lopinavir;ritonavir as suspected or interacting drug.

Adverse events The most commonly reported ADRs continued to be those which are included on the product labelling for lopinavir;ritonavir.11

The most commonly reported ADRs during the review period were diarrhoea (49 reports, 214 cumulative), hypertriglyceridemia (28 reports, 51 cumulative), hepatic enzymes increased (21 reports, 30 cumulative), electrocardiogram QT prolonged (20 reports, 62 cumulative), and transaminases increased (10 reports, 24 cumulative). The most commonly reported ADRs cumulatively are: diarrhoea (176 reports), nausea (66 reports), electrocardiogram QT prolonged (62 reports), hepatocellular injury (54 reports), and hypertriglyceridemia (51 reports). Off-label use has been reported as an ADR in 17 reports during the review period and in 163 reports cumulatively. Notable terms from this review are hypertriglyceridemia and hypercholesterolemia. Hypertriglyceridemia had a total of 28 new reports (51 cumulative) and hypercholesterolemia had four new reports (four cumulative). A review of the reports of hypertriglyceridemia reveals an age range of 33-87 years, 39 male reports / 12 females, cases originated from four countries from two WHO geographical regions. The majority of the reports were non-serious (32 reports, 63%) and three reports were fatal (all others were “unknown”). One of the three fatal reports co-reported the PT pancreatitis acute. Most commonly co-reported ADR were hepatic enzyme increased (11 reports), diarrhoea (five reports), electrocardiogram QT prolonged (five reports), hyperbilirubinemia (four reports) and hypercholesterolemia (three reports). Most commonly co-reported medications were ceftaroline (19 reports), ribavirin (16 reports), azithromycin (14 reports), baricitinib (13 reports), and hydroxychloroquine (12 reports). Time to onset of hypertriglyceridemia varied between two and seven days in the majority of the reports. Hypertriglyceridemia and pancreatitis are included in the


labelling of Kaletra. Of note, it is also included in the label for baricitinib which was concomitantly administered in 25% of the cases. There were six new reports of drug interaction with the interacting drugs in the immunosuppressant class, tacrolimus/everolimus or antidepressant/antipsychotics, duloxetine/venlafaxine/haloperidol/lithium. One of these reports concomitantly reported “serotonin syndrome” which was reviewed in the previous report.

Figure 10. Cumulative report counts for lopinavir;ritonavir in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.

Remdesivir The antiviral remdesivir has just recently been authorized for emergency use in several countries during the time of the pandemic. Publicly available information on its side effects and precautions for its use is therefore still limited and includes hypersensitivity including infusion-related and anaphylactic reactions, transaminase elevations, nausea, headache, renal impairment and interactions including risk of decreased antiviral activity when co-administered with hydroxychloroquine and chloroquine.12 There is a total of 473 reports of remdesivir in VigiBase, where 62% originate from the Americas, see Table 2. During this reviewing period, 47 new remdesivir reports were shared, of which in 34 the drug was reported as single suspected. These concerned 32 female, 13 male patients and two patients of unknown sex. The new reports originated from European Region (37), Region of the Americas (three) and Western Pacific Region (seven). An overview of the cumulative number of reports up until the previous period is available in the previous report. An overview of the cumulative reporting demography is shown in Figure 11 where middle aged and men are the most commonly reported groups. A cumulative overview of other COVID-19 drugs co-administrated with remdesivir is available in Table 4 where, heparin-like substances, corticosteroids, hydroxychloroquine are reported as the most commonly co-administered drugs.


Figure 11. Demographics of VigiBase reports received cumulatively so far for remdesivir as suspected or interacting drug.

