23 | 07 | 2014
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LEVAMISOLE: SAFETY SUMMARY for VETERINARY use on DOGS, CATS, CATTLE, SHEEP, GOATS, SWINE and POULTRY. Poisoning, intoxication, overdose, antidote

LEVAMISOLE: Safety Summary for Veterinary Use

 

Content

Mechanism of action
Acute toxicity & tolerance
Toxic symptoms
Side effects, ADRs
Antidote & treatment
Pharmacokinetics
Environmental toxicity
Warning
  

WHO Acute Hazard classification: Not listed.


Mechanism of action of Levamisole

Levamisol acts as an acetylcholinesterase (also known as AchE) mimetic. AchE is an enzyme that hydrolyzes acetylcholine (Ach). Ach is a molecule involved in the transmission of nervous signals from nerves to muscles (so-called neuromuscular junctions). Levamisole causes a depolarisation of the ganglions and nervous cells of the worms. It also interferes with the metabolism of carbohydrates (sugars) in the worm. Within 1 to 3 hours after administration the worms are paralyzed and die or are expelled.


Acute Toxicity and Tolerance of Levamisole

  • LD50 acute, rats, p.o 180 mg/kg
  • LD50 acute, pigs, s.c. 39.8 mg/kg
  • In cattle, doses 24 to 40 mg/kg (usual therapeutic dose ~8 mg/kg) can cause hypersalivation (drooling). Forr calves with kidney damage (e.g. due to mercury chloride) levamisole is more toxic.
  • In goats, oral doses of 35 mg/kg (usual therapeutic dose ~8 mg/kg) cause transient signs of intoxication already 30 minutes after administration: lacrimation, miosis (constriction of the pupil), hiccups and hyperactivity.
  • In pigs, oral doses of up to 160 mg/kg did not cause fatalities (usual therapeutic dose ~8 mg/kg). Oral doses higher than 24-49 mg/kg caused hypersalivation (drooling). After s.c. injection at 32-62 mg/kg intoxication symptoms appeared already 5 minutes after treatment: vomit, ataxia (uncoordinated movements), tremor, convulsions, CNS depression, enhanced respiratory rate. Breathlessness and death can follows within 5 to 60 minutes after administration. Following i.m. injection at 21 to 33 mg/kg fatalities can follow within 5 minutes after administration.
  • The safety margin in horses is rather low.
  • In dogs and cats treatment at 4x the therapeutic dose can cause fatalities.
  • In birds, the toxic s.c. dose is 40 mg/kg. It can be even lower in sensitive birds such as pigeons, ibises and parakeets. Poultry tolerate levamisol better: fatalities can happen only at oral doses > 480 mg/kg.

Toxic Symptoms caused by Levamisole Poisoning

  • General: restlessness.
  • Gastrointestinal: hypersalivation (drooling), vomit, colic, diarrhea.
  • Cardiovascular: bradycardia (low heart rate), collapse.
  • Respiratory: dyspnea (difficult breathing), tachypnea (rapid breathing).
  • Nervous symptoms: miosis (contraction of the pupil), spasms, cramps, trembling, depression.
  • In extreme cases death can follow within 1 hour after administration due to respiratory failure.
  • Typical for levamisole intoxication is that the symptoms appear very quickly after administration (5 to 15 minutes) and resolve also rather fast (1 to 6 hours). Peak is usually 30 minutes after administration.
  • Post-mortem pathological examination showed infiltration of the lung parenchyma with neutrophils, enteritis, acute liver degeneration and necrosis, subepicardic and thalamic hemorrhage.

