Tensions mount among physicians seeking to treat COVID-19 with safe doses of ivermectin as they face push-back from medical councils. TrialSite has reported on the success stories around the globe of ivermectin reducing COVID-19 transmission, which are impossible to ignore. However, it remains to be established whether the drug is safe for prolonged use as prophylaxis against COVID-19. With the onset of the pandemic, its safety profile has come under close scrutiny. The drug’s credibility has been challenged as a result. The pressure is mounting to determine its long-term safety profile, so that it may be prescribed as a prophylactic measure for those who are at-risk from adverse effects of vaccination.
As featured in earlier reports on TrialSite, ivermectin has demonstrated a safety profile for over three decades, shown through copious epidemiological studies, expert meta-analyses, and peer-reviewed studies. In a systematic review of more than 500 scholarly works commissioned to an independent reviewer, Dr Jacques Descotes, ivermectin revealed very low percentages of adverse events. These were non-fatal and evanescent. Less than 1% resulted in serious implications.
Analyses on neurological impacts of ivermectin, such as seizure, indicated that 0.000000007% of cases exhibited adverse effects. This was derived from a global pharmacology database search. Out of 4 billion doses issued, only twenty-eight cases had negative neurological effects. Again, these were self-limiting and temporary, disputing warnings issued of ivermectin’s possible neurotoxicity.
The rationale behind ivermectin’s extremely low toxicity is because it does not “cross the blood-brain barrier … (and) displays a 100-fold greater affinity for parasitic Cl– channels compared to the human homologs.”
To evaluate the potential risks associated with prolonged use of ivermectin or pre-exposure ivermectin, studies involving susceptible groups such as children, pregnant women, and the elderly are investigated.
Safety profile of off-label ivermectin use in children and infants
Infants and children are the most susceptible groups to any drug implications, so research on this age group can be particularly illuminating. While some non-clinical animal studies caused hypothetical concern around ivermectin toxicity in children, human studies do not support these assertions.
Studies done from 1980 to 2019 on children weighing less than 15 kilograms (33lbs) were analyzed using systematic review and individual patient data (IPD). From this, 1088 children were included to find interactions with the effects of ivermectin treatment. Only 1.4% of cases (15 out of 1088 children) had any negative experience, and these minor cases were resolved on their own without complications.
In France, children between 1-64 months of age, (below 33 lbs.) received oral ivermectin for scabies. The study examined data from 170 infants in 28 different centers treated between July 2012 and November 2015. Even though ivermectin is not recommended for infants, the centers used it as an off-label treatment. Out of all the children treated, seven cases from 170 children (4%) reported mild reactions that were self-limiting.
Safety of ivermectin use in pregnant women
Pregnant women also need to be carefully considered in terms of safety during prolonged dosage, as there are concerns regarding possible teratogenic effects on the fetus after exposure in the womb.
A meta-analysis conducted in one study showed inconclusive results. Other studies indicate that there is no demonstrable cause for alarm.
To better understand these outcomes, retrospective case studies from years of mass distribution administration (MDA) Merck campaigns were systematically reviewed. The outcomes of interest included: neonatal deaths, stillbirths, congenital abnormalities, low birth weights, congenital anomalies, spontaneous abortions, and maternal morbidities.
From the seven outcomes examined, there were zero cases of preterm births, low birth weight, maternal morbidities, or neonatal deaths reported. However, it was unclear whether spontaneous abortion, congenital anomalies, and stillbirths resulted from ivermectin exposure. For babies and infants breastfeeding, the concentration in human milk is very low and has shown to be tolerably below the threshold.
Observational studies done with a control group found that out of 500 pregnancies, 12 cases reported birth anomalies (2.4%), while the control of 2666 had 33 congenital abnormalities (1.2%). The results varied widely across different retrospective case studies with conclusions failing to give definitive answers.
Previously, ivermectin was classified as pregnancy category C by the US Food and Drug Administration (FDA). Pregnancy category C of any drug means that the available data is from animal studies demonstrating teratogenic effects, but no adequate data from controlled human studies. This grouping criteria has since been replaced. The ivermectin animal studies have since been rescinded after finding the lab animals had a defect that gave erroneous results.
Safety of ivermectin in an elderly cohort
The elderly are another vulnerable group that should be considered when investigating ivermectin’s safety. Interestingly, there was a situation in an elderly residential facility in France which served to shed some light on this. Ivermectin was inadvertently served as pre-exposure prophylaxis to the 69 residents there who averaged 90 years old–they received ivermectin treatment after a case of scabies, which proved to be a blessing in disguise.
While recovering from scabies, COVID-19 affected the facility along with others in the area. Only seven of the elderly who had taken ivermectin got COVID-19. No fatalities occurred, unlike neighboring facilities which reported 5% fatalities with 23% infections. This situation revealed that ivermectin may have helped the residents while also being well-tolerated. Concomitant drugs, comorbidities, and dosage were not indicated.
Weighing the risks and benefits of ivermectin pre-exposure
Research indicates a few contraindications of ivermectin with other drugs. In patients taking blood thinners such as warfarin, caution is highly recommended. Immunosuppressed individuals and organ transplant patients taking calcineurin inhibitors are also at risk of drug interaction. Studies advise that it is imperative to carefully evaluate the amount of intake in concurrent administration.
There is a clear consensus of data on ivermectin as a safe pre-exposure drug. Combined studies of more than 50, 000 patients have established the overall safety of ivermectin. Doses have varied from 0.15 mg /kg to 12 mg/kg, from infants to the elderly. Similarly, frequency has differed from daily intake to weekly, monthly, and annually.
Indications for a long-term dosage of ivermectin for pre-exposure prophylaxis
A central question for ivermectin pre-exposure prophylaxis over long-term use is how to ensure safe dosage, while at the same time making sure it provides adequate protection.
In Dhaka, Bangladesh, participants in a clinical study took 12 mg/ month of ivermectin for four months, while in Argentina health workers took 12 mg every week for four weeks as prophylaxis protocol. Since both cohorts reported comparable significant effectiveness, studies asserted that monthly dosing provided an adequate protective effect.
The All India Institute of Medical Sciences (AIIMS) implemented their own efficacious ivermectin prophylaxis procedure in healthcare workers of 0.3 mg/kg taken twice, 72-hours apart, every month. The meta-analysis averred that since there has not been a definitive standardized prophylaxis, “studies should be undertaken to better define … the optimal dose and frequency required.”
The sooner ivermectin’s long-term safety profile is determined, the sooner physicians will be able to use its potential benefits to the advantage of their patients.