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Ivermectin

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Ivermectin
     1.2 Group
       Avermectins
     1.3 Synonyms
     1.4 Identification numbers
       1.4.1 CAS number
             70288-86-7 (mixture)
       1.4.2 Other numbers
             70161-11-4 (component B1a)
             70209-81 (component B1b)
     1.5 Brand names, Trade names
       Cardomec
       Cardotek-30
       Eqvalan
       Heartgard-30
       Ivomec
       Ivomec-F
       Ivomec-P
       Mectizan
       MK-933
       Oramec
     1.6 Manufacturers, Importers
       To be added by the Poisons Control Centre.
    2. SUMMARY
     2.1 Main risks and target organs
       Ivermectin is generally well tolerated when administered to 
       non-infected humans.  Only side effects have been reported: 
       itching, swollen lymph glands, dizziness, hypotension, fever, 
       headache and myalgia.  Side effects are more frequent and 
       severe in patients with high microfilaria counts.
       
       Other persons at risk include veterinarians and farm workers 
       involved in treating animals for worms and ectoparasites.  
       Most cases reported involve accidental self-injection and some 
       ingestions of injectable solutions.  No human deaths have been 
       reported.
     2.2 Summary of clinical effects
       In human poisoning exposures reported, the signs and symptoms 
       reported are: vomiting, tachycardia, mydriasis, somnolence and 
       blood pressure fluctuation.  The effects of small quantities 
       of accidentally injected veterinary formulations appear 
       negligible.  The adverse reactions encountered in patients 
       being treated for filariasis are: fever, headaches, weakness, 
       cough, swollen lymph glands, arthralgia, myalgia and 
       gastrointestinal symptoms.
     2.3 Diagnosis
       The diagnosis is based on history of administration and 
       occurrence of adverse effects or toxic effects.
       
       No specific laboratory tests are necessary unless clinically 
       indicated.  Although a sensitive assay exists for ivermectin, 
       it is unlikely to be useful in the clinical management of 
       poisoning.

     2.4 First aid measures and management principles
       Ingestion: clinical management is symptomatic and supportive. 
       Dilute with water; induce emesis using syrup of ipecac; obtain 
       medical advice.  The management of adverse reactions is purely 
       symtomatic and responds to analgesics and antihistamines.
       
       Eye contact: remove any contact lenses, flush the contaminated 
       eyes gently with water for 10 to 15 minutes holding the 
       eyelids open, and obtain medical advice.
       
       Skin contact: flush the contaminated area gently with water 
       for 10 to 15 minutes.  Obtain medical advice.
       
       Parenteral contact: although the effects on adults following 
       accidental self-injections of small quantities (< 2 ml) 
       appear to be negligible, appropriate measures should be 
       considered in view of the risk of secondary infection from a 
       contaminated syringe.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Ivermectin is a semi-synthetic derivative of one of the 
       avermectins, a group of macrocyclic lactones produced by the 
       soil bacterium Streptomyces avermitilis (Reynolds, 1989).
     3.2 Chemical structure
       A mixture of:
       
       80% ivermectin component B1a (5-O-demethyl-22,23-
       dihydroavermectin A1a)
       
       C48H74O14
       
       MW = 875.1
       
       20% ivermectin component B1b (5-O-demethyl-25-de(1-
       methylpropyl)-22, 23-dihydro-25-(1-methylethyl)avermectin A1a)
       
       C47H72O14
       
       MW = 861.1
       
       (Reynolds, 1989)
     3.3 Physical properties
       3.3.1 Properties of the substance
             Ivermectin forms colourless crystals
             Water Solubility = 4 mg/L
             Soluble in polar organic solvents (e.g. butanol 
             30 g/L)
             (Hayes & Laws, 1991)
       3.3.2 Properties of the locally available formulation
             To be completed by the Poisons Control Centre.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             No data available.
       3.4.2 Shelf-life of the locally available formulation
             To be completed by the Poisons Control Centre.
       3.4.3 Storage conditions

             Store in cool place.  Protect from light.  Keep out of 
             reach of children.
       3.4.4 Bioavailability
             To be completed by the Poisons Control Centre.
       3.4.5 Specific properties and composition
             To be completed by the Poisons Control Centre.
    4. USES
     4.1 Indications
       Ivermectin is an antihelmintic used mainly in the 
       treatment of onchocerciasis in humans, and also for 
       strongyloidiasis, ascariasis, trichuriasis and 
       enterobiasis.  It is being used in mass treatment of 
       programmes in endemic regions.
       