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

  • Painful swellings can appear at the injection sites, which usually resolve in 1 to 2 weeks.
  • Most frequent adverse drug reactions are vomit and diarrhea, particularly in dogs, cats and swine. Other side effects reported for livestock, dogs and cats include drooling, foam at the mouth, lung edema, difficult breathing, bronchospasms, trembling, uncoordinated movements, hyperestesia, weakness, collapse and convulsions. Such adverse drug reaction resolve usually 1 to 2 hours after administration.
  • In dogs infected with the French heartworm (Angiostrongylus vasorum) levamisole treatment can cause anaphylactic shock due to the sudden release of allergens after worm death.
  • Also in dogs, undesired skin immune effects (e.g. erythema multiforme, epidermal necrolysis) have been reported after levamisole treatment.
  • In cattle cases of photosensitization have been reported after administration of levamisole as a pour-on.
  • Fatalities have been reported after simultaneous administration of levamisole and chloramphenicol.
  • Levamisole enhances the effect of medicines that increase blood pressure such as noradrenalin, angiotensin and acetylcholine.
  • Levamisole enhances also the adverse drug effects of certain muscle relaxants (e.g. suxamethonium).
  • Levamisole must not be administered together with other depolarising parasympathomymetic drugs because it enhaces their toxicity (e.g. organophosphates, carbamates, morantel, pyrantel, neostigmine).
  • Piperazine derivatives neutralize the anthelmintic effect of levamisole.
  • Levamisole must no be administered together with compounds that have a nicotinic effect (e.g. morantel, pyrantel, diethylcarbamazine) since it can increase their toxicity (LD50) by a factor of 2.
  • Levamisole reduces the efficacy of phenylbutazone (a non-steroidal anti inflammatory drug).
  • Levamisole is not compatible in-vitro with neomycins, tetracyclins and sulfonamides. Such medicines must be administered with a different needle than the one used for levamisole.
  • Weak or sick animals must not be treated with levamisole.
  • Levamisole should not be administered after vaccinations, castration, dehorning, etc.
  • Levamisole pour-ons must no be administered to animals with a wet hair coat.
  • Never use tablets (or suspensions, pastes, etc.) for dogs on cats, or tablets for large dogs on small dogs. It happens that some users want to save money buying large tablets for treating smaller dogs (or even cats!) twice or more times. The risk of overdosing is considerable, either due to erroneous calculations or to unskilled manipulation. In addition, dog medicines may sometimes contain ingredients that are toxic to cats.
  • Unless prescribed by a veterinary doctor, never use on dogs or cats products for livestock that are not explicitly approved for such use. There is a high risk of overdosing or of adverse drug reactions due to ingredients that are not tolerated by pets or are even toxic to them.

Antidote and Treatment of Levamisole Intoxication

  • There is no specific antidote for levamisole.
  • Nicotine antagonists, anticholinergics and anti-alpha adrenergics can be useful.
  • Atropine can be useful against CNS and parasympathetic symptoms. But atropine alone does not reduce mortality after levamisole intoxications.
  • Use of other supportive measures is essential.
  • Since most fatalities following acute levamisole intoxication are due to asphyxia after respiratory failure, artificial respiration with oxygen administration is vital.
  • After oral intoxication gastric and intestinal lavage are highly recommended, as well as administration of active charcoal.

Pharmacokinetics of Levamisole

  • Levamisole is quickly absorbed into the bloodstream after all usual delivery forms: injectabledrench or pour-on. It is also quickly distributed throughout the whole body, including such body fluids as the bronchial mucus and the tears. It also reaches the gut after injection.
  • Most administered levamisol is quickly metabolized in the liver. Only about 5% of the administered dose is excreted unchanged through urine. It is also quickly excreted, mainly through the kidneys. One day after treatment about 90% of the administered dose is already excreted.
  • In goats levamisole is excreted even faster, which usually requires administering a higher dose than in sheep.
  • After pour-on administration absorption through the skin depends a lot on the outside temperature: the hotter the faster it is absorbed. By hot weather the risk of overdosing increases considerably.

Environmental Toxicity of Levamisole

  • Not being used in crop pesticides or in public hygiene, knowledge on its environmental fate and impact is very scarce.
  • Nevertheless, it can be assumed that correctly used in dogs, cats and livestock levamisole is unlikely to be detrimental for the environment, including coprophagous insects.

Additional information

  • Levamisole belongs to the chemical class of the imidazothiazoles.
  • Levamisole is used in human medicines but has been abandoned in some countries (from the USA).
  • Levamisole is not used in crop pesticides.
  • Levamisole is not used in public or domestic hygiene as a biocide.
  • Click here for technical and commercial information on levamisole.

WARNING

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

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

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

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

 

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