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Levamisole
*(Adverse Effect Reported)

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Chemistry - The levo-isomer of dl-tetramisole, levamisole has a greater safety margin than does the racemic mixture. It is available commercially in two salts, a phosphate and a hydrochloride. Levamisole hydrochloride occurs as a white to pale cream colored, odor­less or nearly odorless, crystalline powder. One gram is soluble in 2 ml of water.

 

Storage/Stability/Compatibility - Levamisole hydrochloride  products should be stored at room temperature (15-30°C), unless otherwise instructed by the manufacturer; avoid tem­peratures greater than 40°C. Levamisole phosphate  injection should be stored at tempera­tures at or below 21°C (70°F); refrigeration is recommended and freezing should be avoided.

Levamisole tablets should not be crushed nor suspensions made from them.

 

Pharmacology - Levamisole stimulates the parasympathetic and sympathetic ganglia in susceptible worms. At higher levels, levamisole interferes with nematode carbohydrate metabolism by blocking fumarate reduction and succinate oxidation. The net effect is a paralyzing effect on the worm which is then expelled alive. Levamisole’s effects are con­sidered to be nicotine-like in action.

 

Levamisole’s mechanism of action for its immunostimulating effects are not well under­stood. It is believed it restores cell-mediated immune function in peripheral T-lympho­cytes and stimulates phagocytosis by monocytes. Its immune stimulating effects appear to be more pronounced in animals that are immune-compromised.

 

Uses/Indications - Depending on the product licensed, levamisole is indicated for the treatment of many nematodes in cattle, sheep & goats, swine, poultry. In sheep and cattle, levamisole has relatively good activity against abomasal nematodes, small intestinal nema­todes (not particularly good against Strongyloides spp.), large intestinal nematodes (not Trichuris spp.), and lungworms. Adult forms of species that are usually covered by lev­amisole, include: Haemonchus spp., Trichostrongylus spp., Osteragia spp., Cooperia spp., Nematodirus spp., Bunostomum spp., Oesophagostomum spp., Chabertia spp., and Dictyocaulus vivapurus. Levamisole is less effective against the immature forms of these parasites and is generally ineffective in cattle (but not sheep) against arrested larval forms. Resistance of parasites to levamisole is a growing concern.

 

In swine, levamisole is indicated for the treatment of Ascaris suum, Oesophagostomum spp., Strongyloides, Stephanurus, and Metastrongylus.

 

Levamisole has been used in dogs as a microfilaricide to treat Dirofilaria immitis infec­tion. It has also garnered much interest as an immunostimulant in the adjunctive therapy of various neoplasms.

 

Because of its narrow margin for safety and limited efficacy against many equine para­sites, levamisole is not generally used in horses.

 

Pharmacokinetics - Levamisole is absorbed from the gut after oral dosing and through the skin after dermal application, although bioavailabilities are variable. It is reportedly distributed throughout the body. Levamisole is primarily metabolized with less than 6% excreted unchanged in the urine. Plasma elimination half-lives have been determined for several veterinary species: Cattle 4-6 hours; Dogs 1.8-4 hours; and Swine 3.5-6.8 hours. Metabolites are excreted in both the urine (primarily) and feces.

 

Contraindications/Precautions - Levamisole is contraindicated in lactating animals (not approved). It should be used cautiously, if at all, in animals that are severely debilitated, or have significant renal or hepatic impairment. Use cautiously or, preferably, delay use in cattle that are stressed due to vaccination, dehorning or castration.

 

There is no information regarding the safety of this drug in pregnant animals. Although levamisole is considered relatively safe to use in large animals that are pregnant, use only if the potential benefits outweigh the risks.

 

Adverse Effects/Warnings - Adverse effects that may seen in cattle can include muzzle-foaming or hypersalivation, excitement or trembling, lip-licking and head shaking. These effects are generally noted with higher than recommended doses or if levamisole is used concomitantly with organophosphates. Symptoms generally subside within 2 hours. When injecting into cattle, swelling may occur at the injection site. This will usually abate in 7-14 days, but may be objectionable in animals that are close to slaughter.

 

In sheep, levamisole may cause a transient excitability in some animals after dosing. In goats, levamisole may cause depression, hyperesthesia and salivation. Injecting levamisole SQ in goats apparently causes a stinging sensation.

 

In swine, levamisole may cause salivation or muzzle foaming. Swine infected with lung­worms may develop coughing or vomiting.

 

Adverse effects that may seen in dogs include GI disturbances (usually vomiting, diarrhea), neurotoxicity (panting, shaking, agitation or other behavioral changes), agranulocy­tosis, dyspnea, pulmonary edema, immune-mediated skin eruptions (erythroedema, ery­thema multiforme, toxic epidermal necrolysis) and lethargy.

 

Adverse effects seen in cats include hypersalivation, excitement, mydriasis and vomiting.

