Christine King BVSc, MANZCVS (equine), MVetClinStud
Precautions against ivermectin horse paste
to prevent or treat COVID-19 in people
As a follow-on to my article on ivermectin and the Hendra virus, I felt the need to write a commentary on people taking ivermectin paste for horses because they don't have access to the ivermectin formulation approved for human use.
The oral paste formulations of ivermectin approved for use as an anthelminthic (dewormer) in horses are a concern for a few reasons:
1. The horse paste is much more concentrated than the human formulation and the veterinary formulations licensed for use in smaller animals.
It is difficult to accurately dose foals, small ponies, and Miniature Horses with the horse pastes because of their small size and the way the dial or other mechanism on the plunger is calibrated for the horse's bodyweight. Typically, the mechanism allows the user to dose to an accuracy of ± 25 kg (55 lb), but in practice, accuracy is more like ± 50 kg (110 lb), or ± one small person.
If it's this easy to get the dose wrong in horses, how much easier it would be to accidentally overdose or underdose a person with these horse products. And when it comes to drug safety and effectiveness, dose matters.
2. Ivermectin is often combined with other drugs for more broad-spectrum anthelminthic treatment. Unless you read the fine print on the box or tube, you may be getting more than just ivermectin in that tube of horse wormer.
3. We don't know what else is in the ivermectin horse pastes because the formulations are proprietary secrets. At least with the sheep drench, we know what else is in it, and that each of the principal components is relatively safe in humans.
For example, one widely available ivermectin sheep drench in the US contains the following ingredients, in addition to ivermectin 0.08% (0.8 mg/ml, which is not a "trade secret," it's written on the label!):
I've been unable to find comparable data for the ivermectin sheep drench in Australia, but it is likely to be very similar in composition.
Ivermectin is used as an anthelminthic drug in a wide variety of animal species. It has a fairly good safety profile in most animals, although there are significant species differences and some very important breed differences, particularly in dogs. For example, the safety margin ranges from around 4x in dogs (but less than 1x in certain breeds) to around 50x in pigs. In horses, a single oral dose that is 10x the standard dose (0.2 mg/kg, or 200 µg/kg) is tolerated, but repeat that dose the next day and neurologic signs are likely to occur.
Ivermectin pastes for horses are safe for use in horses at the label dosages, but their use should be restricted to horses and other domestic equids (donkeys, mules). I would be hesitant to use the horse paste even in another livestock species (e.g., sheep or goats).
It is far safer to use a product that is formulated for the target species or that is known to be safe through experience (e.g., sheep drenches can safely be used in goats) and an understanding of the species similarities and differences in drug metabolism (e.g., dosages of sheep drenches in goats are different from those used in sheep).
In 2002, Merck (the company that developed ivermectin and first brought it to market) published a human study on ivermectin dosage in the Journal of Clinical Pharmacology. They concluded that ...
So, the study indicated a safety profile in humans similar to that seen in horses.
The goal of that particular study was to investigate higher doses of ivermectin and more frequent dosing intervals than are currently approved for human use. Specifically, they examined single doses of 90 mg and 120 mg, as well as repeated doses of 30 mg and 60 mg given twice a week. This was a double-blind, placebo-controlled, dose escalation study. Here are some of the relevant highlights:
HOWEVER, a mini-review of ivermectin pharmacokinetics (how a drug moves through a body) in humans raises some little red flags for me, in relation to the use of formulations not intended for humans. This review was published in 2008, in the AAPS Journal (American Association of Pharmaceutical Scientists), by a group of pharmacologists in Spain. (The funding source is not specified, but I believe this was an independent review.)
Here are my main points of concern:
1. The peak plasma concentration (Cmax) varied with the formulation. It was about twice as high for the solution compared with the powdered formulations (tablet or capsule).
The oral ivermectin product licensed for use in humans is a tablet. The sheep drench is a solution. The horse paste is a bit of a mystery, because we don't know its base ingredients, but it is probably somewhere in between the two and more 'wet' than 'dry'.
So, ivermectin toxicity may be more likely with the sheep drench and horse paste simply because of the different absorption characteristics between dry and liquid formulations of ivermectin in humans.
If you have chosen to take a liquid or paste formulation of ivermectin, it may be safest to use the lower end of the dose range advised by the doctors who are prescribing or recommending the human formulation of ivermectin for the prevention and treatment of COVID-19.
