key: cord-0863302-yqmadkc9 authors: Khan, Zakir; Karataş, Yusuf; Rahman, Hazir; Qayum, Mughal; Alzahrani, Khalid Jamaan; Kashif, Syed Muhammad title: COVID-19 treatments and associated adverse reactions: the need for effective strategies to strengthen pharmacovigilance system in Lower- and middle-income countries date: 2021-06-08 journal: nan DOI: 10.1016/j.phclin.2021.06.001 sha: 314c41b6d03fb42547cf7fad89f60b828462be7e doc_id: 863302 cord_uid: yqmadkc9 nan Previously, drug repurposing of various available drugs was used for COVID-19 treatment [2] . However, several published articles have reported cardiovascular adverse drug reaction (ADRs) associated with hydroxychloroquine and chloroquine [3] , severe unpredictable reactions in rheumatic diseases, drug-induced liver injury, pancreatitis and pulmonary fibrosis due to the tocilizumab [4] , hydroxychloroquine experienced serious psychiatric disorders [5] , an increased risk of infection and thrombotic events due to baricitinib [6] and gender disparities in the reporting patterns of medication used in COVID-19 treatment [7] . Information about some approved drugs (chloroquine, hydroxychloroquine, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs, umifenovir and favipiravir) for other indications has been disseminated, which may have resulted in improper and harmful use and therefore leads to ADRs development [8] . It was also addressed in a recent systematic review and meta-analysis that the efficacy and safety of either hydroxychloroquine alone or in combination with azithromycin in the treatment of COVID-19 might not be guaranteed [9] . Moreover, according to a recent research article, the incidence of ADRs was 4.75-fold higher in COVID-19 patients as compared to non-COVID-19 patients. The frequently reported ADRs were pancytopenia, agranulocytosis, thrombocytopenia, anemia, eosinophilia, hepatitis, pancreatitis, acute kidney injury, rhabdomyolysis, and hyponatremia. Tocilizumab, dexketoprofen, azithromycin, lopinavir-ritonavir, dexamethasone, and chloroquine/hydroxychloroquine were the most commonly recorded medications with ADRs [10] . Adverse effects were common, appeared in up to 90% of patients with higher dose and longer duration [11] . J o u r n a l P r e -p r o o f 3 and some are currently using unlicensed technologies with regulatory bodies promising fast-track approval processes [19] . Monitoring of adverse events following immunization (AEFI) and any approved drugs is an essential strategy for ensuring the safety of vaccines [20] . The monitoring of vaccine and drug safety after licensing relies on spontaneous ADR reporting through a combination of passive and active pharmacovigilance-based surveillance. Pharmacovigilance (PV) addresses studies that focus on the post-marketing safety problems of medications that lead to ADRs [21] . Pharmacovigilance is focused on the science and practices related to the detection, assessment, sharing about COVID-19 related medicines [24] . The United States food and drug administration (FDA) adverse event reporting system (FAERS) is another main repository for passively reported ADRs in the world [25] . It relies on health professionals, consumers, and manufacturers to report all adverse events to the FDA. The database consists of more than fourteen (14) million reports since 1969 [26] . FAERS is a computerized database of information to support the post-marketing safety monitoring program for all licensed drug and biological therapeutic products. FAERS monitor the new ADRs and drug errors that could occur with these products [27] . These pharmacovigilance systems continuously monitor reporting of ADRs from collaborative countries and play a crucial role in the national pharmacovigilance authorities' decision-making process [28] . LMICs have large populations living in overcrowded conditions with financial problems and usually unable to comply with the normal recommendations of public health on how to minimize the spread of viruses and infections [29] . The lack of sufficient education and training programs in LMICs leads to a shortage of trained and experienced health care professionals [30] . In such situations , individuals subjected to risks and confusion tend to pursue self-care strategies and adopt non-conventional methods for treatment [31] . There have been reports about the use of complementary and alternative medicines, home remedies [32] and self-medication practices [33] particularly during COVID-19. Additionally, misinformation about the antibiotics for the management of COVID-19 especially affects clinicians, health policy makers and the public in LMICs due to the inadequate training, overburdened and restricted access to timely and validated information sources [34] . The widespread off-label and irrational use of medicines for COVID-19 is a cause of deep concern and may lead to the overall morbidity and mortality that has been predominantly linked to the infection [1] . A recent study showed that, COVID-19 patients receive co-combination therapies due to the complex nature of disease [35] . Such practices increased the risk of drug related ADRs [8, 35] . According to the published studies, LMICs had the lower ADR reporting rates [36, 37] , lack of knowledge and training about ADR reporting, higher workload among healthcare professionals (HCPs) [21, 38] , economic implications, lack of prioritization, drug safety monitoring and weak pharmacovigilance system as compared to high-income countries. [39, 40] . It is also reported that many herbal medicines have been used in different LMICs to treat COVID-19, and such drugs are readily available to the public without a prescription, but there is no evidence-based support for their use in COVID-19 [41] . It is reported that, developed