Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) 22,23-dihydroavermectin-B1A (H2B1A)
2) Avermectin B1A
3) Mectizan
4) MK-933
5) CAS 70288-86-7

1) MK-0936
2) CAS 65195-55-3 (component B(1a))
3) CAS 65195-56-4 (component B(1b))

1) UK-67994
2) CAS 117704-25-3

1) EMEMECTIN

1) Eprinomectina
2) Eprinomectine
3) MK-397
4) CAS 159628-36-1 (eprinomectin)
5) CAS 123997-26-2 (eprinomectin)
6) CAS 133305-88-1 (component B(1a))
7) CAS 133305-89-2 (component B(1b))

1) MELBEMECTIN

1) Milbemycins
2) CAS 113507-06-5

1) Revolution(R)
2) (5Z,25S)-25-cyclohexyl- 4'-O-de(2,6-dideoxy-3
3) -O-methyl-a-L-arabino-hexopyranosyl)-5-
4) demethoxy-25-de(1-methylpropyl)-22,
5) 23-dihydro-5-hydroxyiminoavermectin A1a

Available Forms Sources

A)

1) IVERMECTIN

a) Soolantra(TM): 1% cream in 30 g, 45 g, and 60 g tubes (Prod Info SOOLANTRA(TM) topical cream, 2014).
b) Sklice(TM): 0.5 topical lotion (Prod Info SKLICE(TM) topical lotion, 2012)
c) Stromectol(R): 3 mg oral tablets (Prod Info STROMECTOL(R) oral tablets, 2010)

2) MOXIDECTIN

a) Moxidectin is available in topical, oral and parenteral formulations. Moxidectin is a semisynthetic derivative of nemadectin (Bayer Animal Health, n.d.).

3) SELAMECTIN

a) Topical selamectin is available as a colorless to yellow, ready to use solution in single dose tubes (Prod Info Revolution(R), selamectin, 2001).

B)

1) The macrocyclic lactone (macrolide) antimicrobial class contains 2 closely related chemical groups, avermectins and milbemycins. These 2 chemical groups have a large complex macrocyclic backbone and have been produced by fermentation of soil dwelling fungal organisms (genus Streptomyces) (Bayer Animal Health, n.d.). Avermectins are used for the control of nematode and arthropod parasites.
2) IVERMECTIN: Ivermectin 0.5% topical lotion is indicated in patients 6 months of age and older for the topical treatment of head lice infestations (Prod Info SKLICE(TM) topical lotion, 2012). Oral ivermectin is indicated for the treatment of nondisseminated strongyloidiasis of the intestinal tract. It is also considered a drug of choice for the treatment of Onchocerciasis (river blindness), due to the non-adult stage of nematode parasite Onchocerca volvulus (Prod Info STROMECTOL(R) oral tablets, 2010). Ivermectin cream is used to treat inflammatory lesions of rosacea (Prod Info SOOLANTRA(TM) topical cream, 2014).
3) ABAMECTIN is an avermectin anthelmintic used for nematode infections. In addition, it is used as a systemic veterinary ectoparasiticide (S Sweetman , 2001).
4) DORAMECTIN is an avermectin anthelmintic used for nematode infections. In addition, it is used as a systemic veterinary ectoparasiticide (S Sweetman , 2001).
5) EPRINOMECTIN is an avermectin anthelmintic used for nematode infections. In addition, it is used as a systemic veterinary ectoparasiticide (S Sweetman , 2001).
6) MOXIDECTIN is a parasiticide given to animals (ie, dogs, cats, livestock, horses) for the prevention, treatment and/or control of parasites, such as heartworms. Moxidectin is from the milbemycin class, and is a semisynthetic derivative of nemadectin (Bayer Animal Health, n.d.).
7) SELAMECTIN is used for the prevention and control of flea infestations (Ctenocephalides felis), prevention of heartworm disease caused by Dirofilaria immitis, and the treatment and control of ear mite (Otodectes cynotis) infestations in dogs and cats. In addition, it is indicated for the treatment and control of sarcoptic mange (Sarcoptes scabiei) and for the control of tick (Dermacentor variabilis) infestations in dogs, and the treatment of intestinal hookworm (Ancylostoma tubaeforme) and roundworm (Toxocara cati) infections in cats (Prod Info Revolution(R), selamectin, 2001).

a) Selamectin is recommended for use in dogs and cats six weeks of age and older (Prod Info Revolution(R), selamectin, 2001).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Avermectins are macrocyclic lactones used for control of nematode and arthropod parasites. Ivermectin 0.5% topical lotion is used for the topical treatment of head lice infestations. Oral ivermectin is indicated for the treatment of nondisseminated strongyloidiasis of the intestinal tract and Onchocerciasis (river blindness), due to the non-adult stage of nematode parasite Onchocerca volvulus. Abamectin, doramectin, and eprinomectin are agricultural miticides and insecticides. Selamectin is a topical parasiticide. Moxidectin is a parasiticide given to animals (ie, dogs, cats, livestock, horses) for the prevention, treatment and/or control of parasites, such as heartworms. Moxidectin is from the milbemycin class, and is a semisynthetic derivative of nemadectin.
B) PHARMACOLOGY: The macrocyclic lactone (macrolide) antimicrobial class contains 2 closely related chemical groups, avermectins and milbemycins. These 2 chemical groups have a large complex macrocyclic backbone and have been produced by fermentation of soil dwelling fungal organisms (genus Streptomyces). Ivermectin is a semisynthetic antiparasitic drug and a member of the avermectin class. It binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of the microfilaria. This binding causes an increase in the permeability of the cell membrane to chloride ions and results in hyperpolarization of the cell, leading to paralysis and death of the parasite. Ivermectin also is believed to act as an agonist of the neurotransmitter gamma-aminobutyric acid (GABA), thereby disrupting GABA-mediated central nervous system (CNS) neurosynaptic transmission.
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE

1) Ivermectin is generally well-tolerated following therapeutic use. Pruritus and tachycardia have been reported.

E) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Rash, urticaria, pruritus, edema, headache, dizziness, somnolence, asthenia, nausea, vomiting, abdominal pain, diarrhea, and mild tachycardia have been reported.
2) SEVERE TOXICITY: In severe overdose, seizures, coma, aspiration pneumonia, metabolic acidosis, respiratory failure, and hypotension may develop.
3) DRUG INTERACTION: Ivermectin is thought to potentiate GABA activity. Other drugs, such as barbiturates, benzodiazepines and valproic acid, which also enhance GABA activity, may increase its toxicity.
4) ANIMAL STUDIES: In animals, high dose ivermectin may produce a CNS toxicosis consisting of tremors, ataxia, weakness, incoordination, recumbency, dehydration and coma.

0.2.20)

A) Ivermectin is classified as FDA pregnancy category C. In a study of pregnant women who received ivermectin, no adverse effects were observed. However, ivermectin has the potential for crossing the blood-brain barrier following high doses and causing CNS effects. In animal studies, ivermectin has resulted in cleft palate following doses at or near levels that are maternotoxic in mice, rats and rabbits. Ivermectin is excreted in breast milk at low concentrations. Breast milk concentrations were a mean of 14 nanograms/mL following administration of oral ivermectin to nursing mothers.

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg. Consider intravenous lipid emulsion in patients with dysrhythmias, hypotension or severe CNS toxicity secondary to ivermectin intoxication.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.

D) AIRWAY MANAGEMENT

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with respiratory or CNS depression or hemodynamic instability.