 

Overdosage/Toxicity - Symptoms of levamisole toxicity often mimic those of organophosphate toxicity. Symptoms may include hypersalivation, hyperesthesias and irri­tability, clonic seizures, CNS depression, dyspnea, defecation, urination, and collapse. These effects are best treated by supportive means, as animals generally recover within hours of dosing. Acute levamisole overdosage can result in death due to respiratory failure. Should respiratory failure occur, artificial ventilation with oxygen should be instituted until recovery takes place. Cardiac arrhythmias may also be seen. If the ingestion was oral, emptying the gut and/or administering charcoal with cathartics may be indicated.

 

Levamisole is considered to be more dangerous when administered parenterally than when given orally or topically. Intravenous administration is particularly hazardous, and is never recommended.

 

In pet birds (cockatoos, budgerigars, Mynah birds, parrots, etc.), 40 mg/kg has been re­ported as a toxic dose when administered SQ. IM injections may cause more severe toxicity. Depression, ataxia, leg and wing paralysis, mydriasis, regurgitation, and death may be seen after a toxic dose in birds.

 

Drug Interactions - Other nicotine-like compounds (e.g., pyrantel, morantel, diethyl­carbamazine), or cholinesterase-inhibitor drugs (e.g., organophosphates, neostig­mine) could theoretically enhance the toxic effects of levamisole; use together with caution.  Levamisole may enhance the immune-reaction and efficacy to Brucella vaccines.  Fatalities have been reported after concomitant levamisole and chloramphenicol administration; avoid using these agents together.

 

Doses -

Cattle:

For treatment of susceptible nematodes (also refer to specific label directions for ap­proved products):

a)   For removal of mature and immature Dictyocaulus vivapurus: 5.5 - 11 mg/kg PO, either given in feed or as a drench or oral bolus. May also be administered SQ at 3.3 - 8 mg/kg. (Bennett 1986)

b)   7.5 mg/kg PO (Brander, Pugh, and Bywater 1982)

 

Elephants:

a) 2.5-3 mg/kg orally as a single dose (Chandrasekharan, 2002), (Chandrasekharan, et.al., 1995), (Chandrasekharan, 1992).

 

b) 3 mg/kg orally for strongylosis (Chandrasekharan, et.al., 1982).

                     

Adverse effects:

c) a case of toxicity in a baby elephant treated with Tetramisole, has been reported (Gnanaprakasam and Mahalingam, 1992).

 

Elephant References:

a) Chandrasekharan,K. 2002. Specific diseases of Asian elephants. Journal of Indian Veterinary Association Kerala 7:(3):31-34

 

         a) Chandrasekharan,K., Radhakrishnan,K., Cheeran,J.V., Nair,K.N.M., and Prabhakaran,T., 1995. Review of the Incidence, Etiology and Control of Common Diseases of Asian Elephants with Special Reference to Kerala. In: Daniel,J.C. (Editor), A Week with Elephants; Proceedings of the International Seminar on Asian Elephants. Bombay Natural History Society; Oxford University Press, Bombay, India pp. 439-449

         a) Chandrasekharan,K., 1992. Prevalence of infectious diseases in elephants in Kerala and their treatment. In: Silas,E.G., Nair,M.K., and Nirmalan,G. (Editors), The Asian Elephant: Ecology, Biology, Diseases, Conservation and Management (Proceedings of the National Symposium on the Asian Elephant held at the Kerala Agricultural University, Trichur, India, January 1989). Kerala Agricultural University, Trichur, India pp. 148-155

         b) Chandrasekharan,K., Cheeran,J.V., Nair,K.N.M., Ramanujam,K.N., and Radhakrishnan,K. 1982. Comparative efficacy of 6 anti-helminthics against strongylosis in elephants. Kerala Journal of Veterinary Science 13:15-20  Summary: Anthelmintic efficacy of six drugs was compared under field conditions against strongylosis in elephants. Mebendazole at 3 and 4 mg/kg, Levamisole 3 mg/kg and Morantel tartrate 5 mg/kg were proved to be 100% effective.  Mebendazole at 2 mg/kg and 2.5 mg/kg, Thiabendazole at 32 mg/kg. Bephenium hydroxynaphthoate at 25 mg/kg and Disophenol at 3 mg/kg were found to be effective only in 79.1 to 92.2 %, 88.1 to 100%, 84.6 to 95.3 %, 85.9 to 100% and 68.3 to 84 % cases respectively.

c) Gnanaprakasam,V. and Mahalingam,P., 1992. Tetramisole toxicity in a baby elephant. In: Silas,E.G., Nair,M.K., and Nirmalan,G. (Editors), The Asian Elephant: Ecology, Biology, Diseases, Conservation and Management (Proceedings of the National Symposium on the Asian Elephant held at the Kerala Agricultural University, Trichur, India, January 1989). Kerala Agricultural University, Trichur, India pp. 166-167 Summary:  A case of toxicity in a 2 year old elephant treated with 1 liter of Nilverm (300 g of Tetramisole)  is presented. Clinical symptoms included muscular tremors, salivation, initially diarrhoea followed by constipation and bradycardia. Treatment with dextrose, B complex, atropine sulfate and liquid paraffin resulted in alleviation of symptoms and slow improvement.  The authors comment that: “tetramisole itself has a safety margin variously estimated to be 2-6 times the therapeutic dose of 15 mg/kg and the safety factor of levamisole is about twice that of the parent compound since levamisole is equally active against parasites in half the dosage.”