countries have defined pharmacovigilance programs to monitor the safety of medicinal products. However, drug monitoring and reporting are facing immense difficulties in the developing world [21] . Unfortunately, LMICs faced several challenges to make effective PV implementation such as; fragile health systems with weak facilities, inadequate supply and quality of drugs, lack of adequately qualified health workers, restricted access to health care and communication networks, lack of supportive staff and collaborative HCP teams in regional/institutional pharmacovigilance centers, poor understanding and involvement of national drug safety stakeholders, regulatory capabilities issues, insufficient financial support by national authorities for healthrelated issues [42, 43] . Recently published article emphasized on the adequate cooperation of international and government health authorities and manufacturers to stimulate and endorse the conduct of studies by academia and research institutions to ensure the risk-benefit profile of drug candidates for COVID-19 treatment, the implementation of spontaneous ADR reporting systems, identification of the misuse of drugs which can lead to unintentional intoxication, enhanced communication techniques based on verbal and written recommendation often supported by scientific experts for the management of real or possible effects of drug misuse [8] . The establishment of compulsory regional pharmacovigilance center in all government and private based hospitals, spontaneous ADR reporting mechanism, electronic prescribing system, upgraded drug information centers, and frequent prescription audits-based studies are needed for better healthcare system [28, 39] . Additionally, enrollment of more pharmacovigilance contact persons, comprehensive follow-up, avoidance of medication errors, timely feedback by national pharmacovigilance center to ADR reporters and pharmacovigilance contact persons, financial support by health care authorities and continuous training and educational programs on the subject of pharmacovigilance for the patients and HCPs may be effective intervention for better pharmacovigilance system in LMICs during and after COVID-19 pandemic [28, 39, [43] [44] [45] . Some low-resource, low provider burden strategies should be implemented in LMICs such as; spontaneous reporting of individual case safety reports should be consistently start in each health care setting, should apply for formal training program in PV offered by the WHO-UMC for the HCPs and academicians, should arrange internships in own wellestablished PV centers or in neighbour countries, try to engage pharmacists in PV centers to overcome physician burden and compulsory inclusion of PV related curricula in undergraduate and graduate levels teaching institutions for all HCPs. Additionally, LMICs can utilize the VigiFlow ADRs data offered by the WHO-UMC for their own PV management system at a very low cost, combine PV activities with drug and poison information service might be economical for LMICs, joint PV activities between medicine regulatory authorities and government and private healthcare institutions, mobile phone SMS-based reporting system for ADRs should be established in LMICs, should emphasized and implement the inclusion of ADRs and medication errors reporting system in private healthcare settings [46] . Moreover, a recent WHO mobile application called "Med Safety" in nine countries with UMC [24] and V-safe smartphone-based application after COVID-19 vaccination health checker developed by Center for disease control and prevention (CDC) should be exchange with LMICs for better PV activities [47] . Global cooperation, timely J o u r n a l P r e -p r o o f 6 detection of ADRs, epidemiological vaccine safety monitoring, post-marking active and passive surveillance systems, vaccine safety communication plans should be urgently put into practice in LMICs to identify AEFIs and safety surveillance for the COVID-19 vaccines [48, 49] . Global investment in vaccine safety and communication infrastructure is also much needed [50] . The implementation of effective strategies to strengthen PV is compulsory for the safe, rational and cost-effective use of medicines for public health care. An effective PV system is crucial in LMICs to overcome the high burden of infectious diseases, a growing proportion of non-communicable diseases, misuses of medicinal products and also for the development of safe new drugs or vaccines for COVID-19 [39, 42] . The implementation of effective pharmacovigilance system is crucial to avoid irrational medication practices and timely identification of ADRs for the safety assessment of COVID-19 drugs [8, 35, 39] . We also suggested that the introduction of effective economical strategies to enhance the PV mechanism in LMICs is essential in order to save lives, improve patients' quality of life and to ensure patient safety and well-being. Continuous financial, legislation and a regulatory structural support is also needed for the development of sustainable PV systems in LMICs. Further research on the effect of organizational structures, economic resources of national PV centers and ADR reporting practices is also required to gain insight into the large variations in ADR reporting rates between LMICs. New problems will certainly emerge once the available vaccines become distributed to the all-developed and LMICs around the world and try to learn from the mistakes made at this point to face the future challenges. It is the right time for developed countries both at the global and community level to address and help the LMICs to strengthen the available PV system and to overcome hurdles for the better global health care. 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