Adverse events The new reports for remdesivir in this review comprise 10 % of the cumulative total of reports. In previous UMC COVID-19 reviews reporting of kidney and liver function disturbances and skin reactions were common for remdesivir and in the current review the pattern continues to be dominated by kidney and liver reactions. Among new reports this period and not part of the above areas and not being recognised as ADRs for remdesivir in the product information we find: two reports of pancreatic enzymes increased and another on oedematous pancreatitis adding to two previous reports of pancreatitis and one of amylase increased. Most notable among all pancreas-related reports are four reports in males between the ages of 38 and 70. Three of them concern the pancreatitis terms the fourth one amylase increased. Remdesivir is here reported as the only suspect drug in three with few concomitant drugs. In the fourth furosemide is reported as a co-suspect drug among a polypharmacy list. Time to onset is between two and seven days in all the four cases. One of the cases (reporting amylase increased) contains a narrative. This patient had no history of positive risk factors for development of pancreatitis except a prior use of simvastatin. The patient was intubated when the increase in amylase occurred, precluding potential symptom evaluation. None of the terms are at this stage disproportionately overreported; neither with the COVID-19 cases or compared to VigiBase as a whole.

As described above and in previous reviews there are some reported ADRs or clusters of ADRs which are not present in the current labelling for remdesivir.12 The general pattern of reported ADRs however lies mostly within what is labelled for this drug recently approved under special circumstances and procedures.

Figure 12. Cumulative report counts for remdesivir in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.


Tocilizumab

Tocilizumab is a monoclonal antibody against the interleukin-6 receptor used in COVID-19 to alleviate the inflammatory cytokine storm, seen in severe cases as part of a response to the viral infection. Among approved indications is cytokine release syndrome (CRS). 13, 14 During this reviewing period there were 61 new reports in which tocilizumab was reported as suspected or interacting adding up to a total cumulative number of 452 reports where 64 % are shared from the European Region. The new reports concerned 37 males, 10 females and 14 where sex was not reported; median age of the patients was 65 (with eight reports lacking information on age). The new reports were shared from the African Region (four), Eastern Mediterranean Region (five), European Region (42), Region of the Americas (five) and Western Pacific Region (five). A cumulative overview of other COVID-19 drugs co-administrated with tocilizumab is available in Table 4 where hydroxychloroquine, heparin-like drugs and azithromycin are most commonly co-reported with tocilizumab. An overview of the cumulative reporting demography is shown in Figure 13 where the drugs is reported in males more than twice as often as in females.

Figure 13. Demographics of VigiBase reports received cumulatively so far for tocilizumab as suspected or interacting drug.

Adverse events

Reports new in this review comprise 13 % of the cumulative number of reports for tocilizumab. The widespread ADR reporting pattern remains the same as in previous reviews. Hepatic reactions and related investigational terms are still present where hepatitis is acknowledged in the labelling as a rare side effect for tocilizumab. Within the cardiac SOC in this review one more report of cardiac arrest and another of tachycardia are reported. The tocilizumab labelling does not include any cardiac reactions.

Gastrointestinal ADRs including perforations and gastrointestinal haemorrhages continue to be reported to a disproportionate level compared to other COVID-19 drugs and compared to the database in general. In this review two more cases are included, one of which was fatal and where the cause of death given was faecal peritonitis. This case concerned a female in her 50s with pre-existing conditions reported being obesity, hypertension, hyperlipidaemia and epilepsy. Tocilizumab was the only suspect drug with concomitant drugs methylprednisolone, hydroxychloroquine lopinavir;ritonavir. Detailed dates were missing and therefore time to onset is not available. Mouth ulceration, Gastritis, Stomatitis and Gastric ulcer are included in the tocilizumab label but not


colitis, perforations and haemorrhages per se other than as a complication of diverticulitis; there is a warning regarding treating patients at risk of perforation.

The risk of infections is labelled for tocilizumab and a large proportion of reports contain infection-related terms (other than COVID-19 per se), some describing new infectious agents. Another case of a dural abscess is now reported, adding up to a total of two such cases. The pattern of reported ADRs for lies largely within what is labelled for the drug except still for the cardiac events and regarding their seriousness, the gastrointestinal events. 13, 14

Figure 14. Cumulative report counts for tocilizumab in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.