E) ANTIDOTE

1) None

F) FAT EMULSION

1) Limited data for ivermectin; animal information only. Patients who develop significant cardiovascular toxicity may be treated with intravenous lipids. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

G) ENHANCED ELIMINATION

1) Hemodialysis is unlikely to be of value because of the high degree of protein binding and large volume of distribution.

H) PATIENT DISPOSITION

1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with unstable vital signs, persistent seizures, coma, metabolic acidosis, or respiratory failure should also be admitted.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

I) PITFALLS

1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.

J) PHARMACOKINETICS

1) Ivermectin is absorbed orally, parenterally, and dermally. Tmax: 3 to 5 hours after oral dosing. Protein binding: approximately 93%. Vd: 46.9 L. Ivermectin and its metabolites are most likely excreted in the bile. Elimination half-life: oral, 10 to 18 hours (may be 1 to 4 days in various animal species).

K) DIFFERENTIAL DIAGNOSIS

1) Includes other chemicals or drugs that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), metabolic acidosis (eg, salicylates), or CNS depression (eg, toxic alcohols, benzodiazepines, opiates/opioids, antipsychotic medications). Diseases or exposures that produce acute respiratory distress (eg, inhalation of acid or alkaline mists, asthma, COPD).

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) Ivermectin is generally well-tolerated following therapeutic use. Pruritus and tachycardia have been reported.

E)

1) MILD TO MODERATE TOXICITY: Rash, urticaria, pruritus, edema, headache, dizziness, somnolence, asthenia, nausea, vomiting, abdominal pain, diarrhea, and mild tachycardia have been reported.
2) SEVERE TOXICITY: In severe overdose, seizures, coma, aspiration pneumonia, metabolic acidosis, respiratory failure, and hypotension may develop.
3) DRUG INTERACTION: Ivermectin is thought to potentiate GABA activity. Other drugs, such as barbiturates, benzodiazepines and valproic acid, which also enhance GABA activity, may increase its toxicity.
4) ANIMAL STUDIES: In animals, high dose ivermectin may produce a CNS toxicosis consisting of tremors, ataxia, weakness, incoordination, recumbency, dehydration and coma.

Vital Signs

3.3.3)

A) WITH THERAPEUTIC USE

1) FEVER has been reported during therapeutic use (Greene et al, 1985; (Rothova et al, 1989).

B) WITH POISONING/EXPOSURE

1) HYPOTHERMIA: A 16-month-old who ingested by 6.7 to 8.7 mg/kg developed a temperature of 35 degrees Celsius (Hall et al, 1985; Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) ANIMAL STUDIES: Mydriasis was reported in pharmacologic testing of dogs given 1 to 2 mg/kg/day (Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).
2) MYDRIASIS developed in one pupil of a child who accidentally ingested approximately 7 mg/kg (Hall et al, 1985; Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).
3) EYE IRRITATION: Ivermectin, accidentally sprayed into the eye of an adult, caused stinging, but no systemic symptoms or ocular sequelae were noted (Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985). Topical selamectin is irritating to eyes (Prod Info Revolution(R), selamectin, 2001).
4) VISUAL CHANGES: A 46-year-old man who was to receive 25 mg of oral ivermectin for Demadex folliculitis, presented with mental status and visual changes (blurred vision with black spots and flashing lights) after receiving an inadvertent single 200 mg oral dose (Graeme et al, 2000).

3.4.6)

A) WITH THERAPEUTIC USE

1) PHARYNGITIS: Sore throat was reported as an adverse effect of ivermectin (Kumaraswami et al, 1988).

Cardiovascular

3.5.2)

A) TACHYCARDIA

1) WITH THERAPEUTIC USE

a) Tachycardia was reported in 3.5% of adult patients who received 100 to 200 mcg/kg ivermectin (n=963) during clinical trials (Prod Info STROMECTOL(R) oral tablets, 2010).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Mild tachycardia (numbers not available) was reported in an overdose of a 15 kg child who ingested 100 to 130 mg ivermectin (Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985; Hall et al, 1985).

B) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) In clinical trials (n=963), orthostatic hypotension occurred in 1.1% of patients treated with 100 to 200 mcg/kg ivermectin. Orthostatic hypotension has also been reported in association with ivermectin therapy during postmarketing experience (Prod Info STROMECTOL(R) oral tablets, 2010).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Blood pressure readings for an overdose of 100 to 130 mg ivermectin in a 15 kg child were 40 to 100 mmHg (systolic) (Hall et al, 1985; Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).
b) CASE SERIES: In a series of 13 patients with avermectin toxicity, 3 presented with severe symptoms including hypotension, following ingestions of 1 gram ivermectin or 2.5 to 12.5 grams abamectin (mean = 6.9 grams). All patients recovered within 6 days (Chung et al, 1998).
c) CASE SERIES: In another series of 19 patients with avermectin exposure, 3 patients developed hypotension, all after deliberate ingestion (Chung et al, 1999).
d) CASE REPORT: A 25-year-old woman presented with altered mental status (Glasgow Coma Scale score of 6), tremor, and vomiting 3 hours after ingesting 108 mg/kg of abamectin in Akarmec Gold(R) (total abamectin concentration of 18 grams/L). Her blood pressure was 102/59 mmHg with a pulse rate of 64 bpm. The mean arterial blood pressure (calculated in the ICU) was less than 80 mmHg during the 24- to 48-hour period after ingestion. Following supportive treatment, she recovered completely without further sequelae (Soyuncu et al, 2007).

C) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: One study reported 13 patients with avermectin toxicity. Six of these patients presented with minor symptoms, including transient bradycardia following ingestions of 0.25 to 0.75 grams abamectin (mean, 0.5 grams) (Chung et al, 1998).

3.5.3)

A) ANIMAL STUDIES

1) LACK OF EFFECT

a) No hypotensive effects were reported during pharmacologic testing on dogs at doses of 0.5 mg/kg ivermectin IV (Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).

Respiratory

3.6.2)

A) COUGH

1) WITH THERAPEUTIC USE

a) Cough was reported in one study in humans (Kumaraswami et al, 1988).

B) ASPIRATION PNEUMONIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: In a case series of 13 avermectin poisonings, 2 patients presented with aspiration pneumonia with respiratory failure following the ingestion of either 1 gram ivermectin or 2.5 to 12.5 grams abamectin (mean, 6.9 grams). All patients recovered within 6 days (Chung et al, 1998).
b) CASE SERIES: In a series of 19 patients with avermectin exposure, 4developed aspiration pneumonia and respiratory failure, all after suicidal ingestion (Chung et al, 1999).
c) CASE REPORT: A 67-year-old man developed aspiration pneumonia after ingesting approximately 500 mL of Proclaim (Syngenta, Taiwan) containing 100 mL of an insecticide concentrate (2.15% w/w emamectin benzoate in 2, 6-bis (1, 1-dimethylethyl)-4-methyl-phenol and 1-hexanol) and 400 mL of tap water. Every 100 mL of the product contained 19.2 grams of emamectin benzoate per liter of formulation (25.6 mg/kg of emamectin benzoate). The chest radiograph showed a right lower-lung field infiltrate. Following supportive care, he recovered without further sequelae (Yen & Lin, 2004).