       Ivermectin is an antiparasitic agent with a broad 
       spectrum of activity against nematode worms and 
       ectoparasites in animals, and has been in use for nearly 
       a decade.  Veterinary dosages range from 20 to 3000 
       g/kg.
     4.2 Therapeutic dosage
       4.2.1 Adults
             Oral:  3 to 12 mg as a single dose per os (about 150 to 
             200 g/kg bodyweight) for onchocerciasis and other 
             parasitic infections.
       4.2.2 Children
             Ivermectin is not given to children weighing less than 
             15 kg.  The dose is 150 g/kg bodyweight (in children 
             weighing more).
     4.3 Contraindications
       Ivermectin is contraindicated in persons with an immediate 
       hypersensitivity to the drug.  It should not be given to 
       mothers who are breast-feeding until the infant is at least 
       three months old (Reynolds, 1993).
    5. ROUTES OF ENTRY
     5.1 Oral
       Ivermectin is moderately well absorbed following oral 
       administration (Hayes & Laws, 1991).
     5.2 Inhalation
       Not applicable.
     5.3 Dermal
       Animal studies indicate that ivermectin can be absorbed 
       through the skin to a limited extent (MSD, 1988).
     5.4 Eye
       No data available.
     5.5 Parenteral
       Ivermectin is well absorbed from subcutaneous or intramuscular 
       injections (Hayes & Laws, 1991).
     5.6 Other
       No data available.
    6. KINETICS
     6.1 Absorption by route of exposure
       An alcoholic oral solution of ivermectin was reported to have 
       approximately twice the systemic availability of ivermectin 
       capsules or tablets.  In this study, peak serum concentrations 
       of ivermectin were 81, 50 and 46 ng/ml following single 12 mg 
       oral doses of the solution (40% v/v ethanol), capsules (6 mg 

       each) and tablets (6 mg each), respectively, to healthy 
       volunteers. Values of area under the concentration-time curve 
       (AUC) were 1473, 1034, and 885 ng/hr/ml, respectively.  The 
       greater availability of the alcoholic solution suggests that 
       the extent of absorption of ivermectin is limited in part by 
       its solubility (Edwards et al., 1988).
     6.2 Distribution by route of exposure
       The highest tissue concentrations occur in the liver and the 
       fat (Reynolds, 1993).  Extremely low levels of ivermectin are 
       found in the brain,  which probably accounts for the paucity 
       of CNS side effects (Reynolds, 1993).
       
       Radioactive residues and metabolic studies have been conducted 
       in a variety of animal species, including rats, cattle, sheep 
       and swine.  The animals were given radio-labelled ivermectin 
       in single doses of 300 to 400 g/kg bodyweight subcutaneously 
       or orally.  Liver and fat contained the highest residues in 
       all species, with very little residue in the muscle and kidney 
       (MSD, 1988).
     6.3 Biological half-life by route of exposure
       From plasma analyses in humans and in laboratory animals, 
       after oral and/or parenteral administration of ivermectin, the 
       following half-lives have been calculated (MSD, 1988).
       
       SPECIES         ROUTE        T1/2
       
       Human           Oral         10 - 12 hours
       Rat             I.V.         1 day
       Cattle          Oral         2.7 days
                       S.C.         2.9 days
                       Topical      15.9 days
       
