WHO Acute Hazard classification: Not listed

Mechanism of Action of Selamectin

As all macrocyclic lactones, selamectin 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 Selamectin

• LD50 acute, rat, p.o. >1600 mg/kg
• LD50 acute, mice, p.o. >1600 mg/kg
• Mice treated at 100 mg/kg showed a slightly higher respiratory rate and muscular weakness, reversible after 24 hours. Other mice treated at 300 mg/kg showed also ptosis (drooping or falling of the eyelids) and piloerection (bristling of hairs) during 24 hours.
• In one study ivermectin-sensitive Collies treated orally with selamectin at 15 mg/kg (1.2x to 2.1x the therapeutic dose) showed no adverse drug reactions excepting ataxia (uncoordinated movements) in one animal. In another study, 3 topical monthly treatments (spot-on) at 1x, 3x and 5x the therapeutic dose (6 mg/kg) caused no adverse drug reactions excepting sporadic and transitory salivation (drooling).
  
• As a general rule, selamectin has a higher therapeutic index that ivermectin and can be used in dogs with the MDR-1 gene defect without side effects. Ivermectin-sensitive dogs tolerated up to 5x the therapeutic dose of selamectin without side effects.
  
• Cats infected with Dirofilaria immitis (heartworm) treated monthly at 4x the therapeutic dose during 6 months tolerated treatment very well. In another study male cats treated 16-17 times every 2 weeks at 3x the therapeutic dose didn't suffer any detrimental effect on their health or reproduction.

Toxic Symptoms caused by Selamectin Poisoning

General symptoms

• The symptoms of selamectin poisoning are similar to those of ivermectin poisoning and are the consequence of an excessive concentration of the molecule in the CNS (Central Nervous System) and the subsequent increase of GABA activity. Moxidectin 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. 
• Besides erroneous dosing, overdosing can occur due to excessive licking after spot-on delivery to dogs and cats (particularly in cats due to intense grooming).
• A frequent administration error in dogs is erroneous partial administration to small dogs of spot-ons approved for large dogs.
• A frequent administration error in cats is erroneous partial administration to cats of spot-ons 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. 
• The most frequent symptoms observed after selamectin overdose include salivation (drooling), vomit, diarrhea, loss of appetite, slight tremor (uncoordinated trembling or shaking movements) and lethargy. 

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

• Never use spot-ons for dogs in cats, and never use spot-ons for large dogs in small dogs. It happens that some users want to save money buying large 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 are sensitive to selamectin, 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)
  
• Selamectin 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 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 Selamectin Intoxication

• There is no antidote for selamectin 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 Selamectin

In dogs, after topical spot-on administration selamectin spreads rapidly through the dogs hair-coat within the first 24 hours. Only a small part of the administered dose is absorbed through the skin into the bloodstream. Highest blood levels are achieved about 70 hours after administration. In cats the amount absorbed into blood is significantly higher, probably due to the thinner cat skin and to oral intake after grooming. As a consequence, bioavailability is much higher in cats (~75%) than in dogs (~5%).

Excretion runs faster in dogs than in cats. In both dogs and cats, most selamectin is excreted through feces and only a small amount through urine, mostly in the form of the parent molecule.

Environmental Toxicity of Selamectin

• Selamectin is toxic to fish and aquatic invertebrates.
• 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 selamectin is very low.

Additional information

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

• Selamectin belongs to the chemical class of the macrocyclic lactones.
• Selamectin is not used in livestock
• Selamectin is not used in human medicine.
• Selamectin is not used in crop pesticides.
• Selamectin is not used as a biocide in 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 for technical and commercial information on selamectin.