C) DYSPNEA

1) WITH POISONING/EXPOSURE

a) Dyspnea has been reported with ivermectin overdose (Prod Info Stromectol(R), ivermectin tablets, 1998).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 46-year-old man who was to receive 25 mg of oral ivermectin for Demadex folliculitis, presented with mental status changes (drowsy, weak, ataxic) and visual changes after receiving a single inadvertent 200 mg oral dose (Graeme et al, 2000).
b) Ataxia, asthenia, and paresthesia have been reported with overdose (Prod Info Stromectol(R), ivermectin tablets, 1998).

B) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Somnolence was reported after ingestion of 100 to 130 mg in a 15 kg child (Prod Info, 1985).
b) CASE REPORT: A 67-year-old man developed mild disturbance of consciousness after ingesting approximately 500 mL of Proclaim (Syngenta, Taiwan) containing 100 mL of an insecticide concentrate (2.15% w/w emamectin benzoate in 2, 6-bis (1, 1-dimethylethyl)-4-methyl-phenol and 1-hexanol) and 400 mL of tap water. Every 100 mL of the product contained 19.2 grams of emamectin benzoate per liter of formulation (25.6 mg/kg of emamectin benzoate). Following supportive care, he recovered without further sequelae (Yen & Lin, 2004).

C) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache has been reported with overdose (Prod Info Stromectol(R), ivermectin tablets, 1998) Greene et al, 1985; (Rothova et al, 1989).

D) DIZZINESS

1) WITH POISONING/EXPOSURE

a) Dizziness or light-headedness may occur following toxic exposures to avermectins (Prod Info Stromectol(R), ivermectin tablets, 1998; Kumaraswami et al, 1988; Chung et al, 1998).

E) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizure has been reported with overdose (Prod Info Stromectol(R), ivermectin tablets, 1998).

F) COMA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Chung et al (1998) reported a series of 13 patients with avermectin poisoning. Of these, 5 presented with coma following ingestion of either 1 gram ivermectin or 2.5 to 12.5 grams abamectin (mean, 6.9 grams) (Chung et al, 1998).
b) CASE SERIES: In a series of 19 patients with avermectin exposure, 7 developed severe toxicity with coma (Chung et al, 1999); all had ingested avermectin, 6 deliberately.
c) CASE REPORT: A 25-year-old woman presented with altered mental status (Glasgow Coma Scale score of 6), tremor, and vomiting 3 hours after ingesting 108 mg/kg of abamectin in Akarmec Gold(R) (total abamectin concentration of 18 grams /L). Her blood pressure was 102/59 mmHg with a pulse rate of 64 bpm. Physical examination showed decreased deep tendon reflexes and a bilateral diminished pupillary light reaction with pupil sizes of 3 mm. Following supportive treatment, she recovered completely without further sequelae (Soyuncu et al, 2007).

3.7.3)

A) ANIMAL STUDIES

1) TREMOR

a) Doses of 5 to 10 mg/kg produced ataxia and severe tremors in dogs. In pharmacologic testing, ivermectin was found to have anticonvulsant activity, but only above doses of 12.8 mg/kg (Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).
b) Treatment with 10 to 56 mg/kg ivermectin orally in mice produced dose-dependent signs and symptoms of toxicity over a 3 day period including tremors, ataxia, recumbency, dehydration, coma and death (Shoop et al, 1991).
c) Lewis et al (1994) report ivermectin toxicosis in a kitten treated with 0.3 mg/kg subcutaneous. Mild tremors, ataxia, weakness, incoordination, and miosis were observed 6 hours later. Within 12 hours the kitten became comatose with miotic pupils. The kitten received extensive supportive care but died 7 to 8 days after treatment with ivermectin (Lewis et al, 1994).

Gastrointestinal

3.8.2)

A) ABDOMINAL PAIN

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A woman who accidentally self-injected 200 mcg/kg ivermectin subcutaneously developed abdominal pain and nausea which cleared within 12 hours (Prod Info Stromectol(R), ivermectin tablets, 1998).
b) CASE REPORT: A 67-year-old man developed nausea, vomiting, and abdominal pain after ingesting approximately 500 mL of Proclaim (Syngenta, Taiwan) containing 100 mL of an insecticide concentrate (2.15% w/w emamectin benzoate in 2, 6-bis (1, 1-dimethylethyl)-4-methyl-phenol and 1-hexanol) and 400 mL of tap water. Every 100 mL of the product contained 19.2 grams of emamectin benzoate per liter of formulation (25.6 mg/kg of emamectin benzoate). Endoscopy revealed gastric erosion and superficial gastritis. Following supportive care, he recovered without further sequelae (Yen & Lin, 2004).

B) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and vomiting has been reported following toxic ingestions of avermectins (Chung et al, 1999; Prod Info Stromectol(R), ivermectin tablets, 1998; Chung et al, 1998), and abamectin (Soyuncu et al, 2007).
b) CASE REPORT: Frequent vomiting was reported in a 16-month-old boy who ingested 100 to 130 mg ivermectin (6.7 to 8.7 mg/kg) (Hall et al, 1985; Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).
c) CASE REPORT: A 67-year-old man developed nausea, vomiting, and abdominal pain after ingesting approximately 500 mL of Proclaim (Syngenta, Taiwan) containing 100 mL of an insecticide concentrate (2.15% w/w emamectin benzoate in 2, 6-bis (1, 1-dimethylethyl)-4-methyl-phenol and 1-hexanol) and 400 mL of tap water. Every 100 mL of the product contained 19.2 grams of emamectin benzoate per liter of formulation (25.6 mg/kg of emamectin benzoate). Endoscopy revealed gastric erosion and superficial gastritis. Following supportive care, he recovered without further sequelae (Yen & Lin, 2004).

C) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Diarrhea has been reported following toxic ingestion of ivermectin (Prod Info Stromectol(R), ivermectin tablets, 1998).

Acid-Base

3.11.2)

A) METABOLIC ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis has been reported in a few patients with severe poisoning after deliberate ingestion of avermectin. Other manifestations in these patients included coma, respiratory failure, and hypotension (Chung et al, 1999).

Hematologic

3.13.2)

A) PROTHROMBIN TIME LOW

1) WITH THERAPEUTIC USE

a) CASE REPORT: Prolonged prothrombin times and hematoma formation developed in two males 27 and 30 days, respectively, after single 150 mcg/kg oral doses (Homeida et al, 1988).
b) Whitworth et al (1992) conducted a double-blind placebo-controlled study measuring prothrombin ratios 13 to 16 days after ivermectin treatment in 148 patients. Prolonged prothrombin ratios occurred more frequently in ivermectin-treated patients than in placebo, but the difference was not clinically significant. No patient suffered bleeding complications. Some interference with vitamin K metabolism is suspected, however, ivermectin appears to have minimal effects on coagulation.

B) EOSINOPHIL COUNT RAISED

1) WITH THERAPEUTIC USE

a) A significant rise in the number of eosinophils occurred on days 8 to 10 following one 300 mcg/kg dose or one 400 mcg/kg dose in 31 adult subjects. At day 92 to 109 post-treatment, the mean eosinophil count was significantly lower than pre-treatment values. There were no significant differences between subjects with or without intestinal parasites (Martin-Prevel et al, 1993).

Dermatologic

3.14.2)

A) PALE COMPLEXION

1) WITH POISONING/EXPOSURE

a) Pallor was reported in one case where 6.7 to 8.7 mg/kg was ingested (Hall et al, 1985).

B) URTICARIA

1) WITH POISONING/EXPOSURE

a) Urticaria has been reported with overdose (Prod Info Stromectol(R), ivermectin tablets, 1998).

C) ERUPTION

1) WITH THERAPEUTIC USE

a) In one study, 60% of ivermectin treated patients experienced pruritus (Martin-Prevel et al, 1993).

