WHO Acute Hazard classification: Not listed

Mechanism of Action of Milbemycin Oxime

As all macrocyclic lactones, milbemycin oxime 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).

Toxicity and Tolerance of Milbemycin Oxime

  • LD50 acute in rats: p.o. 980 mg/kg
  • LD50 acute in mice: p.o. 300 mg/kg
  • LD50 acute in dogs: p.o. >200 mg/kg
  • Dogs not sensitive to ivermectin (i.e. without the MDR-1 gene defect) tolerate an oral dose of 2.5 mg/kg milbemycin oxime on 3 consecutive days, repeated during 10 months without undesirable side effects.
  • In one study, 8 weeks-old puppies tolerated oral dose 8x the therapeutic dose during 3 consecutive days without toxicity symptoms. In another study in puppies, a single oral dose of 2.5 mg/kg resulted in slight intoxication symptoms
  • As a general rule, milbemycin oxime has a higher therapeutic margin than ivermectin and can be used in dogs with the MDR-1 gene defect at the therapeutic dose with low risk of adverse drug reactions.

Toxic Symptoms caused by Milbemycin Oxime

General symptoms

  • The symptoms of milbemycin oxime poisoning are similar to those of ivermectin and other macrocyclic lactones. They are the consequence of an excessive concentration of the molecule in the CNS (Central Nervous System) and the subsequent increase of GABA activity. Milbemycin oxime 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)
    • 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. 
  • A frequent administration error in dogs that may lead to overdosing is erroneous partial administration to small dogs of tablets approved for large dogs.
  • A frequent administration error in cats is erroneous partial administration to cats of tablets approved only for dogs.

Poisoning Symptoms in Dogs

  • In dogs without the MDR-1 gene defect, the dominant macrocyclic lactone 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 and other macrocyclic lactone intoxication, and the most frequent symptom in dogs. 
  • In dogs with the MDR-1 gene defect treated with milbemycin oxime at oral doses of 5 to 10 mg/kg (10x to 20x the therapeutic dose) several symptoms of ivermectin sensibility were observed (these symptoms appear already with ivermectin at a dose >0.120 mg/kg): depression, ataxia (uncoordinated movements), mydriasis (dilatation of the pupils), hypersalivation (drooling). The animals recovered completely within 2 days.
  • These symptoms can appear in dogs not sensitive to ivermectin or in cats after accidental massive overdose with milbemycin oxime.

Milbemycin Oxime Side Effects, Adverse Drug Reactions (ADRs) and Warnings

  • At high therapeutic doses transient tremor (uncoordinated trembling or shaking movements), ataxia (uncoordinated movements) and stupor (daze) have been observed.
  • Do not use tablets for dogs in cats, and never use tablets for large dogs in small dogs. It happens that some users want to save money buying tablets for large dogs 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 are sensitive to milbemycin oxime, 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 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 by the MDR-1 gene defect 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 due to Dirofilariasis (heartworm infection)
    • Milbemycin oxime 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, particularly by hot and warm weather during the mosquito season. Cats 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 remains 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.

Antidote and Treatment of Milbemycin Oxime Intoxication

  • There is no antidote for milbemycin oxime poisoning.
  • Treatment consists in supportive and symptomatic measures.
  • It can be helpful to read the safety summary for ivermectin, the most used macrocyclic lactone.

Pharmacokinetics of Milbemycin Oxime

After oral administration to dogs milbemycin oxime is quickly and almost completely absorbed. Peak plasma concentration is reached 2 to 4 hours later, and subsequently declines with a half-life of 1-3 days. Bioavailability is about 80%.

In rats, metabolism seems to be complete, since unchanged milbemycin oxime was not found in urine or feces. High concentrations of milbemycin oxime are found in the liver and in body fat.

As a general rule, due to a different pharmacokinetic behavior the anthelmintic effect is longer for milbemycin oxime than for ivermectin, although this strongly depends on the delivery form and the administered dose.

Environmental Toxicity of Milbemycin Oxime

  • Not being used on livestock, agriculture or public hygiene, there are no thorough studies on its environmental impact. Nevertheless, it can be assumed that correctly used in dogs and cats the risk of environmental pollution due to milbemycin oxime is very low.

Additional information

Click here for a list and overview of all safety summaries of antiparasitic active ingredients in this site.

  • Milbemycin oxime belongs to the chemical class of the macrocyclic lactones.
  • Milbemycin oxime is not used in livestock
  • Milbemycin oxime is not used in human medicines.
  • Milbemycin oxime is not used in crop pesticides.
  • Milbemycin oxime is not used in biocides for public or domestic hygiene.
  • Click here for General safety of antiparasitics for domestic animals.
  • Click here for General safety of antiparasitics for humans.
  • Click here for General safety of antiparasitics for the environment.
  • Click here here for technical and commercial information on milbemycin oxime.


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.

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