     6.4 Metabolism
       Ivermectin undergoes metabolism and is excreted mainly in the 
       faeces.  Ivermectin is little metabolised by mammals; 90% of 
       the administered dose is excreted in the faeces and tissue 
       residues are of the parent compound (Campbell, 1985)
     6.5 Elimination by route of exposure
       Ivermectin is excreted mainly in the faeces (unchanged), less 
       than 1% appearing in the urine and less than 2% in breast milk 
       (Reynolds, 1993).  In animal studies, regardless of whether 
       ivermectin is administered parenterally or orally, only 0.5 to 
       2% of the dose is excreted in urine; the remainder (about 90%) 
       appears in the faeces (Campbell et al., 1983).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Ivermectin acts on insects by potentiation of GABA-ergic 
             neural and neuromuscular transmission but since mammals 
             have only central GABA-ergic synapses which are to a 
             large extent protected by the blood-brain barrier they 
             are relatively resistant to ivermectin.  Some 
             penetration of the blood-brain barrier does occur at 
             relatively high doses, with brain levels peaking between 
             two and five hours after administration.  Symptoms seen 
             in a range of mammalian species are CNS depression, and 

             consequent ataxia, as might be expected from 
             potentiation of inhibitory GABA-ergic synapses (Hayes & 
             Laws, 1991).
       7.1.2 Pharmacodynamics
             Ivermectin inactivates parasitic nematodes, arachnids, 
             and insects.  Its action on the nematodes is by 
             inhibiting signal transmission from the ventral cord 
             interneurons to the inhibitory transmitter GABA from pre-
             synaptic nerve terminals, as well as by potentiating 
             GABA binding to the post-synaptic receptors.  The target 
             species become paralysed and die.
             
             At recommended doses, ivermectin does not readily 
             penetrate the CNS of mammals, where GABA functions as a 
             neurotransmitter.  The principal peripheral 
             neurotransmitter, acetylcholine, is unaffected by 
             ivermectin (MSD, 1988).
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     Amounts approaching the therapeutic doses in 
                     animals (100 to 200 g/kg bodyweight) are not 
                     hazardous to humans.  Ingestions of large 
                     quantities (10 to 100 times the animal 
                     therapeutic dosage) may produce symptoms 
                     resembling those observed in animal toxicology 
                     studies at high toxic levels.
                     
                     An adult female accidentally self-injected a 
                     small quantity (approximately 200 g/kg) 
                     subcutaneously.  Twelve hours later she 
                     experienced colicky pain with nausea but 
                     recovered within 12 hours (MSD, 1988).
                     
                     Clinical studies of oral ivermectin given in 
                     doses from 2 to 200 g/kg (maximum 12 mg) have 
                     shown a pattern of adverse experiences that 
                     included only one serious event (transient 
                     stupor).  The remaining adverse experiences were 
                     considered not serious and were chiefly of the 
                     type expected based on the characteristics of 
                     the underlying disease and the responses seen 
                     after treatment with other microfilaricidal 
                     drugs, except for reports of "depression" (not 
                     psychiatrically tested) in four patients in open 
                     studies (MSD, 1988).
             7.2.1.2 Children
                     A 16-month-old boy weighing 15 kg ingested 
                     approximately 100 to 130 mg of ivermectin (as an 
                     injectable solution).  Ten hours post-ingestion 
                     he had mydriasis in one pupil, with frequent 
                     vomiting, pallor, 35C temperature, tachycardia, 
                     somnolence and variable blood pressure.  He 
                     developed urticaria the following day, and had 
                     recovered after three days (MSD, 1988).
       7.2.2 Relevant animal data

             Acute toxicity studies - LD50 (mg/kg) (MSD, 1988):
             
             Oral
             
             Mouse:  Female  24.6 - 41.6;  Male  11.6
             
             Rat (Infant):  Male & Female  2.3
             
             Rat (Young Adult):  Female  44.3 - 52.8;  Male  42.8 - 
             52.8
             
             Dermal
             
             Rat:  660
             
             At relatively high doses in animal toxicity studies, CNS 
             effects and visual disturbances have been observed.  
             Higher doses cause death due to respiratory depression.
             
             Ivermectin, given to rats IV at a dose of 4 mg/kg, 
             produced moderate incoordination; 6 mg/kg induced a 
             state resembling anaesthesia which began one minute 
             after injection and lasted for four to five hours.  
             Higher doses caused death due to respiratory depression 
             (Hayes & Laws, 1991).
             
