By Dr. Sheikh Mohammad Fazle Akbar and Prof Mamun Al Mahtab (Shwapnil)
Due to devastating effects of SARS-CoV-2 infection and complicated pathologies of COVID-19, several antiviral drugs were provided emergency use authorization (EUA), such as hydroxychloroquine, ivermectin, favipiravir, remdesivir, nitazoxanide, lopinavir/ritonavir as well as other proteases. As the pandemic has stepped into its second year, the utility of these drugs against COVID-19 deserves proper review and analysis. Some of these drugs are no more in use due to considerable adverse effects and some others are endowed with minimal utility.
The major concern is now prevailing about ivermectin, a drug initially developed as an anti-parasitic medication and repurposed for use in COVID-19 after the pandemic began. The drug entered into COVID-19 treatment when Caly et al. first described that ivermectin had antiviral property by studying ivermectin in African Green Monkey kidney cells (Vero/hSLAM cells)-transfected SARS-CoV-2 in vitro. This lab study is animal cells paved the path for using the drug in millions of human beings. As there was no available drug during the initial phase of COVID-19, we also studied the effect of ivermectin along with other investigators in COVID-19 patients in Bangladesh.
Any drug is judged by three fundamental properties: (1) Adverse effects and safety record, (2) preventive capacity, if any and (3) therapeutic efficacy. Possibly, ivermectin is the only repurposed drug to date that has been considered to have both preventive capacity and therapeutic potentials against COVID-19. However, proper clinical trials have never been accomplished with appropriate design to address these two important issues. Ivermectin has widely been used in Latin American countries due to existence of parasitic diseases for which ivermectin was developed. WHO and John Hopkins compiled the worldwide data of prevalence and deaths due to COVID-19 on a day to day basis by receiving data from respective governments. These show that although Latin American countries harbor 5.5% of world population and the total cases of COVID-19 in this region has been 37 million, which is 16.8% of total COIVID-19 patients of the world. However what is most notable is the number of deaths due to COVID in Latin America, which now stands at 1.1 million and is 24% of the total global deaths due to COVID-19. These data clearly demonstrate that ivermectin does not have any preventive or therapeutic potentials against COVID-19.
Let’s focus on the reality of Bangladesh. From March 2020 to March 2021, Bangladesh had registered 611,296 confirmed cases of COVID-19. However, 889,323 confirmed patients of COVID-19 have been recorded from May 2021 to August 2021. Regarding deaths due to COVID-19 in Bangladesh, similar picture is prevailing. A total of 9048 COVID-19 patients died in Bangladesh from March 2000 to March 2021, whereas, 17,147 COVID-19 patients died only in recent 5 months i.e. May 2021 to August 2021. Ivermectin is well known to people of almost all sectors of Bangladesh and many in Bangladesh have taken ivermectin in 2020 and 2021. Thus, epidemiological data indicate that ivermectin had nothing to do with curtailing COVID-19 prevalence and mortality in Bangladesh.
The other factors that have been advocated for use of ivermectin is regarding safety of the drug. It is generally assumed that that even if ivermectin is not an efficacious drug, it is safe. Thus, many people including physicians have advocated the use of ivermectin as a safe and somehow efficacious drug for COVID-19 in developing countries like Bangladesh and other Asian and African countries. This initiated us to analyze the overall safety profile of ivermectin through literature search.
Ivermectin is not a safe drug as has been described. Ivermectin can cause pain in neck and back and serious eye problems, including redness, bleeding, swelling, pain and loss of vision. The list does not exhaust here. The drug can also lead to shortness of breath, inability to control urination, inability to control bowel movements, difficulty in standing or walking, confusion, extreme tiredness, extreme drowsiness and even seizures and coma. Most dangerous is the fact that ivermectin may interact with other medications: Warfarin is a drug used as blood thinner. Taking warfarin with ivermectin can thin blood too much and cause catastrophic bleeding. Constant monitoring of international normalized ratio (INR) is required when both of these drugs are taken simultaneously. This also suggests that the present situation of dengue outbreak may have more adverse effects on dengue patients taking ivermectin. Ivermectin can cause severe allergic reaction. Symptoms can include difficulty in breathing, swelling of throat or tongue and skin rash. Finally, ivermectin is a category C pregnancy drug. This means research in animals has shown adverse effects to the fetus when the mother takes the drug (https://www.medicalnewstoday.com/articles/ivermectin-oral-tablet#interactions). In addition, additional adverse effects of ivermectin in COVID-19 have not been properly elucidated. However, there remains serious concern as the COVID-19 is a viral disease with immune anomaly.