 

Monitoring Parameters -

1)   Clinical efficacy

2)   Adverse effects/toxicity observation

 

Client Information - Levamisole is not approved to be used in dairy animals of breeding age. Follow directions on the product label unless otherwise directed by veterinarian. Animals that are severely parasitized or in conditions with constant helminth exposure should be retreated 2-4 weeks after initial treatment. Do not administer injectable products IV. Report serious adverse effects to veterinarian.

 

Dosage Forms/Preparations/FDA Approval Status/Withdrawal Times -

In cattle, sheep, and swine a level of 0.1 ppm has been established for negligible residues in edible tissues.

 

Veterinary-Approved Products:

 

Dosage Forms/Preparations/FDA Approval Status/Withdrawal Times -

In cattle, sheep, and swine a level of 0.1 ppm has been established for negligible residues in edible tissues.

 

Veterinary-Approved Products:

Levamisole Phosphate Injection 136.5 mg/ml (13.65%)

Levasole®  Injectable Solution (Schering Plough); Tramisol®  Injectable (Cyanamid). (OTC)  Approved for use in beef cattle and non-lactating dairy cattle. Slaughter withdrawal=7 days.

 

Levamisole HCl Soluble Powder for Oral Use

Levasole® Soluble Drench Powder 11.7 grams/packet (Schering Plough); (OTC)  Approved for use in sheep. Slaughter withdrawal=3 days.

 

Levasole® Soluble Pig Wormer 18.15 grams/packet (Schering Plough); (OTC)  Approved for use in swine. Slaughter withdrawal=9 days.

 

Levasole® Soluble Drench Powder 46.8 grams/packet (Schering Plough); (OTC)  Approved for use in beef cattle, non-lactating dairy cattle, and sheep. Slaughter withdrawal=2 days (cattle); 3 days (sheep).

 

Tramisol® Soluble Drench Powder, Tramisol Drench 46.8 grams/packet (American Cyanamid). (OTC)  Approved for use in beef cattle, non-lactating dairy cattle, and sheep. Slaughter withdrawal=2 days (cattle); 3 days (sheep).

 

Ripercol® L  9.075 grams (American Cyanamid). (OTC)  Approved for use in swine. Slaughter withdrawal=3 days.

 

Levamisole Oral Feed Mixes

Tramisol® Hog Wormer (American Cyanamid) Each 2.05 oz packet contains lev­amisole resinate equivalent to 45.5 grams levamisole. (OTC)  Approved for use in swine. Slaughter withdrawal=3 days.

 

Medicated Feed Premix 50% (American Cyanamid) 227 g levamisole HCl/lb. (OTC)  Approved for use in non-lactating dairy and beef cattle and swine. Slaughter withdrawal=2 days (cattle); 3 days (swine).

 

Levamisole HCl Oral Pastes/Gels

Levasole® Gel 11.5% (115 mg/gram) (Schering Plough) 237.4 g cartridge. Each cartridge will deliver 27.3 g of levamisole HCl. (OTC)  Approved for use in beef cattle, and non-lactating dairy cattle. Slaughter withdrawal=6 days.

 

Tramisol® Gel 11.5% (115 mg/gram) (American Cyanamid). (OTC)  Approved for use in beef cattle, and non-lactating dairy cattle, and swine. Slaughter with­drawal=6 days (cattle); 11 days (swine).

 

Levamisole HCl Oral Tablets/Boluses; 184 mg bolus: Levasole® Sheep Wormer Bolus (Schering Plough); Tramisole® Sheep Wormer (Cyanamid); Ripercol® L Wormer Oblets (American Cyanamid). (OTC)  Approved for use in sheep. Slaughter withdrawal=3 days.

 

2.19 gram bolus: Levasole® Cattle Wormer Bolus (Schering Plough); Ripercol® L Bolus (Cyanamid); (OTC)  Approved for use in beef and non-lactating dairy cat­tle. Slaughter withdrawal=2 days.

 

Levamisole Topical (Pour-On) 200 mg/ml; Totalon®  (Schering); Tramisol® Pour On (American Cyanamid). (OTC)  Approved for use on beef and non-lactating dairy cattle. Slaughter withdrawal=9 days.

 

 

Human-Approved Products:

Levamisol HCl Tablets:  50 mg levamisole base; Ergamisol® (Janssen) (Rx)

 

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