             In a 14-week oral toxicity study in dogs, no treatment-
             related effects were observed in animals given 0.5 
             mg/kg/day.  Dogs given 1 and 2 mg/kg/day development 
             mydriasis and lost a small amount of weight.  Four of 
             eight dogs given 2 mg/kg/day developed tremors, ataxia, 
             anorexia and became dehydrated (MSD, 1988).
             
             Dogs given oral doses of ivermectin at 10 mg/kg produced 
             ataxia with tremor; at 40 mg/kg, death occurred due to 
             respiratory depression (Campbell & Benz, 1984).
             
             Collie dogs have been shown to be more sensitive than 
             other dogs to the  toxic effects of ivermectin.  
             Depression, tremors, mydriasis, ataxia, coma and death 
             have been seen in Collie dogs at 100 g/kg orally and 
             greater, but not at the recommended dose of the 
             commercial product (6 g/kg) (Campbell & Benz, 1984).
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       The rates of major congenital malformations are not altered in 
       treated mothers.  In a Liberian community-based ivermectin 
       therapy programme, the incidence of major congenital 
       malformations in children born both to ivermectin-treated and 
       untreated mothers was about 2.5%, a figure comparable with 
       rates previously reported in the population at large in Africa 
       (WHO, 1990b).
       

       No adverse effects were reported when pregnant mares were 
       given six oral doses of ivermectin 0.6 mg/kg paste at two-week 
       intervals during organogenesis and early pregnancy, and six 
       intramuscular injections of ivermectin at 0.6 mg/kg at two-
       month intervals during the last two trimesters.  The foals 
       born were also unaffected (Campbell & Benz, 1984).
       
       Ivermectin is teratogenic in rats, rabbit and mice at or near 
       materno-toxic dose levels.  The abnormalities are limited 
       mainly to cleft palate.  Mice are the most sensitive species 
       to the effect of ivermectin with maternotoxicity at a dose of 
       0.2 mg/kg/day (MSD, 1988).
     7.5 Mutagenicity
       Ivermectin was negative in the AMES Assay, and in a mouse 
       lymphoma mutation assay. In addition, it did not induce 
       unscheduled DNA synthesis in a human fibroblast cell culture, 
       suggesting that it does not damage DNA (MSD,  1988).
     7.6 Interactions
       Preliminary in vivo studies demonstrate that ivermectin can 
       enhance some of the pharmacological actions of diazepam (MSD, 
       1988).
     7.7 Main adverse effects
       Following the therapeutic use of ivermectin for onchocerciasis,
        adverse effects reported include hypersensitivity, transient 
       headache, dizziness, insomnia and elevated body temperature, 
       and occasional joint and muscle pain (Ali & Bashir, 1990).
       
       The clinical picture on onchocerciasis therapy is often 
       complicated by antigens released by micro filariae.  Therefore,
        the types of signs and symptoms encountered worldwide in 
       accidental exposures to ivermectin may differ from the types 
       of adverse exeperiences seen in onchocerciasis patients.
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)

             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Most human clinical effects have been reported following 
             therapeutic clinical trial with ivermectin.  However, 
             the clinical picture in onchocerciasis therapy is often 
             complicated by antigens released by microfilariae.  
             Therefore, the types of signs and symptoms encountered 
             worldwide in accidental exposures to ivermectin may 
             differ from the types of adverse experiences seen in 
             onchocerciasis patients.
             
             Of the various human poisoning exposures reported, only 
             one report mentioned some findings resembling those 
             observed in animal toxicology studies at high toxic 
             levels: vomiting, tachycardia, mydriasis, somnolence and 
             blood pressure fluctuation (see Section 7.2.1.2).
             
             At relatively high doses in animal toxicity studies, CNS 
             effects and mydriasis have been observed.  Higher doses 
             cause death due to respiratory depression.
       9.1.2 Inhalation
             Not applicable.
       9.1.3 Skin exposure
             No data available.  However, dermal absorption is 
             appreciable and systemic effects may occur.
       9.1.4 Eye contact
             Local irritation has been reported following eye contact 
             (MSD, 1988).
       9.1.5 Parenteral exposure
             The effects of small quantities of accidentally injected 
             veterinary formulations appear negligible (see Section 
             7.2.1.1).
       9.1.6 Other

