Analysis of hydroxychloroquine adverse events in COVID-19 patients reported throughout Iraqi pharmacovigilance center in VigiBase™: A study based on WHO database

Introduction

The coronavirus disease 2019 (COVID-19) pandemic began in Wuhan, China, in December 2019. High body temperature, dry cough, headache, dyspnea, and diarrhea were all symptoms of this viral illness. The earliest occurrences of these symptoms were linked to a food market in Wuhan, China. Since then, some cases have developed into severe respiratory distress, with an approximate death rate of 2%.^1–4 The global impact of the SARS-CoV-2 pandemic has been unprecedented, prompting the scientific community to investigate all potential remedies.⁵ Because hydroxychloroquine (HCQ) has previously been shown to be successful in the treatment and prevention of SARS-CoV,⁶ and because COVID-19 is similar to SARS-CoV, many investigators have advocated HCQ as a possible therapeutic drug.⁷ HCQ is a medication used in the treatment and prevention of malaria and autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).⁸ In vitro investigations suggest that HCQ inhibits SARS-CoV-2 infection and multiplication.^9–11 HCQ has antiviral action through entrance inhibition, replication inhibition, or immunological manipulation.^12,13 Endosomal antigen processing is altered by HCQ, and innate and adaptive immune responses are modulated.^14,15 This reduces the production of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6.

Furthermore, HCQ optimizes endothelial function and suppresses the prothrombotic condition. These characteristics may benefit people with severe COVID-19.¹⁶ In patients with malaria or autoimmune disorders, the most common adverse effects of HCQ encompass gastrointestinal distress (vomiting, diarrhea, stomach cramps), skin rash, headache, dizziness, and ophthalmic toxicity. In addition, these medications may potentially induce significant adverse effects such as arrhythmia, bronchospasm, angioedema, and seizures.¹⁷ Cardio-toxicity is the most devastating adverse effect of HCQ therapy in severely infected COVID-19 patients. A double-blind clinical study from Brazil revealed that medication dose may be a contributor in HCQ cardiotoxicity.¹⁸ The purpose of this research was to examine the adverse events related to HCQ administration (alone or in combination with other medicines) in COVID-19 patients in Iraq to determine any new/altered safety information connected to HCQ.

Methods

Results

The Iraqi Pharmacovigilance Centre reviewed and recorded 132 episodes of adverse events related to HCQ use in VigiBase over 2020 in the COVID-19 pandemic; the study involved 132 ICSRs, all cases were qualitatively screened, 49 reports were found for women, which accounted for 37.1% of cases, while 80 reports were found for men (60.6% of cases), and three unknown reports 2.3% were found. The age group of affected patients varied from 28 days to 75 years, as seen in Figure 1.

Figure 1. Reported percentages of age groups reporting adverse events for HCQ.

HCQ, hydroxychloroquine.

Azithromycin is the most often documented co-reported active component with HCQ, with 45 reports as suspected/interacting and five as a concomitant, totaling 50 reports (37.9% of cases). Oseltamivir has 29 suspected/interacting reports and seven concomitant reports, for a total of 36 reports (27.3%), paracetamol has one report as suspect/interacting and 21 reports as a concomitant, for a total of 22 reports (16.7%). Centrum (an American brand of multivitamins) has one report as suspected/interacting, and 20 reports were simultaneous, for a total of 21 reports (15.7%). Enoxaparin has three reports as questioned/interacting and nine as a concomitant, 12 reports in total (9.1%). Bromhexine received no reports as suspected/interacting and 10 reports as a concomitant, for a total of 10 reports (7.6%). Meropenem has four reports as suspected/interacting and four as a concomitant, eight reports in total. Clopidogrel has five reports as suspected/interacting and one as a concomitant, total of six reports (4.5%). In a quantitative assessment of the Iraqi database, the Iraqi Pharmacovigilance Centre found 44 combinations involving 177 adverse medication reactions for patients who took HCQ in various dosage strengths throughout 2020. There were 13 instances of QT prolongation on an electrocardiogram (ECG), 17 cases of upper abdominal pain, 21 cases of abdominal pain, nine cases of palpitation, five cases of dyspepsia, 13 cases of diarrhea, four cases of abdominal discomfort, 14 cases of nausea, and two cases of oral fungal infection. Many side effects, such as upper abdominal discomfort, palpitation, and dyspepsia, are more prevalent in Iraqi records than in foreign cases. The severity of these responses was assessed at 48%. Cardiac arrest, abdominal pain, fatigue, gastroesophageal reflux disease, diarrhea, headache, and dyspepsia were among the co-reported side effects as presented in Table 1.