2) WITH POISONING/EXPOSURE

a) Rash and pruritus have been observed following human overdose (Prod Info Stromectol(R), ivermectin tablets, 1998) Greene et al, 1985; (Aziz, 1986; Rothova et al, 1989).

3.14.3)

A) ANIMAL STUDIES

1) LACK OF EFFECT

a) Animal testing has shown ivermectin to be non-irritating to abraded or unabraded skin (Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).

Musculoskeletal

3.15.2)

A) JOINT PAIN

1) WITH THERAPEUTIC USE

a) Arthralgia, synovitis, and bone pain have been reported in human trials (Greene et al, 1985; (Rothova et al, 1989).

B) MUSCLE PAIN

1) WITH THERAPEUTIC USE

a) Myalgia was reported in one study (Kumaraswami et al, 1988).

Reproductive

3.20.1)

A) Ivermectin is classified as FDA pregnancy category C. In a study of pregnant women who received ivermectin, no adverse effects were observed. However, ivermectin has the potential for crossing the blood-brain barrier following high doses and causing CNS effects. In animal studies, ivermectin has resulted in cleft palate following doses at or near levels that are maternotoxic in mice, rats and rabbits. Ivermectin is excreted in breast milk at low concentrations. Breast milk concentrations were a mean of 14 nanograms/mL following administration of oral ivermectin to nursing mothers.

3.20.2)

A) CONGENITAL ANOMALY

1) In a randomized, open-label trial of pregnant women (n=832) who received either ivermectin (n=198), albendazole (n=194), or albendazole plus ivermectin (n=199) during the second trimester for soil-transmitted helminth (STH) infections and a reference group with no STH infections (n=241), no significant differences among the groups were reported for congenital abnormalities. Talipes equinovarus of the right foot was reported in 1 infant in the ivermectin group and talipes equinovarus of left foot, cleft palate and multiple fingers resulting in death were reported in 1 infant in the reference group (Ndyomugyenyi et al, 2008).

B) CENTRAL NERVOUS SYSTEM EFFECTS

1) Ivermectin has the potential for crossing the blood-brain barrier following high doses and causing central nervous system adverse effects including depression, tremors, ataxia, coma, and breathing difficulties (Burkhart & Burkhart, 1999).

C) LACK OF EFFECT

1) In a study of 203 pregnant women who received ivermectin as prophylaxis for onchocerciasis, no adverse effects were observed including developmental status (Pacque et al, 1990).

D) ANIMAL STUDIES

1) MICE, RATS, RABBITS: In animal studies, oral doses of ivermectin up to 1.6 mg/kg/day administered to pregnant female rats during organogenesis resulted in maternal death and cleft palate in groups with doses greater than or equal to 0.4 mg/kg/day. Exencephaly was also observed in the group administered 0.8 mg/kg/day. Administration of oral ivermectin doses up to 10 mg/kg/day in pregnant female rats during organogenesis also resulted in maternal death and cleft palate as well as preimplantation loss and wavy ribs in the 10 mg/kg/day group. Maternal toxicity, abortions, and cleft palate occurred in pregnant female rabbits administered ivermectin doses up to 6 mg/kg/day during organogenesis. Clubbed forepaws were also reported to occur in the fetuses exposed to ivermectin 3 or 6 mg/kg/day (Prod Info SKLICE(TM) topical lotion, 2012).
2) MICE, RATS, RABBITS - In animal studies, ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given in repeated doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively. Cleft palate was observed in mice, rats, and rabbits, and clubbed forepaws were observed in rabbits. These developmental effects were observed only at or near doses that were maternotoxic to the pregnant female (Prod Info STROMECTOL(R) oral tablets, 2008).

3.20.3)

A) PREGNANCY CATEGORY

1) The manufacturer has classified ivermectin as FDA pregnancy category C (Prod Info SKLICE(TM) topical lotion, 2012).

B) BIRTH PREMATURE

1) In a randomized, open-label trial of pregnant women (n=832) who received either ivermectin (group A; n=198), albendazole (group B; n=194), or albendazole plus ivermectin (group C; n=199) during the second trimester for soil-transmitted helminth (STH) infections and a reference group with no STH infections (group D; n=241), no significant differences among the groups were reported for premature deliveries. There were 9 (5.3%), 9 (5.6%), 8 (4.7%), and 10 (4.8%) premature deliveries in groups A, B, C, and D, respectively (p=0.98) (Ndyomugyenyi et al, 2008).

C) LOW BIRTH WEIGHT

1) In a randomized, open-label trial of pregnant women (n=832) who received either ivermectin (group A; n=198), albendazole (group B; n=194), or albendazole plus ivermectin (group C; n=199) during the second trimester for soil-transmitted helminth (STH) infections and a reference group with no STH infections (group D; n=241), no significant differences among the groups were reported for low birth weight (LBW). LBWs were reported in 9.4%, 11.3%, 12.3% and 7.7% of groups A, B, C, and D, respectively (p=0.47) (Ndyomugyenyi et al, 2008).

D) STILLBIRTH

1) In a randomized, open-label trial of pregnant women (n=832) who received either ivermectin (group A; n=198), albendazole (group B; n=194), or albendazole plus ivermectin (group C; n=199) during the second trimester for soil-transmitted helminth (STH) infections and a reference group with no STH infections (group D; n=241), stillbirths were reported in 1, 5, 3, and 1 infants in groups A, B, C, and D with no significant difference among the groups (p=0.13) (Ndyomugyenyi et al, 2008).

E) NEONATAL ANEMIA

1) In a randomized, open-label trial of pregnant women (n=832) who received either ivermectin (group A; n=198), albendazole (group B; n=194), or albendazole plus ivermectin (group C; n=199) during the second trimester for soil-transmitted helminth (STH) infections and a reference group with no STH infections (group D; n=241), no significant differences among the groups were reported for neonatal hemoglobin (Hb) levels or anemia. Neonatal anemia was reported in 10 (5.8%), 6 (3.8%), 6 (3.5%), and 9 (4.6%) infants in groups A, B, C, and D, respectively (p=0.73) (Ndyomugyenyi et al, 2008).

F) NEONATAL MORTALITY

1) In a randomized, open-label trial of pregnant women (n=832) who received either ivermectin (group A; n=198), albendazole (group B; n=194), or albendazole plus ivermectin (group C; n=199) during the second trimester for soil-transmitted helminth (STH) infections and a reference group with no STH infections (group D; n=241), no significant differences among the groups were reported for neonatal mortality. Neonatal mortality was reported in 6 (4.1%), 1 (0.7%), 2 (1.4%), and 5 (2.5%) infants in groups A, B, C, and D, respectively (p=0.23). Cause of death included respiratory tract infection (57.1%), prematurity-related death (21.4%), and gastroenteritis/vomiting (14.3%) (Ndyomugyenyi et al, 2008).

G) MATERNAL ANEMIA

1) In a randomized, open-label trial of pregnant women (n=832) who received either ivermectin (group A; n=198), albendazole (group B; n=194), or albendazole plus ivermectin (group C; n=199) during the second trimester for soil-transmitted helminth (STH) infections and a reference group with no STH infections (group D; n=241), no significant differences among the groups were reported for maternal or hemoglobin (Hb) levels or anemia. Maternal anemia was reported in 15 (10.9%), 12 (11.5%), 11 (7.7%), and 12 (6.9%) patients (p=0.4) (Ndyomugyenyi et al, 2008).