             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Clinical experience of 50,000 patients who received a 
             dose of 150 g/kg in community-based trials undertaken 
             in Africa and Central America demonstrate an incidence 
             of 9% reporting adverse effects.  The large majority of 
             these were of the Mazzotti-type (oedema, pruritis and 
             rash), and dizziness, lymphadenitis, transient 
             hypotension, arthralgia, myalgia, headache, and ocular 
             irritation resulting from the sudden death of massive 
             numbers of microfilariae, but in only 0.25% of patients 
             were these rated as severe (WHO, 1990a).
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       At high doses in humans and animals vomiting, tachycardia, 
       blood pressure fluctuation, CNS effects (somnolence, ataxia) 
       and visual disturbances (mydriasis) have been observed.  
       Higher doses may cause death due to respiratory depression.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Transient ECG changes have been reported in several 
             patients receiving single doses of 150 or 200 g/kg of 
             ivermectin.  These ECG changes were not associated with 
             symptoms or any clinical findings.  Transient changes in 
             supine or standing blood pressure, and tachycardia, have 
             been reported (Awadzi et al., 1985).
             
             Tachycardia and variable blood pressure featured in a 
             case involving a 16-month-old boy ingesting 
             approximately 100 to 130 mg of ivermectin (as an 
             injectable solution) (see Section 7.1.2.2).
       9.4.2 Respiratory
             Coughing has been reported as a side effect of treatment 
             with ivermectin.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Headache, dizziness and insomnia have been 
                     reported in clinical trials.
                     
                     Four of eight dogs given ivermectin 2 mg/kg/day 
                     developed tremors and ataxia, (MSD, 1988).
             9.4.3.2 Peripheral nervous system
                     No data available.
             9.4.3.3 Autonomic nervous system
                     No data available.
             9.4.3.4 Skeletal and smooth muscle

                     Joint pain and muscle aches have been 
                     occasionally reported with ivermectin use 
                     (Diallo, 1987).
       9.4.4 Gastrointestinal
             Nausea and vomiting has been reported (MSD, 1988).
       9.4.5 Hepatic
             In patients receiving single doses of 150 or 200 g/kg 
             of ivermectin, a temporary mild to moderate elevation of 
             alanine amino transferase activity occurred in some 
             patients, but no consistent pattern emerged (Ali & 
             Bashir, 1990).
       9.4.6 Urinary
             9.4.6.1 Renal
                     No data available.
             9.4.6.2 Other
                     No data available.
       9.4.7 Endocrine and reproductive systems
             No effects on the breeding performance of stallions were 
             observed following single intramuscular administration 
             of ivermectin 0.6 mg/kg (MSD, 1988).
       9.4.8 Dermatological
             A Mazzotti-type reaction (oedema, pruritis and rash) can 
             follow administration of ivermectin to treat 
             onchocerciasis (WHO, 1990a) (see Section 9.2.1).
       9.4.9 Eye, ear, nose, throat: local effects
             Mild transient conjunctivitis and blurred vision have 
             been reported with the therapeutic use of ivermectin;  
             symptoms resolved within four days (Coulad et al., 
             1984).
             
             At high doses in humans and animals visual disturbances 
             (mydriasis) have been observed.
       9.4.10 Haematological
              Haematological changes occurred in patients receiving 
              single doses of 150 or 200 g/kg of ivermectin.  There 
              was an increase in total leucocyte count eight days 
              after treatment.  No change in platelet counts or 
              erythrocyte sedimentation rate occurred (Ali & Bashir, 
              1990).
              
              A single oral dose of ivermectin (150 g/kg) in 28 
              patients resulted in haematoma in two patients and 
              prolongation of prothrombin time in all patients.  This 
              was suggested to be due to a possible ivermectin-
              induced deficiency of Vitamin K (Homeida et al., 1988).
       9.4.11 Immunological
              In patients receiving single doses of 150 or 200 g/kg 
              of ivermectin a slight fall in eosinophil counts 
              occurred followed by a steady rise; by day 28 the level 
              was more than twice the initial level.  There was also 
              a slight fall in lymphocyte counts and a rise in 
              neutrophil counts (Ali & Bashir, 1990).
              
