23 | 07 | 2014
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IVERMECTIN: SAFETY SUMMARY for VETERINARY use on Dogs, Cats, Cattle, Sheep, Goats, Swine and Poultry. Poisoning, intoxication, overdose, antidote

IVERMECTIN: Safety Summary for Veterinary Use

WHO Acute Hazard classification: Not listed


Mechanism of Action of Ivermectin

As all macrocyclic lactones, ivermectin acts as agonist of the GABA (gamma-aminobutyric acid) neurotransmitter in nerve cells and also binds to glutamate-gated chloride channels in nerve and muscle cells of invertebrates. In both cases it blocks the transmission of neuronal signals of the parasites, which are paralyzed and expelled out of the body, or they starve. It also affects the reproduction of some parasites by diminishing oviposition or inducing an abnormal oogenesis.

In mammals the GABA receptors occur only in the central nervous system (CNS), i.e. in the brain and the spinal chord. But mammals have a so-called blood-brain barrier that prevents microscopic objects and large molecules to get into the brain. Consequently macrocyclic lactones are much less toxic to mammals than to parasites without such a barrier, which allows quite high safety margins for use on livestock and pets. A notable exception to this are dog breeds that carry the MDR-1 gene defect (see later).


Acute Toxicity of Ivermectin

  • LD50 acute, mice, p.o. 25 mg/kg
  • LD50 acute, rat, p.o. 50 mg/kg
  • LD50 acute, rat: dermal >600 mg/kg
  • LD50 acute, dog without MDR-1 gene defect: p.o. 80 mg/kg
  • LD50 acute, dog with MDR-1 gene defect:  p.o. 0.2 mg/kg


Ivermectin Tolerance

Dogs without MDR-1 gene defect

  • Safety margin: ~4
  • After single dose delivery, oral
    • 2.0 mg/kg: usually without neurotoxic symptoms
    • 2.5 mg/kg: mydriasis (dilatation of the pupils)
    • 5.0 mg/kg: mydriasis, tremor (uncoordinated trembling or shaking movements)
    • 10 mg/kg: mydriasis, serious tremor, ataxia (uncoordinated movements)
    • 40 mg/kg: coma (persistence unconsciousness), death possible
  • Daily oral administration during 14 days
    • 0.5 mg/kg/day: usually without symptoms
    • 1.0 mg/kg/day: mydriasis (dilatation of the pupils)
  • Single subcutaneous injection
    • 4.7 mg/kg: mydriasis (dilatation of the pupils), salivation
    • 9.7 mg/kg: ataxia (uncoordinated movements), depression, death

Dogs with MDR-1 gene defect

  • Lowest single oral dose without symptoms: 0.06 mg/kg (= 60 mcg/kg)
  • Doses > 0.1 mg/kg (= 100 mcg/kg) cause massive neurological symptoms: mydriasis (dilatation of the pupils), tremor (uncoordinated trembling or shaking movements), ataxia (uncoordinated movements), vomit
  • Doses > 0.15 mg/kg (= 150 mcg/kg) cause comatose state and possible death

Cats

  • Cats, including exotic breeds (e.g. Siamese, Persian) usually tolerate well doses up to 1 mg/kg. But cat intoxications have also been reported.
  • Oral pastes for horses are not recommended at > 0.5 mg/kg.

Cattle

  • Cattle tolerate ivermectin very well.
  • The therapeutic margin or index is ~30.
  • Well tolerated doses:
    • Single subcutaneous injection: up to 6 mg/kg
    • Single oral administration: up to 2 mg/kg
    • Daily oral administration: up to 1.2 mg/kg x 3 days
  • Doses that cause neurological symptoms:
    • Single oral dose: 4 mg/kg
    • Single subcutaneous injection: 8 mg/kg

Sheep

  • Sheep tolerate ivermectin very well.
  • The safety margin is ~30.
  • Doses of up to 4.0 mg/kg do not cause clinical symptoms.

Swine

  • Swine tolerate ivermectin very well.
  • Doses 10 a 50 times higher than the therapeutic dose of 0.3 mg/kg (single subcutaneous injection) caused no toxic symptoms.
  • A single subcutaneous injection of 30 mg/kg (100 times the therapeutic dose) causes lethargy, ataxia (uncoordinated movements), mydriasis (dilatation of the pupils) and tremor (uncoordinated trembling or shaking movements).