H) LACK OF EFFECT

1) During an open label study of 397 women, no differences in pregnancy outcomes were observed in women treated with ivermectin tablets and albendazole for soil-transmitted helminths during the second trimester of pregnancy when compared with untreated populations (Prod Info SKLICE(TM) topical lotion, 2012).
2) In a study of 203 pregnant women who received ivermectin as prophylaxis for onchocerciasis, no adverse effects were observed (Pacque et al, 1990).

3.20.4)

A) BREAST MILK

1) Ivermectin is excreted in breast milk at low concentrations (Prod Info SKLICE(TM) topical lotion, 2012; Prod Info STROMECTOL(R) oral tablets, 2008). Following administration of oral ivermectin 150 mcg/kg to nursing mothers, breast milk concentrations were a mean of 14 nanograms/mL, with the highest concentrations obtained within 4 to 12 hours in 4 of the mothers ( Ogbuokiri et al, 1993).

3.20.5)

A) ANIMAL STUDIES

1) RATS: Studies conducted in rats using repeated doses of ivermectin up to 3.6 mg/kg/day have shown no adverse effects on fertility (Prod Info SKLICE(TM) topical lotion, 2012).
2) RATS - Studies conducted in rats using repeated doses of ivermectin up to 3 times the maximum recommended human dose of 200 mcg/kg (on a mg/m(2) per day basis) have shown no adverse effects on fertility (Prod Info STROMECTOL(R) oral tablets, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) No specific laboratory tests are necessary in patients with mild overdose.
B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
C) Monitor vital signs and mental status following significant overdose. Monitor serum electrolytes, pulse oximetry and respiratory status in patients with severe overdose.
D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Methods

A)

1) High performance liquid chromatography may be used to identify ivermectin in biological tissues (Prod Info, 1985; (Njoo et al, 1995).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities. Patients with unstable vital signs, persistent seizures, coma, metabolic acidosis, or respiratory failure should also be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.

2) MANAGEMENT OF SEVERE TOXICITY

a) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg. Consider intravenous lipid emulsion in patients with dysrhythmias, hypotension or severe CNS toxicity secondary to ivermectin intoxication.

B) MONITORING OF PATIENT

1) No specific laboratory tests are necessary in patients with mild toxicity.
2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
3) Monitor vital signs and mental status following significant overdose.
4) Monitor serum electrolytes, pulse oximetry and respiratory status in patients with severe toxicity.
5) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

C) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

4) EPINEPHRINE: In a rat model of abamectin intoxication, epinephrine was effective in preventing abamectin induced hypotension and the increase in nitric oxide production associated with that hypotension (Hsu et al, 2003).

D) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

E) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.

F) FAT EMULSION

1) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015).
2) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011):

a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

3) ANIMAL DATA: A miniature Shetland Pony colt presented with acute onset of generalized seizures, followed by unconsciousness and recumbency 34 hours after receiving a massive (greater than 25-fold) overdose of deworming paste (140 mg ivermectin and 1.05 g praziquantel). Despite supportive care, no neurological improvement was observed. His neurologic symptoms gradually improved after receiving 2 doses of IV lipid emulsion approximately 71 hours and 90 hours after ivermectin overdose (Bruenisholz et al, 2012).

Enhanced Elimination

A)

1) Hemodialysis is unlikely to be of value because of the high degree of protein binding and large volume of distribution.

Abstracts

Case Reports

A)

1) An adult accidentally injected 1 to 2 mL of ivermectin (1%) developed no significant symptoms and reported only stinging at the injection site (Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).
2) A 61-year-old female ingested 100 mL of Ivomec(R) (15.4 mg/kg ivermectin) and presented to the emergency department in a coma. She also developed agitation, drowsiness, dizziness, and rhabdomyolysis (CK peak 1032 International Units/L). With supportive care, the patient recovered and was discharged on hospital day 9 (Chung et al, 1999).
3) A 39-year-old male intentionally ingested 250 mL Agri-Mek(R) (109.8 mg/kg abamectin) along with alcohol. The man initially appeared relatively well with only nausea and vomiting, but his clinical picture rapidly deteriorated to a comatose state with hypotension and tachycardia. Intubation was necessary, and aspiration pneumonia developed on day 2. With antibiotic therapy and fluids, the man's pneumonia cleared on day 6, and he was discharged one week later (Chung et al, 1999).

B)

1) A 16-month-old boy weighing about 15 kg accidentally drank an estimated 10 to 13 mL of a 1% ivermectin injectable solution.

a) Mydriasis was noted in one pupil, along with frequent vomiting, pallor, 35 degree Celsius temperature, tachycardia, somnolence and variable blood pressure (40 to 100 mmHg) 10 hours later. The next morning, urticaria occurred (Hall et al, 1985; Prod Info Poison Control Monograph for Ivermectin by Teresa P Dowling, Pharm.D, 1985).

Range Of Toxicity

Summary

A)

Therapeutic Dose

7.2.1)

A) ROUTE

1) ORAL

a) STRONGYLOIDIASIS: The recommended dose is 200 mcg/kg of body weight, in one dose. Additional doses may be administered if eradication was not complete(Prod Info STROMECTOL(R) oral tablets, 2010).
b) ONCHOCERCIASIS: The recommended dose is 150 mcg/kg of body weight per day, intervals ranging from 3 to 12 months (Prod Info STROMECTOL(R) oral tablets, 2010).

2) TOPICAL

a) For the treatment of pediculosis capitis, apply up to 1 tube topically to dry hair, coating hair and scalp thoroughly; rinse with water after 10 minutes (Prod Info SKLICE(TM) topical lotion, 2012).
b) For the treatment of inflammatory lesions of rosacea, apply a pea-size amount of the 1% cream topically to each affected area of the face (forehead, chin, nose, each cheek) once daily. Each gram of the 1% cream contains 10 mg of ivermectin in a white to pale yellow cream base (Prod Info SOOLANTRA(TM) topical cream, 2014).

7.2.2)

A) ROUTE

1) ORAL

a) The safety and effectiveness in pediatric patients weighing less than 15 kg have not been established (Prod Info STROMECTOL(R) oral tablets, 2010).

2) TOPICAL

a) 6 MONTHS AND OLDER: For the treatment of pediculosis capitis, apply up to 1 tube topically to dry hair, coating hair and scalp thoroughly; rinse with water after 10 minutes (Prod Info SKLICE(TM) topical lotion, 2012).
b) YOUNGER THAN 6 MONTHS: Safety and efficacy of topical ivermectin have not been established in pediatric patients less than 6 months of age; not recommended due to increased risk for systemic absorption and toxicity (Prod Info SKLICE(TM) topical lotion, 2012).
c) For the treatment of inflammatory lesions of rosacea, safety and efficacy of ivermectin 1% cream have not been established in pediatric patients (Prod Info SOOLANTRA(TM) topical cream, 2014).

Minimum Lethal Exposure

A)

Maximum Tolerated Exposure

A)

B)

C)

D)

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) Doses of 30 mcg/kg, given to humans produced levels of 4 to 5 nanograms (ng)/mL at 4 hours. Similarly, 50 mcg/kg doses produced levels of 9 to 13 ng/mL (Aziz et al, 1982).
2) Single oral doses of 150 mcg/kg in humans produced mean serum levels at 24 and 48 hours of 16.4 and 6.6 ng/mL, respectively (Njoo et al, 1995).