The Iraqi number of observed cases was compared to the expected data in VigiBase for Iraq and the global registry, as well as the Iraq-IC₀₂₅/Global-IC₀₂₅ ratio, sex, severity, and patient age were enlisted in Table 2.

Discussion

Findings from this study demonstrate how a medication’s safety profile depends on how it is administered. When administered outside of its marketing authorization, any medicine, even one that is well-known and is thought to be understood, may show higher frequent and serious adverse effects than anticipated. To guarantee patient safety, spontaneous reporting and pharmacovigilance are crucial in informing healthcare providers of possible issues.²⁰ This research found that within the first wave of the pandemic, off-label use of HCQ in patients with COVID-19 has been related to greater reporting than in the preceding years. Adverse drug reactions (ADRs) are generally predicted and are stated in the French summary of product features for PLAQUENIL®, as previously documented in a study by P. Lory et al.²¹ Abdominal pain and QT prolongation were the most widely reported ADRs in individuals taking HCQ for the treatment of COVID-19, which agrees with the most consistently encountered ADRs recognized by Zekarias et al., throughout an evaluation of 2,573 reports on COVID-19-specific therapies from VigiBase.²² High dosages of the antimalarial²³ and concomitant treatment with azithromycin have been associated with a greater risk of significant side effects. Furthermore, the HCQ pharmacokinetics are distinguished by their prolonged half-life and a large volume of dispersion.²⁴ The most remarkable findings are the relatively high proportion of cardiac ADRs (ECG QT prolonged = 3.5/5 of overall ICSRs), which demonstrate that HCQ may directly damage the myocardium and cause cardiac rhythm disturbances. The relatively high incidence of toxicosis also explains the low therapeutic window of HCQ.²⁵ The current findings further reveal that the cardiac signal (QT prolongation, arrhythmias, etc.) seen with HCQ in COVID-19 patients was previously prevalent in inflammatory arthritis or SLE patients.^26,27 According to Funck-Brentano et al.,²⁸ there are several potential causes for the elevated risk of cardiac toxicity. The first one could be connected to how SARS-CoV-2 affects the heart. In reality, individuals with coronavirus infections are more likely to have drug-induced rhythm abnormalities due to frequent hypokalemia and fever, which exacerbates the effects of drug-induced cardiac channel blocking.

Furthermore, elevated IL-6 levels following infection may contribute to the QT prolongation brought on by inflammation. According to Guo et al., myocardial damage linked to cardiac dysfunction and arrhythmias was seen in almost 30% of COVID hospitalized patients in a Chinese hospital. There is a strong correlation between these cardiac lesions and fatal results.²⁹ Additionally, COVID-19 patients often received large dosages of HCQ in addition to other medications that cause QT prolongation (including azithromycin). HCQ and azithromycin were combined in 80% of the interaction situations, and the QT interval was lengthened in every single one. Other medications that interact with HCQ in a potentiating or additive way, such as spiramycin, fluoroquinolones, antivirals, or antidepressants, have also been linked to heart harm. Cardiac toxicity (QT prolongation, heart failure, and cardiac arrest) was the cause of the seven recorded fatalities during the COVID era. Our research points up several instances when a “drug interaction” with HCQ might negatively impact the heart.

Our investigation has some limitations and strengths, despite the inevitable biases of such research (under-reporting, absence of extensive information on dosages and exposure period in VigiBase, use of HCQ in simultaneous rheumatic or autoimmune illnesses, and not just COVID-19). Nevertheless, the findings have significant strengths: we utilized the world’s biggest pharmacovigilance database, which includes over 90% of people worldwide, to identify and analyze possible safety signals during the COVID-19 pandemic outbreak. These worldwide database results strengthen the external validity of our findings. Furthermore, unlike clinical trials, dealing with this data from VigiBase enables us to be in the setting of real-world practice. Data from the real world that were not analyzed in clinical trials allow for outcomes’ applicability.

Conclusions

The events reported to the Iraqi pharmacovigilance center include the concurrent use of other drugs, making it difficult to verify whether HCQ is responsible for these adverse effects. According to WHO global data, most of these impacts have minor differences. However, several have negative correlations, indicating that the predicted number of cases is greater than the actual number. In addition, some of the reported side effects, such as upper abdominal discomfort, abdominal pain, palpitations, and dyspepsia, showed a significant difference in IC₀₂₅ between cases reported in Iraq and those reported internationally. This adverse effect may influence patient adherence; however, it seldom affects their use.

Data availability