Horses

  • Horses tolerate ivermectin very well.
  • The safety margin is ~10.
  • Orals doses  of 1.2 and 1.8 mg/kg were well tolerated.
  • Oral doses of 2 mg/kg during 2 consecutive days causes slight ataxia (uncoordinated movements), depression and apparent blindness. 
  • Oral doses from 3 to 6 mg/kg (15 to 30 x the therapeutic dose of 0.2 mg/kg) caused mydriasis (dilatation of the pupils) and loss of ocular reflexes.

Birds

  • Most poultry species tolerate ivermectin quite well.
  • However, some birds (parakeets, parrots, canaries, finches, etc.) do not tolerate ivermectin. Ivermectin spot-ons are particularly dangerous.

Toxic Symptoms caused by Ivermectin Poisoning

General symptoms

  • The symptoms of ivermectin poisoning are the consequence of an excessive concentration of the molecule in the CNS (Central Nervous System) and the subsequent increase of GABA activity. Ivermectin stimulates the release of the GABA neurotransmitter (gamma-Aminobutyric acid) in the presynaptic neurons and enhances its postsynaptic binding to its receptors. This increases the flow of chloride ions in the neurons, which causes hyperpolarization of the cell membranes. This on its turn disturbs normal nervous functions and causes a general blockage of the stimulus mechanisms in the CNS. The resulting cerebral and cortical deficits include mainly
    • Ataxia (uncoordinated movements)
    • Hypermetria (excessive or disproportionate movements)
    • Disorientation
    • Hyperesthesia (excessive reaction to tactile stimuli)
    • Tremor (uncoordinated trembling or shaking movements)
    • Mydriasis (dilatation of the pupils); in cattle and cats also myosis (contraction of the pupils)
    • Recumbency (inability to rise)
    • Depression
    • Blindness
    • Coma (persistence unconsciousness)
  • As a general rule, young animals are more sensitive to overdosing, react stronger and prognosis is worse than for adult animals. 
  • Besides erroneous dosing, overdosing can occur due to excessive licking after pour-on delivery to livestock (usually licking of other animals in the same herd) or spot-on delivery to dogs and cats (particularly in cats due to intense grooming).
  • Frequent administration errors in livestock include intramuscular or intravenous instead of subcutaneous injection. This results in excessive blood levels. Another frequent error is repeated unintended treatment in short intervals due to animal mistaking.
  • A frequent administration error in dogs is partial administrating to small dogs of tablets or spot-ons approved for large animals.
  • A frequent administration error in cats is partial administration to cats of tablets or spot-ons approved only for dogs.

Poisoning Symptoms in Dogs

  • In dogs without the MDR-1 gene defect, the dominant poisoning symptom is extreme mydriasis (dilatation of the pupils) together with incomplete and deregulated pupillary reflex. Mydriasis in both eyes is the most sensitive indicator of ivermectin intoxication and the most frequent symptom in dogs. 
  • At higher doses and in dogs with the MDR-1 gene defect other symptoms have been observed as well: weakness, lethargy, hypothermia (too low body temperature), hypersalivation (drooling), vomit, difficult breathing, behavioral disturbances, confusion, seizure, death.
  • Symptoms develop usually 5 to 24 hours after treatment and can last for several days until coma. As a general rule, poisoning is more serious and prognosis is worse if the symptoms develop faster.

Poisoning Symptoms in Cats

  • Poisoning symptoms in cats resemble those in dogs. Additional symptoms reported are diarrhea, anorexia (lack of appetite), posterior paralysis, disturbed or lacking reflexes.
  • As a general rule neurological symptoms in cats tend to recede in the days following poisoning and most cats recover within 2 to 4 weeks.

Poisoning Symptoms in Cattle

  • Most frequent symptoms in cattle are general depression of the CNS (Central Nervous System), including deafness and ataxia (uncoordinated movements).
  • Calves can show poisoning symptoms at doses only 3 x the therapeutic dose. They include ataxia (uncoordinated movements), hypermetria (excessive or disproportionate movements) and tremor (uncoordinated trembling or shaking movements). Colics have also been reported. Deaths cannot be excluded.

Poisoning Symptoms in Sheep, Swine, Goats and Horses

  • Those general symptoms previously described.

Birds

  • In birds intoxicated with ivermectin lethargy and anorexia (lack of appetite) have been reported.