Pharmacology Toxicology

Pharmacologic Mechanism

A)

B)

Toxicologic Mechanism

A)

B)

Physicochemical

Animal Toxicology

Clinical Effects

11.1.2)

A) Signs include anorexia, depression, ataxia, recumbency, and death. The death of migrating larva of Hypoderma bovis (grubs) can result in hematomas in the spinal canal and associated paralysis, or edematous esophagitis with anorexia and bloat (Hsu et al, 1989).

11.1.3)

A) Mild toxicosis causes signs of salivation, confusion, and disorientation. In severe cases this will progress to include ataxia, vomiting, tremors, depression, stupor, and eventually coma (Paul et al, 1987).
B) Rapid die-off of microfilaria in heartworm (Dirofilaria immitus) positive dogs has been associated with vomiting, trembling, tachypnea, and shock (Kirk, 1989).

11.1.5)

A) Signs include depression, mydriasis, ataxia, bradypnea, recumbency, and death (Hsu et al, 1989).
B) Acute die-off of Onchocerca microfilaria has been associated with ventral edema and colic (Beasley et al, 1989).
C) Injectable ivermectin for horses, given at the recommended dose, caused local injection site reactions including swelling, pain, and systemic signs associated with clostridial infections such as anorexia, ventral edema, anaphylaxis, and sudden death (Hsu et al, 1989). These signs were due to reactions to the polysorbate 80 carrier causing histamine release, not due to the ivermectin compound (Beasley et al, 1989). This preparation is no longer available, and has been replaced by an oral paste and an oral drench.

11.1.6)

A) Signs usually appear within 10 hours of ingestion (Plumb, 1991), and include anorexia, ataxia, disorientation, aggression, mydriasis, tremors, and death (Hsu et al, 1989).

11.1.9)

A) Signs include ataxia and depression (Plumb, 1991).

11.1.10)

A) Signs include depression, mydriasis, tremors, recumbency, and death (Hsu et al, 1989). Neonatal pigs are believed to be more sensitive to overdosage due to a more permeable blood brain barrier (Plumb, 1991).

11.1.11)

A) REPTILE

1) Signs in red-footed tortoises (Geochelone carbonaria) included paresis, flaccid paralysis, and death (Hsu et al, 1989). Similar signs were noted in leopard tortoises (Geochelone pardalis) (Beasley et al, 1989).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Goals of treatment are to prevent absorption, maximize elimination, maintain hydration and electrolyte balance, and provide nutritional support.
2) Good nursing care is required to avoid secondary complications associated with recumbency.
3) Treatment should always be done on the advice and with the consultation of a veterinarian.

a) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.

4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 mL/kg syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 mg) apomorphine diluted in 3 to 5 mL water and instilled into the conjunctival sac or per os.
2) Dogs may also be given apomorphine intravenously at 40 mcg/kg. Do not use an emetic if the animal is hypoxic.
3) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
4) Pass large bore stomach tube and instill 5 to 10 mL/kg water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL - Administer activated charcoal, 2 grams/kg per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and, if necessary, tracheal intubation.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kg). If access to these agents is limited, give 5 to 15 mL magnesium oxide (Milk of Magnesia) per os for dilution.
d) If the route of exposure is subcutaneous injection, and exposure occurred recently, surgical excision of the injection site may be useful to reduce continued absorption (Beasley et al, 1989).

2) RUMINANTS/HORSES/SWINE

a) DO NOT attempt emesis in ruminants or equids.
b) ACTIVATED CHARCOAL - Give 2 grams/kg of activated charcoal in a slurry of 1 gram charcoal per 3 to 5 mL warm water via stomach tube.
c) CATHARTIC - Give 0.5 kilograms sodium sulfate per 400 kg. Dissolve in 0.5 to 1 L water and give via stomach tube. Another option is to give 1 L mineral oil per 400 kg via stomach tube (Howard, 1986).

11.2.5)

A) GENERAL

1) There is no known antidote for treatment of ivermectin toxicosis.

B) DOG

1) FLUID AND ELECTROLYTE THERAPY - If patient is not able to drink, give intravenous fluids at maintenance rate (66 mL/kg/hour).

a) In severely dehydrated patients give fluids at a higher rate (up to shock rate of 66 mL/kg/hour).
b) Use a balanced electrolyte solution alternated with 5% dextrose in water (D5W).

2) MONITOR HEART RATE AND EKG - Maintain heart rate above 80 bpm with:

a) GLYCOPYRROLATE at 0.01 mg/kg intravenously (Kirk, 1989).
b) Or with ATROPINE at 0.02 mg/kg intravenously (Beasley et al, 1989). Atropine's short duration of action requires frequent dosing.

3) DEXAMETHASONE - Although there is no evidence of ivermectin toxicosis resulting in CNS edema, 0.25 mg/kg intravenously every 8 hours may be beneficial (Kirk, 1989).
4) CIMETIDINE - If the patient is recumbent or if dexamethasone is administered, give 300 mg cimetidine intramuscularly twice daily to decrease gastric irritation (Heit et al, 1989).
5) PHYSOSTIGMINE - Physostigmine has been given in the dose of 1 mg intravenously every 12 hours to stimulate responsiveness in severely depressed or comatose patients. The effects will last 30 to 90 minutes (Kirk, 1989).

a) When physostigmine was given to a dog exhibiting only mild ataxia and confusion, seizures resulted, so it is not recommended in cases of minimal toxicity (Kirk, 1989).

6) TRIMETHOPRIM-SULFA - Give 30 mg/kg subcutaneously every 12 hours to prevent aspiration pneumonia in severely depressed or recumbent patients (Heit et al, 1989).
7) Recumbent patients require good nursing care to prevent secondary complications such as bed sores or pneumonia.
8) Shock caused by ivermectin administration to dogs with circulating microfilaria should be treated with epinephrine (Beasley et al, 1989) and intravenous fluids (Kirk, 1989).

C) REPTILE

1) One tortoise showed marked improvement in 6 hours after treatment with 0.2 mg of picrotoxin (Hsu et al, 1989).

D) HORSE

1) Horses that develop edema and/or pruritus due to the death of Onchocerca cervicalis microfilaria may be treated with prednisone at 0.5 mg/kg or with nonsteroidal anti-inflammatory drugs (Robinson, 1987).
2) Reactions to the polysorbate 80 in the equine injectable (no longer marketed) product should be treated with antihistamines (Beasley et al, 1989) and penicillin.

Range Of Toxicity

11.3.1)

A) BIRD

1) The therapeutic dose in birds is 200 mcg/kg given orally or subcutaneously to control endo- and ectoparasites (Plumb, 1989).

a) The injectable preparations may be diluted to 2 mg/mL with propylene glycol for accurate dosing of patients with low body weights. Ivermectin is not FDA approved for use in birds.

B) CAT

1) The therapeutic dose in cats is 200 mcg/kg given orally or subcutaneously to control endo- and ectoparasites (Kirk, 1989).

a) The injectable preparations may be diluted to 2 mg/mL with propylene glycol for accurate dosing of patients with low body weights. Ivermectin is not approved for use in cats.

C) CATTLE

1) The therapeutic dose in cattle is 200 mcg/kg (1 mL of 1% Ivomec(R) per 110 pounds body weight) given subcutaneously (Plumb, 1989), or 500 mcg/kg (1 mL of 0.5% Ivomec(R) Pour-On per 22 pounds body weight) applied dermally, to control endo- and ectoparasites.

a) Ivermectin is not approved for use in dairy cattle of breeding age (Prod Info Heartgard(R), 1991).