Cautions about ivermectin by recognized international authorities
WHO warns against use of ivermectin for COVID-19 treatment (Coronavirus, Ivermectin Efficacy_ WHO Warns Against Use Of Ivermectin For COVID-19 Treatment.pdf).
US-FDA has also provided repeated warnings for not using ivermectin (FDA, other health officials warn about ivermectin as COVID treatment.pdf). Also, US-FDA has even gone that far as to comment “You are not a horse” (FDA warns against use of animal dewormer as COVID-19 treatment, prevention. FDA, other health officials warn about ivermectin as COVID treatment.pdf).
American Medical Association calls for 'immediate end' to use of ivermectin for COVID-19 as many factors related to adverse effects of ivermectin were unknown during initial phase of COVID-19 pandemic (https://thehill.com/policy/healthcare/570519-american-medical-association-calls-for-immediate-end-to-use-of-ivermectin).
Also US CDC and FDA along with doctors have advised not to use ivermectin (FDA, CDC, doctors warn not to use ivermectin for COVID treatment, prevention, https://abc7chicago.com/ivermectin-covid-humans-side-effects-treatment/10994919/)
The first target of development of any new drug is to confirm its safety followed by efficacy. Thalidomide is a drug that was developed in the 1950s by the West German pharmaceutical company Chemie Grünenthal GmbH. It was originally intended as a sedative or tranquiliser, but was soon used for treating a wide range of other conditions, including colds, flu, nausea and morning sickness in pregnant women. In the 1950s, scientists did not know that the effects of a drug could cross the placental barrier and harm fetus in the womb and so the use of medications during pregnancy was not strictly controlled. And in the case of thalidomide, no tests were done involving pregnant women. In the few years that thalidomide was available, it's estimated that over 10,000 babies were affected by the drug worldwide. Around half died within months of being born. The thalidomide babies who survived and their families still live with the adverse effects of the drug. In 1968 Chemie Grünenthal was brought to trial in Germany. Ivermectin is a category C pregnancy drug. That means two things research in animals has shown adverse effects to the fetus when the mother takes the drug. It is now time to think, who will take responsibility for any remote adverse effect of ivermectin, if any, in pregnancy.
Use of ivermectin should be discouraged in Bangladesh
Based on the above observations, we would like to suggest that ivermectin should be banned for COVID-19 patients until safety and efficacy of this drug is confirmed by conventional clinical trials. The world as well as Bangladesh is not in state to provide EUA for repurposed drug like ivermectin to treat COVID-19. Its use can have different implications. What would happen to COVID-19 patients taking blood thinner with ivermectin? How about the effect of ivermectin on pregnant mothers as well as ladies? Is there any study planned to assess the adverse effects of ivermectin in COVID-19 patients? As we are not informed about proper logics for several “WHATS”, we should be cautious regarding recommending such a drug. The prescriber should come with proper logics and scientific evidences to rationalize their prescription in 2021, when considerable insights have been developed during the last several months. Why the recommendations of WHO, FDA, AMA and European Medical Agency (EMA) were overturned to prescribe ivermectin? Most importantly, after usage of millions of doses of ivermectin in Bangladesh, either by prescription or self-prescription, why there is no attempt to initiate a double-blind, randomized clinical trial with ivermectin at national level?
Illegal drug prescription
The Directorate General of Drug Administration (DGDA) and the Government of Bangladesh are the final authority to allow or disallow any drug use in Bangladesh. It is natural that the DGDA and the relevant authority of Bangladesh has possibly approved emergency use authorization (EUA) of ivermectin during COVID-19 pandemic. Physicians are endowed with ultimate capacity of prescribing any drug for their patients. However, when a drug included in posters for prescription and for mass propagation, such action needs to be reviewed by DGDA and Government of Bangladesh and, if that is illegal, proper action should be initiated.
Compilation
From the prevailing scientific evidences, it become evident that ivermectin has never been fully approved for use in COVID-19 patients, except an emergency approval for some time in Bangladesh. The drug is endowed with serious adverse effects, some of which may be life-threatening. FDA, CDC and WHO have uttered significant cautions for not using this drug. Prescription of this drug should be immediately stopped until a detailed clinical trial provides insights about its adverse effects and efficacy. The authors are committed to share scientific information and updates about ivermectin in COVID-19 and the concepts of WHO, FDA, CDC, European Medical Agency and MERK, the producer of ivermectin in this regard.
Dr. Sheikh Mohammad Fazle Akbar is a researcher of the Department of Gastroenterology & Metabology at Ehime University, Japan while Professor Mamun Al Mahtab (Shwapnil) is the head of the Interventional Hepatology Division at Bangabandhu Sheikh Mujib Medical University, Bangladesh