Ivermectin Side Effects, Adverse Drug Reactions (ADRs) and Warnings

  • Due to lack of data and the higher susceptibility in young animals it is advisable not to administer cattle and horses younger than 4 months, as well as puppies and kittens younger than 6 weeks.
  • Due to lack of date it is also advisable not to administer ivermectin to pregnant sows before the 40th day of gestation, and to pregnant mares before the 45th day of gestation.
  • After ivermectin injection a painful and rather large swelling may develop at the injection site. It usually recedes in a few days.
  • In horses, the risk of Chlostridium infection after injection is particularly high. If left untreated such infections are fatal. However it is not related to ivermectin, but to the use of contaminated needles. For this reason in most countries ivermectin for horses is usually available only as oral paste and not as an injectable.
  • In dogs and cats administration of spot-ons can cause a reversible skin irritation. Alopecia (hair loss) and squamation (appearance of skin scales) have also been reported.
  • Never use spot-ons or tablets for dogs on cats, and never use spot-ons or tablets for large dogs on small dogs. It happens that some users want to save money buying large tablets or spot-ons for treating smaller dogs (or even cats!) twice or more times. The risk of overdosing is considerable, either due to erroneous calculations or to unskilled manipulation. In addition, dog medicines may sometimes contain ingredients that are toxic to cats.
  • WARNING: Dogs of some breeds do not tolerate ivermectin, other macrocyclic lactones or other drugs (e.g. emodepside) that can cross the blood-brain barrier. They can suffer more or less serious adverse effects if treated at dose rates slightly higher than the recommended ones. Consequently dosing must be as accurate as possible. This is the case for Collies and related breeds, which have a mutation in the MDR-1 gene that affects the blood-brain barrier and makes it more permeable to such compounds than in dogs without this mutation. Besides Collies, other dog breeds have shown similar problems, although the MDR-1 mutation has not been confirmed in all of them. The breeds more affected by this mutation are (% frequency): Collie (70%), Long-haired Whippet (65%), Australian Shepherd (50%, also mini),  McNab (30%), Silken Windhound (30%), English Shepherd (15%), Shetland Sheepdog (15%), English Shepherd (15%), German Shepherd (10%), Herding Breed Cross (10%). Other less affected breeds are: Old English Sheepdog, Border Collie, Berger Blanc Suisse, Bobtail, Wäller. The only way to be sure that a dog is affected or not is to test for it. As more dogs are tested it is likely that the mutation is discovered in other breeds, or that the frequencies change.
  • Complications in dogs, cats and horses due to Dirofilariasis
    • Most products with ivermectin and other macrocyclic lactones are effective against heartworm larvae in the blood. Heartworm infection (Dirofilaria spp) is a common disease in dogs in regions with hot or mild weather. The disease is called dirofilariasis and is transmitted by mosquitoes. It is less frequent in cold regions but can occur there as well. Cats and horses can be affected too. Heartworm preventatives hinder larvae (microfilariae) in the pet's blood to develop to adult worms. The sudden death of microfilariae releases enormous amounts of allergens that can cause an allergic shock. The following symptoms may develop about 5 hours after treatment: pale mucosae, tachypnea (rapid breathing), dispnea (difficult breathing), vomit, weak and accelerated pulse, weakness, fever and ataxia (uncoordinated movements). Therapy requires shock treatment, including administration of corticosteroids and fluid supply.
    • Another possible complication is that treatment at the therapeutic dose against microfilariae can also kill some adult worms, if not all. Now, dead adult worms or their rests in the heart or in the pulmonary artery can physically obstruct the pulmonary blood vessels with the consequent damage to the lungs, which can be fatal. This means that any dog that is treated with a macrocyclic lactone should be checked for already existing heartworm infection. If the check is positive, the heartworm infection has to be treated with other specific heartworm products under strict supervision of a veterinary doctor.
  • It has been reported that off-label administration of micellar formulations of ivermectin can cause anaphylactic reactions in dogs. Ivermectin is not the cause of such reactions but polysorbate 80 (= Tween 80) one of the formulation ingredients.
  • In horses, allergic reactions with ventral midline pruritus (=itching) and edema (swelling) are often reported. They are mostly due to the sudden death of microfilariae of Onchocerca spp after treatment. Left untreated swelling recedes in 5 to 10 days and itching in about 3 weeks.
  • Unless prescribed by a veterinary doctor, never use on dogs or cats products for livestock that are not explicitly approved for such use. There is a high risk of overdosing or of adverse drug reactions due to ingredients that are not tolerated by pets or are even toxic to them.