              Hypersensitivity reactions have been reported (MSD, 
              1988).
       9.4.12 Metabolic

              9.4.12.1 Acid-base disturbances
                       No data available.
              9.4.12.2 Fluid and electrolyte disturbances
                       Electrolyte and fluid imbalance may occur 
                       following vomiting.
              9.4.12.3 Others
                       Both hyperthermia and hypothermia have been 
                       reported (Awadzi et al., 1985;  MSD, 1988).
       9.4.13 Allergic reactions
              Hypersensitivity reactions have been reported (MSD, 
              1988).
       9.4.14 Other clinical effects
              No data available.
       9.4.15 Special risks
              In 203 children exposed to ivermectin before birth, no 
              significant increase in the incidence of major 
              congenital malformations was observed (see Section 7.4) 
              (WHO, 1990b).
              
              Ivermectin is present in the milk of lactating animals 
              and humans.  A sensitive HPLC assay is available (see 
              Section 8.2).
              
              Preliminary in vivo studies demonstrate that ivermectin 
              can enhance some of the pharmacological actions of 
              diazepam (MSD, 1988).
     9.5 Other
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Treatment is symptomatic and supportive in cases of 
         overdose.  Adverse effects are transient, but analgesics and 
         antihistamines may be required.  Since ivermectin is 
         believed to enhance GABA activity in animals, it is probably 
         wise to avoid drugs that enhance GABA activity 
         (benzodiazepines, barbiturates, valproate, valproic acid) in 
         patients with potentially toxic ivermectin exposure (MSD, 
         1988).
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Not applicable.
         10.2.2 Biomedical analysis
                No specific analyses unless clinically indicated.
         10.2.3 Toxicological analysis
                Although a sensitive assay exists for ivermectin, it 
                is unlikely to be useful in the clinical management 
                of poisoning.
         10.2.4 Other investigations
                Not applicable.
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         Supportive measures are indicated in case of life-
         threatening poisoning (which is rare).  Analgesics and 
         antihistamines are indicated for the treatment of adverse 
         effects.

      10.4 Decontamination
         In case of ingestion of significant amounts of ivermectin, 
         induce emesis using syrup of ipecac.  Gastric lavage may be 
         undertaken.
         
         Eye contact:  Remove any contact lenses then flush the 
         contaminated eyes gently with water for 10 to 15 minutes 
         holding eyelids open.
         
         Skin contact:  Flush the contaminated area gently with water 
         for 10 to 15 minutes.
         
         Parenteral contact:  Although the effects on adults 
         following accidental self-injections of small quantities (< 
         2 ml) appear to be negligible, appropriate measures should 
         be considered in view of the risk of secondary infection 
         from a contaminated syringe.
      10.5 Elimination
         No specific elimination techniques are indicated.
      10.6 Antidote treatment
         10.6.1 Adults
                No specific antidote is available.
         10.6.2 Children
                No specific antidote is available.
      10.7 Management discussion
         As ivermectin has been identified as the possible drug of 
         choice in the treatment of human filariasis its 
         pharmacokinetics and metabolism need to be extensively 
         studied in humans. Currently there are no published reports 
         about these aspects of the drug, although in animals several 
         such studies have been conducted (Ali & Bashir, 1990).
         
         The efficacy of activated charcoal in gut decontamination 
         following ingestion of ivermectin has not been documented 
         and warrants investigation.
         
         A clinical trial of ivermectin as a single oral dose 
         produced haematomata in two patients and prolongation of 
         prothrombin time in all patients (see Section 9.4.10).  It 
         was suggested that this was due to possible ivermectin-
         induced deficiency in Vitamin K, and it would be of interest 
         in future trials to measure the plasma concentration of 
         Vitamin K in ivermectin-treated patients, and/or determine 
         if administration of Vitamin K in these patients would 
         affect the status of Vitamin K and other coagulation factors 
         (Homeida et al., 1988).
         
         Some authors have suggested the use of picrotoxin and 
         physostigmine as antidotal therapies.  However, animal 
         studies with these agents employing these agents as 
         antidotes in ivermectin toxicity have been unsatisfactory 
         and are not recommended (Iliff-Sizemore et al., 1990).
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Case 1 - A 4-year-old child ingested an unknown amount of 
         ivermectin veterinary paste formulation and remained 

         asymptomatic (Hall et al., 1985).
         