D) DOG

1) Heartworm prevention: 5 to 7 mcg/kg orally, given once monthly. Heartgard 30(R) comes in 3 dosages, 68 mcg for dogs up to 25 pounds, 136 mcg for dogs 26 to 50 pounds, and 272 mcg for dogs 51 to 100 pounds.

a) Combine appropriate doses for dogs over 100 pounds.
b) Give the initial dose within 30 days of a negative heartworm test, initial exposure to mosquitos, or microfilarial treatment.
c) Give the final dose after the last possible exposure to mosquitos (Prod Info Heartgard(R), 1991).

2) Microfilarial clearance: 50 mcg/kg orally or subcutaneously given 4 weeks after adulticide therapy (Kirk, 1989).

a) The injectable preparations may be diluted to 2 mg/mL with propylene glycol for accurate dosing of patients with low body weights.
b) Ivermectin is not approved for dogs at this dose. Do NOT use this dose in collies and related breeds.

3) Parasiticide: 200 mcg/kg orally or subcutaneously to control endo- and ectoparasites (Kirk, 1989).

a) he injectable preparations may be diluted to 2 mg/mL with propylene glycol for accurate dosing of patients with low body weights.
b) Ivermectin is not approved for dogs at this dose. Do NOT use this dose in collies and related breeds.

E) GOAT

1) The therapeutic dose in goats is 200 mcg/kg subcutaneously to control endo- and ectoparasites (Plumb, 1991). Ivermectin is not approved for use in goats.

F) HORSE

1) The therapeutic dose in horses is 200 mcg/kg orally (1 mL of 1% Eqvalan(R) liquid per 110 pounds of body weight) to control endo- and ectoparasites (Prod Info Eqvalan(R), 1991).

G) SWINE

1) The therapeutic dose in pigs is 300 mcg/kg subcutaneously (Prod Info Ivomec(R), 1991), or 300 to 500 mcg/kg orally (Leman, 1986), to control endo- and ectoparasites. Ivomec(R) is not approved for oral use in pigs.

H) REINDEER

1) The therapeutic dose in reindeer is 200 mcg/kg subcutaneously for treatment of Warbles (Oedemagena tarandi) (Prod Info Ivomec(R), 1991).

I) REPTILE

1) The therapeutic dose in reptiles is 25 to 200 mcg/kg to control endo- and ectoparasites (Kirk, 1989). Ivermectin is not approved for use in reptiles.

J) RODENT

1) The therapeutic dose in rodents is 200 mcg/kg subcutaneously to control endo- and ectoparasites (Kirk, 1989). Ivermectin is not approved for use in rodents.

K) SHEEP

1) The therapeutic dose in sheep is 200 mcg/kg orally (3 mL of 0.08% Ivomec(R) drench per 26 pounds body weight) or subcutaneously (1 mL of 1% Ivomec(R) per 110 pounds body weight) to control endo- and ectoparasites (Plumb, 1989). Ivermectin is not approved for subcutaneous use in sheep.

L) OTHER

1) LLAMA - The therapeutic dose in llamas is 200 mcg/kg orally or subcutaneously to control endo- and ectoparasites (Plumb, 1989).

11.3.2)

A) BIRD

1) Orange-cheeked waxbill finches and budgerigars may be more sensitive to ivermectin than other birds (Plumb, 1989).

B) CAT

1) Doses up to 1330 mcg/kg have been well tolerated (Lovell, 1990), but a dose of approximately 4 mg caused severe toxicity in one cat (Hsu et al, 1989).
2) A single ingestion of abamectin from an ant poison resulted in death for a 4.5 kg cat. Estimated dose of abamectin was 1 mg/kg (Webb, 2000).

C) CATTLE

1) 4 to 8 mg/kg is toxic to cattle. This is 20 to 40 times the recommended dose. There is no effect on breeding performance at the recommended dose (Hsu et al, 1989; Plumb, 1989; Roder & Stair, 1998) (Prod Info, Ivomec(R), 1991).

a) The Pour-On formulation is at least as safe as the injectable form based on plasma levels (Prod Info Ivomec(R), 1991).

D) DOG

1) Collies, shelties, border collies, Australian shepards, and related breeds and crosses may show sensitivity to ivermectin at doses of 100 to 200 mcg/kg or higher (Lovell, 1990; Roder & Stair, 1998).
2) A single oral dose of 150 mcg/kg will identify sensitive individuals without inducing life threatening signs (Fassler, 1991).

a) No reactions are seen at doses of 60 mcg/kg even in proven sensitive individuals (Fassler, 1991).

3) Collies that were proven nonsensitive to ivermectin showed signs of toxicity at 2.5 mg/kg (Fassler, 1991).
4) In beagles, 2.5 mg/kg caused mydriasis, 5 mg/kg caused tremors, and 40 mg/kg caused death (Beasley et al, 1989).
5) 50 mcg/kg (microfilaricide dose) given after adulticide therapy in heartworm infected dogs caused reactions in less than 5% of treated dogs (Kirk, 1986).
6) 2.5 to 4 mg/kg is toxic to beagles. This is greater than 200 times the therapeutic dose (Roder & Stair, 1998).
7) 80 mg/kg is the LD 50 for beagles (Hopkins et al, 1990).

E) HORSE

1) 2 mg/kg is toxic to horses. This is 10 times the recommended dose. Foals less than 30 days old showed no signs of toxicosis at doses of 1 mg/kg (Plumb, 1989; Roder & Stair, 1998).
2) The recommended dose is safe for breeding stallions and mares at any stage of gestation (Prod Info Eqvalan(R), 1991).
3) Mares given 3 times the recommended dose every 2 weeks for 6 doses starting at conception had no reactions and delivered normal foals (Hsu et al, 1989).

F) SWINE

1) 30 mg/kg is toxic to pigs. This is 100 times the therapeutic dose (Plumb, 1989; Roder & Stair, 1998). The recommended dose is safe during any stage of gestation (Prod Info, Ivomec(R), 1991).

G) REPTILE

1) 25 mcg/kg caused paresis in leopard tortoises (Geochelone pardalis) (Kirk, 1986).
2) 100 mcg/kg or less caused toxicosis in red-footed (Geochelone carbonaria) and leopard tortoises (Beasley et al, 1989; Roder & Stair, 1998).
3) Leopard frogs demonstrated toxicity resulting in death at 2 mg/kg IM. Doses of 20 mg/kg topically showed no effect (Roder & Stair, 1998).

H) RODENT

1) 1.2 mg/kg given daily caused no signs of toxicosis, and had no effect on reproduction.
2) 3.6 mg/kg given daily caused increased gestation length, high neonatal mortality, decreased birth weight, and decreased gain of offspring (Lankas et al, 1989).

I) SHEEP

1) 4 mg/kg is toxic to sheep (Plumb, 1989). This is 20 times the recommended dose. The recommended dose is safe for ewes at all stages of gestation (Prod Info Ivomec(R), 1991).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) Goals of treatment are to prevent absorption, maximize elimination, maintain hydration and electrolyte balance, and provide nutritional support.
2) Good nursing care is required to avoid secondary complications associated with recumbency.
3) Treatment should always be done on the advice and with the consultation of a veterinarian.

a) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.