Antidote and Treatment of Ivermectin Intoxication

  • There is no antidote for ivermectin poisoning.
  • Treatment consists in supportive and symptomatic measures.
  • Most patients recover in 7 to 10 days, but recovery of comatose patients usually needs longer.

Possible measures for dogs (application to other animals is left at the discretion of the veterinary doctor)

  • Administration of supplemental electrolytic solutions (intravenously if required)
  • Keeping the animals warm
  • Frequent turning of recumbent patients
  • Corneal protection with adequate ocular ointment
  • Artificial feeding (intravenous or with feeding tube)
  • Mechanical respiration in case of severe breathing disturbance.
  • If intoxication followed oral administration induce vomiting, gastric lavage, and charcoal administration are often indicated.
  • In case of bradycardia (low resting heart rate) administration of glycopyrrolate (0,01 mg/kg s.c.). Glycopyrrolate is a muscarinic antagonist. It is preferred over atropine because it does not cross the blood-brain barrier.
  • Physostigmine improves the condition of affected dogs very quickly, already 1 minute after injection of 1 mg. It is a reversible acetylcholinestrase inhibitor but is not an ivermectin antidote and must not be the only measure for treating ivermectin intoxication. It is unclear whether daily physostigmine treatments accelerate recovery. But it is very useful to confirm diagnosis and helps encouraging dog owners to continue the therapy of their intoxicated dogs. Recommended dose is 40 mcg/kg/day i.v. (administered every 12 hours). Warning: do not administer to dogs with only slight symptoms because it can enhance tremor and ataxia. To avoid bradycardia and other side effects, treatment with glycopyrrolate before physostigmine administration is advisable.
  • Picrotoxine, a GABA antagonist, has also been used for treating ivermectin intoxications. However, it caused severe side effects and it has a very narrow safety margin.
  • Intravenous lipid infusions have been used in human medicine to treat bupivacaine intoxications. They have been tried on ivermectin-intoxicated dogs, but little is still known regarding their efficacy and safety. It is postulated that they help extracting the toxic compound from contaminated tissues.

Pharmacokinetics of Ivermectin

Ivermectin is a rather lipophilic molecule. Regardless of the delivery form (topical, oral or injection) it is well absorbed into blood and distributed throughout the host's organism. It tends to be deposited in the body fat and the liver, from where it is progressively released and metabolized. The pharmacokinetic behavior varies for each species and depends strongly on the delivery form and the formulation. 

Absorption into blood in cattle and sheep after subcutaneous injection varies with the vehicle. After injection with a lipophilic vehicle absorption is slower than with a hydrophilic one and persistence in the organism is longer. But the blood peak reached is also lower. After oral administration (e.g. drench), absorption into blood is significantly faster, the maximum concentration achieved in blood is also higher, and it is reached earlier than after injection. The consequence is also a shorter residual effect than after injection. In cats and dogs absorption after injection is usually faster than on ruminants.

In the last years so-called long-acting (LA) injectable formulations of ivermectin (or other macrocyclic lactones) have been introduced for ruminants in many countries (e.g. Latin America). They are now very popular and have vastly replaced the slow-release boluses. Many brands contain 3,15% ivermectin, other brands slightly less or even more (up to 4%). The usual dose is 630 mcg/kg bw (instead of 200 mcg/kg bw for the classic 1% formulation). The pharmacokinetic behavior of such LA formulations is similar to the classic 1% formulation. However, the massive higher dose substantially prolongs the residual effect against most parasites, and the higher blood peaks allow higher efficacy against several parasites than the 1% formulation.

After oral administration (mainly to sheep and goats) the type and amount of feed can influence ivermectin's bioavailability. Blood concentrations achieved are lower in grazing sheep than in those fed on hay or concentrate. It is known that ivermectin and its metabolites bind strongly to food particles in the stomach. And food type can significantly influence the time that feed remains in the rumen of ruminants before passing to the abomasum. The faster the food leaves the rumen, the shorter and lower is the absorption. It has been determined that a 50% reduction of food 36 hours prior to and after drenching increases bioavailability of orally administered ivermectin in sheep by about 50%, because it prolongs the time that food remains in the rumen.