Oseltamivir During this reviewing period there were 11 new reports in which oseltamivir was reported as suspected or interacting adding up to a total cumulative number of 168 reports. The new reports concerned 10 males and one female; median age of the patients was 50 (with one report lacking information on age). The new reports were shared from the Eastern Mediterranean Region (seven) and European Region (four). An overview of the cumulative reporting demography is shown in Figure 15.

Figure 15. Demographics of VigiBase reports received cumulatively so far for oseltamivir as suspected or interacting drug.

Adverse events

The most commonly reported ADRs during the review period were nausea (five reports, 35 cumulative), vomiting (three reports, 24 cumulative), abdominal discomfort (two reports, two cumulative), abdominal pain upper (two reports, nine cumulative), and abdominal pain (two reports, 23 cumulative).


The most commonly reported ADRs cumulatively are: nausea (35 reports), diarrhoea (27 reports), vomiting (24 reports), abdominal pain (23 reports), and pruritus (12 reports) and rash. (12 reports). The most commonly reported ADRs are those which are in line with the product labelling for oseltamivir.15

Figure 16. Cumulative report counts for oseltamivir in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.

Enoxaparin During this reviewing period there were 20 new reports in which enoxaparin was reported as suspected or interacting adding up to a total cumulative number of 132 reports. The new reports concerned 13 males and seven females; median age of the patients was 67. The new reports were shared from the Eastern Mediterranean Region (two), European Region (13), Region of the Americas (four) and Western Pacific Region (one). An overview of the cumulative reporting demography is shown in Figure 17. Enoxaparin was in a majority of cases co-reported with at least two other drugs and hence there is an overlap between enoxaparin and other drugs that have already been covered in the report, e.g. remdesivir, lopinavir;ritonavir, azithromycin and hydroxychloroquine. Apart from this the ADRs reported correspond largely to what is known for enoxaparin.16

Figure 17. Demographics of VigiBase reports received cumulatively so far for enoxaparin as suspected or interacting drug.


Adverse events The 20 new reports showed a similar pattern to previous periods and mainly contains what would be expected for this drug in relation to its mode of action and labelling. Previously unreported preferred terms were drug interaction, acute generalised exanthematous pustulosis(AGEP), ear haemorrhage, haematochezia, intestinal haemorrhage, face oedema, localised oedema, potentiating drug interaction, rash pustular, toxicity to various agents, cell death, electrolyte imbalance, cerebral haematoma, dermatitis bullous, rash, skin exfoliation, thrombosis. Examination of individual reports with previously unreported preferred terms revealed the following: 1) acute generalised exanthematous pustulosis was reported in two patients. In both cases however several other drugs were reported as co-suspect. 2) Drug interaction and potentiation of drug interaction was reported in three patients. In all cases haemorrhagic terms were co-reported and the interaction in all cases relate to pharmacodynamic interactions through other anticoagulants such as warfarin, heparin and acetylsalicylic acid.

Figure 18. Cumulative report counts for enoxaparin in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.

Sarilumab During this reviewing period there were 16 new reports in which sarilumab was reported as suspected or interacting adding up to a total cumulative number of 135 reports. The new reports concerned 14 males, two females and zero where sex was not reported; median age of the patients was 55 (with zero reports lacking information on age). The new reports were shared from the European Region (16). An overview of the cumulative reporting demography is shown in Figure 19.

Figure 19 Demographics of VigiBase reports received cumulatively so far for sarilumab as suspected or interacting drug.