4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 mL/kg syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 mg) apomorphine diluted in 3 to 5 mL water and instilled into the conjunctival sac or per os.
2) Dogs may also be given apomorphine intravenously at 40 mcg/kg. Do not use an emetic if the animal is hypoxic.
3) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
4) Pass large bore stomach tube and instill 5 to 10 mL/kg water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL - Administer activated charcoal, 2 grams/kg per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and, if necessary, tracheal intubation.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kg). If access to these agents is limited, give 5 to 15 mL magnesium oxide (Milk of Magnesia) per os for dilution.
d) If the route of exposure is subcutaneous injection, and exposure occurred recently, surgical excision of the injection site may be useful to reduce continued absorption (Beasley et al, 1989).

2) RUMINANTS/HORSES/SWINE

a) DO NOT attempt emesis in ruminants or equids.
b) ACTIVATED CHARCOAL - Give 2 grams/kg of activated charcoal in a slurry of 1 gram charcoal per 3 to 5 mL warm water via stomach tube.
c) CATHARTIC - Give 0.5 kilograms sodium sulfate per 400 kg. Dissolve in 0.5 to 1 L water and give via stomach tube. Another option is to give 1 L mineral oil per 400 kg via stomach tube (Howard, 1986).

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Ongoing treatment should always be done on the advice and with the consultation of a veterinarian.

11.4.3.6) OTHER

A) OTHER

1) GENERAL

a) LABORATORY -

1) BLOOD GASES - If the patient becomes comatose, blood gas analysis can be used to determine the degree of hypoxia, and whether or not a respirator may be needed to prevent hypoxic damage to the CNS (Heit et al, 1989).
2) Plasma should be submitted for ivermectin concentration to verify exposure and toxicosis (Lovell, 1990).

Kinetics

11.5.1)

A) SPECIFIC TOXIN

1) Ivermectin is well absorbed orally and parenterally. In monogastrics, ivermectin is 95% absorbed after oral administration, but in ruminants it is only 25 to 33% absorbed due to inactivation by rumen microbes.

a) Subcutaneous administration provides greater bioavailability, but slower absorption than oral administration (Plumb, 1991).
b) Plasma concentrations peak between 2 and 5 days after subcutaneous administration in cattle (Hsu et al, 1989).
c) Peak plasma concentrations are similar for sensitive and nonsensitive collies, and do not correlate with the development of neurologic signs (Tranquilli et al, 1989).

11.5.2)

A) SPECIFIC TOXIN

1) Ivermectin is well distributed to most tissues and is concentrated in the liver and body fat. In reasonable doses, it is excluded from the CNS of mammals by the blood brain barrier.

a) In some collies and related breeds of dogs, as well as in chelonians (tortoises) and some equids (horses), ivermectin is not excluded by the blood brain barrier and will achieve high CNS concentrations at relatively low doses (Beasley et al, 1989).

11.5.3)

A) SPECIFIC TOXIN

1) Ivermectin is metabolized into methyl alcohol and monosaccharides by the liver (Hsu et al, 1989).

11.5.4)

A) SPECIFIC TOXIN

1) Ivermectin and its metabolites are primarily excreted in bile and feces, with less than 5% being excreted in the urine (Plumb, 1991).

a) It is only minimally metabolized, and is primarily eliminated as the parent compound. This persistence of the parent compound in the body may account for the duration of effects seen in poisoned animals (Beasley et al, 1989).

2) COW - Subcutaneous administration resulted in half lives ranging from 3 to 7 days (Hsu et al, 1989).
3) DOG - Intravenous administration resulted in a plasma half life of 1.8 days (Lovell, 1990).

Pharmacology Toxicology

A)

1) Ivermectin is an off-white powder that is soluble in propylene glycol, polyethylene glycol, and vegetable oils (Plumb, 1989).
2) It is an avermectin compound produced by the soil fungus Streptomyces avermitilis. It increases the releases of the inhibitory neurotransmitter gamma amino butyric acid (GABA).
3) In nematodes, increased GABA release blocks normal transmission of signals in the peripheral nervous system from interneurons to excitatory motor neurons, resulting in paralysis and death.

a) In arthropods, GABA release occurs at the neuromuscular junction, producing the same end results of paralysis and death.
b) It is presumed that ivermectin's lack of effect on trematodes and cestodes is due to an absence of GABA as a neurotransmitter in these classes (Hsu et al, 1989).

4) In mammals GABA is present only in the central nervous system where ivermectin is normally excluded by the blood-brain barrier (Kirk, 1989).

Sources

A)

1) Eqvalan(R) (ivermectin) Oral Liquid for Horses, MSD-AGVET, liquid anthelmintic administered by stomach tube. 10 mg/mL ivermectin available in 50 and 100 mL bottles (Prod Info Eqvalan(R), 1991). Not for use in horses intended for food.
2) Eqvalan(R) (ivermectin) Oral Paste for Horses, MSD-AGVET, 1.87% ivermectin, available in 0.21 ounce (6.08 grams) individual dose syringes (Prod Info Eqvalan(R), 1991). Not for use in horses intended for food.
3) Heartgard 30(R) tablets and chewables for heartworm prevention in dogs, MSD-AGVET. Available in three dose strengths, 68 mcg for dogs 0 to 25 pounds, 136 mcg for dogs 26 to 50 pounds, and 272 mcg for dogs 51 to 100 pounds.

a) Combine appropriate doses for dogs exceeding 100 pounds. Packets contain 6 or 9 tablets or 6 chewables for each dose (Prod Info Heartgard(R), 1991).

4) Ivomec(R) (ivermectin) 1% Injection for Cattle, MSD-AGVET, 10 mg/mL ivermectin for subcutaneous injection, available in 50, 200, 500, and 1000 mL bottles (Prod Info Ivomec(R), 1991). 48 day slaughter withdrawal for cattle and 56 day slaughter withdrawal for reindeer.
5) Ivomec(R) (ivermectin) Pour-on for Cattle, MSD-AGVET, 5 mg/mL ivermectin for dermal application, available in 250 or 1000 mL bottles with squeeze-measure-pour system (Prod Info Ivomec(R), 1991). A 48 day slaughter withdrawal is necessary.
6) Ivomec(R) (ivermectin) 1% Injection for Swine, MSD-AGVET, 10 mg/mL ivermectin for subcutaneous injection, available in 50, 200, and 500 mL bottles (Prod Info Ivomec(R), 1991). An 18 day withdrawal for slaughter is necessary.
7) Ivomec(R) (ivermectin) 0.27% Injection for Feeder and Grower Pigs, MSD-AGVET, 2.7 mg/mL ivermectin for subcutaneous injection, available in 200 mL bottles (Plumb, 1989). An 18 day withdrawal for slaughter is necessary.
8) Ivomec(R) (ivermectin) Sheep Drench, MSD-AGVET, 0.08% weight to volume solution (Prod Info Ivomec(R), 1991). An 11 day withdrawal for slaughter is necessary.

Other

A)

1) SPECIFIC TOXIN

a) POSTMORTEM - There are no diagnostic lesions in ivermectin poisoned animals (Beasley et al, 1989). Plasma, liver, fat, and brain samples should be submitted to verify toxicosis (Lovell, 1990).
b) Ivermectin may cause illness or death in fish and wildlife if disposed of in the water (Plumb, 1989).
c) No adverse reactions have been reported when Heartgard 30(R) is combined with commonly used flea collars, dips, shampoos, anthelmintics, vaccinations, or steroid preparations (Prod Info Heartgard(R), 1991).
d) All dogs should be tested for heartworms, and infected dogs should be treated to remove adults and microfilaria, prior to starting on Heartgard 30(R) (Prod Info Heartgard(R), 1991).

References

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