Distribution of ivermectin to all organs and most body fluids is sufficient to achieve effective concentrations against the major parasites after oral, injectable and topical administration. Highest tissue residues are detected in body fat and liver.

Excretion of ivermectin is independent from the delivery form and is achieved to >90% through bile and feces. Only about 2% is excreted through urine. About 45% of the eliminated ivermectin is the parent molecule and the rest are various metabolites. Excretion in goats is significantly faster than in sheep. In sheep it takes about 11 days for ivermectin to drop below the detectable level in blood, whereas in goats this level is reached 4 to 5 days after administration.

Withholding periods for meat vary for each host, delivery form and dosage and are between 3 and 7 weeks for the usual dose (200-300 mcg/kg bw after injection; 500 mcg/kg after pour-on administration). For the LA injectables the withholding period is usually about 4 months. Surprisingly, exactly the same formulation at the same dose and for the same target animal may have significantly different withholding periods in different countries: unfortunately regulatory authorities do not follow the same safety standards everywhere.

In lactating animals about 5% of the administered dose is excreted though the milk. It can be detected in milk already 12 hours after administration. Peak concentrations are achieved aprox. 2 days after administration. Residues in milk remain detectable during aprox. 18 days (after the usual dose of 200 mcg/kg). This is why ivermectin is usually not approved for use on dairy animals whose milk is intended for human consumption.

Injectable formulations of ivermectin are not used on horses. The reason is apparently that, shortly after introduction, it was noticed that horses were more prone to develop severe clostridial infections at the injection site (due to contamination of the needles) and other undesired side effects than cattle or sheep. In addition, the pharmacokinetic behavior of ivermectin on horses is different than in ruminants. For these reasons oral pastes were developed for horses that do not show such side effects.


Environmental Toxicity of Ivermectin

  • Ivermectin is highly toxic to fish and extremely toxic to invertebrates. For this reason disposal of ivermectin residues (e.g. in empty containers) in watercourses must be absolutely avoided. There is a certain environmental risk of water pollution from run-off after pour-on administration to large cattle herds. However this risk is substantially lower than the one associated with the use of ivermectin as a crop pesticide.
  • Ivermectin binds strongly to soil particles and is unlikely to contaminate groundwater.
  • Degradation in soil depends on soil type and structure, but also on temperature. At high summer temperatures it is degraded in 1 to 2 weeks, but it can persist for up to one year at low temperatures.
  • Sunlight quickly degrades ivermectin solved in water. Half-life in clear and calm water oscillates between 12 and 40 hours.
  • Ivermectin administered to livestock is partially excreted in the feces and has a negative impact on coprophagous invertebrates (fly larvae, dung beetles, etc.) that feed or breed on dung of cattle or other livestock. Ivermectin in dung kills some invertebrates and/or hampers their development or fertility. However, it has not been demonstrated that it prevents normal dung decomposition and recycling. After decades of massive worldwide use in the livestock industry and numerous investigations, there are no reports on significant environmental problems associated with unrecycled livestock dung after ivermectin use.

Additional Information

  • Ivermectin belongs to the chemical class of the macrocyclic lactones.
  • Ivermectin is used in human medicines against human parasites.
  • Ivermectin is used in crop pesticides.
  • Ivermectin is used as a biocide in public and domestic hygiene.
  • Click here for technical and commercial information on ivermectin.

WARNING

If you intend to use a veterinary drug containing this active ingredient you must carefully read and follow the safety instructions in the product label.  Always ask your veterinary doctor, or pharmacist, or contact the manufacturer. Be aware that the safety instructions for the same veterinary medicine may vary from country to country.

The information in this page must not be confused with the Materials and Safety Datasheets (MSDS) officially issued by manufacturers for active ingredients and many other chemicals. MSDSs target safety during manufacturing, transport, storage and handling of such materials. This safety summary is a complement to the information on product labels and MSDS.

The toxicity of an active ingredient must not be confused with the toxicity of finished products, in this case parasiticidal drugs or pesticides. Finished products contain one or more active ingredients, but also other ingredients that can be relevant from the safety point of view.

All information in this site is made available in good faith and following a reasonable effort to ensure its correctness and actuality. Nevertheless, no this regarding guarantee is given, and any liability on its accuracy, integrity, sufficiency, actuality and opportunity is denied. Liability is also denied for any possible damage or harm to persons, animals or any other goods that could follow the transmission or use of the information, data or recommendations in this site by any site visitor or third parties.

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