Adverse events

The most commonly reported ADRs during the review period were pneumonia (six reports, nine cumulative), hepatocellular injury (four reports, 13 cumulative), abscess (three reports, three cumulative), septic shock (three reports, eight cumulative), and staphylococcal infection (three reports, eight cumulative). The most commonly reported ADRs cumulatively are: ALT increased (30 reports), AST increased (28 reports), transaminases increased (14 cumulative), hepatocellular injury (13 reports), and pneumonia bacterial (13 reports). The most commonly reported ADRs are those which are in line with the product labelling for sarilumab.17 In previous reviews were mentioned two ADRs that are not included in the sarilumab labelling: acute kidney injury and deep vein thrombosis / pulmonary embolism- There was only one report for acute kidney injury (11 cumulative) and no new reports of deep vein thrombosis / pulmonary embolism (seven cumulative) in the current reporting period.

Figure 20. Cumulative report counts for sarilumab in one bar for each preferred term, sorted by SOC (which is abbreviated as in Table 5). Red bars reflect preferred terms significantly more reported with this drug than in the total set of COVID-19 reports covered in this report. The widths of the bars carry no meaning.

Drugs for use in COVID-19 reported less than 100 times into VigiBase Besides reports for WHO Solidarity trial drugs, some of which have since been discontinued (see above), many ADR reports describe the use of other drugs for the treatment of COVID-19. As ADR data accumulate for such substances, treatment and patterns of reported adverse events for them are being reviewed once the number of reports for a drug exceeds 100. The rest of the drugs identified as being used are presented as “other” (Table 3). For the non-solidarity drug reports (marked as “other” in the table) individual case validation has not been performed.

Disclaimer Data in the reports are not complete and only a subset of the reports in the analysis unfortunately contained narratives precluding quality causality assessment. With limited data available at this stage of the pandemic and the uncertainty over other confounders (such as the underlying disease), this report is no more than a preliminary overview of cases and reported ADRs. No automated deduplication method was used. Any signals detected from this monitoring will be communicated separately.


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[cited 2020 Jul 1]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments

2. Test ER, Vezzoli P, Carugno A, Raponi F, Gianatti A, Rongioletti F, et al. Acute generalized exanthematous pustulosis with erythema multiforme-like lesions induced by Hydroxychloroquine in a woman with coronavirus disease 2019 (COVID-19). J Eur Acad Dermatol Venereol [Internet]. [cited 2020 Aug 11];. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/jdv.16613

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4. Delaleu J, Deniau B, Battistella M, Masson A de, Bensaid B, Jachiet M, et al. Acute generalized exanthematous pustulosis induced by hydroxychloroquine prescribed for COVID-19. J Allergy Clin Immunol Pract [Internet]. 2020 Jun 7 [cited 2020 Aug 11];0(0). Available from: https://www.jaci-inpractice.org/article/S2213-2198(20)30587-0/abstract

5. Zanoni L, Mosconi C, Cervati V, Diegoli M, Monteduro F, Golfieri R, et al. [18F]-FDG PET/CT for suspected lymphoma relapse in a patient with concomitant pneumococcal pneumonia during COVID-19 outbreak: unexpected SARS-Cov-2 co-infection despite double RT-PCR negativity. Eur J Nucl Med Mol Imaging. 2020 May 19;1–2.

6. Bun S-S, Taghji P, Courjon J, Squara F, Scarlatti D, Theodore G, et al. QT Interval Prolongation Under Hydroxychloroquine/Azithromycin Association for Inpatients With SARS-CoV-2 Lower Respiratory Tract Infection. Clin Pharmacol Ther [Internet]. [cited 2020 Aug 11];n/a(n/a). Available from: https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1968

7. Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A, et al. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2020 Jul;20(7):1875–8.