2. The elimination half-life (t1/2), which the authors described as being “around a day,” ranged from 11 hrs to almost 55 hrs. In most studies it was in the range of 12–24 hrs, but in one study it was around 36 hrs, and in another it was 54.5 hrs.
These figures are for a single oral dose. They don't tell us what happens when a person takes a second, third, fourth, or fifth dose. Here is where t1/2 becomes very important. The trick is to maintain effective levels of the drug in the bloodstream and tissues, without reaching toxic levels. Repeat the dose within the t1/2 window, and the drug can accumulate in the body (bioaccumulate), potentially reaching toxic levels after multiple doses.
The most recent ivermectin protocols I’ve seen for the prevention and early outpatient treatment of COVID-19 recommend repeated doses of ivermectin at variable intervals from daily to twice a week, depending on the circumstances. Given the pharmacokinetics of ivermectin in humans, the drug could quickly accumulate with daily dosing, particularly if taking a more bioavailable formulation such as horse wormer or sheep drench.
These protocols typically cap the daily dosing of ivermectin at 5 days in patients who are self-medicating (for prevention or early outpatient treatment). Pay attention to the dosing recommendations by experienced doctors who are using ivermectin in their hospitals and clinics. This drug does have a fairly good safety profile in humans, but overdose is certainly possible with daily dosing.
If you have chosen to take a liquid or paste formulation of ivermectin, it may be safest to use a longer interval between doses than the one(s) advised by the doctors who are prescribing or recommending the human formulation of ivermectin for the prevention and treatment of COVID-19.
3. There may be significant gender differences in the clearance of ivermectin from the body. In one study of healthy people given 150 µg/kg (0.15 mg/kg) of ivermectin, total body clearance of ivermectin was almost twice as high in women as in men.
So, if clearance is lower in men (a big IF, as that was just one study), then repeated daily dosing may be more likely to cause toxicity in men than in women.
If you have chosen to take a liquid or paste formulation of ivermectin and you are male, it may be safest to use a longer interval between doses than the one(s) advised by the doctors who are using the human formulation of ivermectin for the prevention and treatment of COVID-19.
4. Ivermectin is a highly lipophilic molecule, meaning that it has a high affinity for fats (lipids). Of the body tissues examined in ivermectin distribution studies, “Fat showed the highest and most persistent levels..."
So, because ivermectin is such a fat-loving molecule, significant accumulation of ivermectin with repeated dosing may be more likely in people with greater amounts of body fat than in lean people.
If you have chosen to take a liquid or paste formulation of ivermectin and you are overweight, it may be safest to use a longer interval between doses than the one(s) advised by the doctors who are using the human formulation of ivermectin for the prevention and treatment of COVID-19.
The sad irony here is that being overweight is a specific risk factor for COVID-19. Please, if you are ... er ... 'generously padded', take good care of yourself, and go easy with the ivermectin.
5. Food and drink affects ivermectin absorption, but not in consistent ways.
(a) Alcohol may increase the absorption of ivermectin.
(b) Fruit juice may decrease the absorption of ivermectin.
(c) A fatty meal may increase the absorption of ivermectin.
If you have chosen to take a liquid or paste formulation of ivermectin, avoid taking it with alcohol, fruit juice, or a fatty meal. What is already a gamble becomes a bigger risk when these other influences are in play.
6. The pharmacokinetics of ivermectin have not been studied in people with impaired liver or kidney function, nor in people aged 65 years and older.
As ivermectin is primarily metabolised by the liver and eliminated in the faeces (stool, 'poop'), patients with impaired liver function should probably be especially careful with this drug.
Merck issues this warning in the package insert for their Australian product: "Clinical studies of [their ivermectin tablets] did not include sufficient numbers of elderly subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, treatment of elderly patients should be cautious, reflecting the greater frequency of decreased hepatic [liver], renal [kidney] or cardiac [heart] function, and of concomitant disease or other drug therapy.
If you have chosen to take a liquid or paste formulation of ivermectin and your liver is impaired or if you are over 65 years of age, it may be safest to use a lower dose and a longer interval between doses than the one(s) advised by the doctors who are using the human formulation of ivermectin for the prevention and treatment of COVID-19.
We still don't know enough about this drug as an antiviral agent, and optimal dosage (dose and dosing interval) is one important aspect that we are still exploring. In the meantime, the precautionary principle seems prudent: proceed with caution or don't do it at all if there is significant potential for harm.