8. Electronic Medicines Compendium. Hydroxychloroquine - Summary of Product Characteristics (SmPC) - (emc) [Internet]. [cited 2020 Aug 11]. Available from: https://www.medicines.org.uk/emc/product/11516/smpc

9. Electronic Medicines Compendium. Kaletra 200 mg/50 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc) [Internet]. [cited 2020 Aug 11]. Available from: https://www.medicines.org.uk/emc/product/221/smpc

10. European Medicines Agency. Summary of products characteristics for remdesivir [Internet]. [cited 2020 Jul 19]. Available from: https://www.ema.europa.eu/en/documents/other/veklury-product-information-approved-chmp-25-june-2020-pending-endorsement-european-commission_en.pdf

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Appendix

Table 1. N_old display reports described in previous reports, which included reports received to VigiBase no later than the 12th of July. N_new includes reports received to VigiBase no later than the 2nd of August. Other drugs are selected from medical expertise from the set of corona virus indicated drugs reported to VigiBase, see Table 3. Counts include suspected or interacting drugs. As one report may contain several drugs, rows are not mutually exclusive.


Table 2. Counts are cumulative and include suspected and interacting drugs. As one report may contain several drugs, columns are not mutually exclusive. Other drugs are selected from medical expertise from the set of corona virus indicated drugs reported to VigiBase, see Table 3. Single susp. = Drug was reported as single suspected or interacting drug, Q1-Q3 = First to third quartile.


Table 3. Drugs included in the Other drugs-category. Counts are cumulative and include drugs reported as suspected or interacting. As one report may contain several drugs, rows are not mutually exclusive.


Table 4. Co-medication frequencies. First row gives total number of reports including a drug irrespectively of drug role (suspected/interacting/concomitant). Second row gives number of reports on which the drug was the single suspected or interacting drug. Remaining rows give frequencies of co-reporting of a drug pair, irrespectively of drug role.


Table 5. Abbreviations used for SOCs displayed in the reaction overview bar charts.


CAVEAT DOCUMENT Statement of reservations, limitations and conditions relating to data released from VigiBase, the WHO global database of individual case safety reports (ICSRs). Understanding and accepting the content of this document are formal conditions for the use of VigiBase data.

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). It is important to understand the limitations and qualifications that apply to this information and its use.

Tentative and variable nature of the data Uncertainty: The reports submitted to UMC generally describe no more than suspicions which have arisen from observation of an unexpected or unwanted event. In most instances it cannot be proven that a specific medicinal product is the cause of an event, rather than, for example, underlying illness or other concomitant medication.

Variability of source: Reports submitted to national centres come from both regulated and voluntary sources. Practice varies: some national centres accept reports only from medical practitioners; others from a broader range of reporters, including patients, some include reports from pharmaceutical companies.

Contingent influences: The volume of reports for a particular medicinal product may be influenced by the extent of use of the product, publicity, the nature of the adverse effects and other factors.

No prevalence data: No information is provided on the number of patients exposed to the product, and only a small part of the reactions occurring are reported.

Time to VigiBase: Some national centres make an assessment of the likelihood that a medicinal product caused the suspected reaction, while others do not. Time from receipt of an ICSR by a national centre until submission to UMC varies from country to country. Information obtained from UMC may therefore differ from that obtained directly from national centres.

For these reasons, interpretations of adverse effect data, and particularly those based on comparisons between medicinal products, may be misleading. The data comes from a variety of sources and the likelihood of a causal relationship varies across reports. Any use of VigiBase data must take these significant variables into account.

Prohibited use of VigiBase Data includes, but is not limited to: • patient identification or patient targeting • identification, profiling or targeting of general practitioners or practice

Any publication, in whole or in part, of information obtained from VigiBase must include a statement: i. recording ‘VigiBase, the WHO global database of individual case safety reports (ICSRs)’ as the source of the

information ii. explaining that the information comes from a variety of sources, and the probability that the suspected

adverse effect is drug-related is not the same in all cases iii. affirming that the information does not represent the opinion of the UMC or the World Health Organization.

Omission of this statement may exclude the responsible person or organization from receiving further information from VigiBase.

UMC may, in its sole discretion, provide further instructions to the user, responsible person and/or organization in addition to those specified in this statement and the user, responsible person and/or organization undertakes to comply with all such instructions.

2018-11-20

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