         Case 2 - A 16-month-old Brazilian boy weighing about 15 kg 
         accidentally drank an estimated 10 to 13 ml of Ivomec  (1% 
         ivermectin) injectable solution.  Mydriasis was noted in one 
         pupil along with frequent vomiting, pallor, 35C temperature,
          tachycardia, somnolence, and variable blood pressure (40 to 
         100 mm Hg) ten hours later.  The next morning urticaria 
         occurred.  After three days, the boy was normal.  Therapy in 
         hospital included calcium gluconate, caffeine, and an 
         antihistamine.  The clinical indications for the calcium 
         gluconate therapy were unclear (MSD,1988).
         
         Case 3 - An adult was reported to have accidentally self-
         injected a small quantity of Ivomec  (1% ivermectin) 
         (estimated 200 g/kg).  Twelve hours later she experienced 
         colicky pain, with nausea, but recovered within 12 hours 
         (MSD, 1988).
         
         Case 4 - A veterinarian, eight months pregnant, sprayed 
         Eqvalan  (2% ivermectin) into her eye.  The eye was rinsed.  
         Stinging at the contact site was the only adverse effect 
         described (MSD, 1988).
      11.2 Internally extracted data on cases
         Case 1 - An adult accidentally injected an ivermectin animal 
         formulation into the back of his left hand.  The needle 
         stuck the base of his first metacarpal posteriorly, and 
         about 2 ml were administered.  Gross swelling occurred, but 
         no systemic effects were noted.  He was given an 
         antihistamine and recovered uneventfully.
         
         Case 2 - A child was admitted to hospital after ingesting an 
         unknown quantity of Ivomec  Cattle Drench (0.4% ivermectin) 
         and appeared drowsy and hypotonic.  Both pupils were normal. 
          He exhibited tachycardia and vomiting, and his ECG pattern 
         was abnormal.  Treatment was symptomatic and supportive, and 
         he recovered uneventfully.
      11.3 Internal cases
    12. Additional information
      12.1 Availability of antidotes
         No specific antidote is available.
      12.2 Specific preventive measures
         Store in a cool place out of direct sunlight.  Keep out of 
         reach of children.
         
         Ivermectin is contraindicated in patients who have a history 
         of immediate hypersensitivity to the drug.
         
         Rapid in-vivo killing of large numbers of microfilariae may 
         induce a systemic or ocular response.  This reaction may 
         include optic neuritis, choreoretinitis, proteinuria, 
         pruritus, rash and oedema.
         
         Ivermectin should not be administered to pregnant or 
         lactating women, or to young children, unless it is 
         considered that the benefits of therapy outweigh the 

         potential risks from the drug.  At therapeutic doses, 
         clinical evidence to date indicates no increase in 
         congenital abnormalities in humans.  However, in animal 
         studies at high maternotoxic doses foetal abnormalities have 
         occurred.  ivermectin is excreted in breast milk.
         
         Preliminary in vivo studies demonstrate that ivermectin can 
         enhance some of the pharmacological actions of diazepam.
      12.3 Other
    13. REFERENCES
    Ali BH, Bashir AA (1990)  Ivermectin in human filariasis: a mini 
    review.  Vet Hum Toxicol, 32: 110-113.
    
    Awadzi K, Dadzie KY, Shulz-Key H, Haddock DRW, Gilles HM, Aziz MA 
    (1985)  The chemotherapy of onchocerciasis X.  An assessment of 
    four single dose regimes of MK-933 (ivermectin) in human 
    oncorciasis.  Ann Trop Med Parasitol, 79: 63-78.
    
    Campbell WC, Fisher MH, Stapley EO et al. (1983)  Ivermectin: a 
    potent new antiparasitic agent. Science, 221: 823-828.
    
    Campbell WC & Benz GW (1984)  Ivermectin: a review of efficacy 
    and safety.  J Vet Pharmacol Ther, 7: 1-16.
    
    Campbell WC (1985)  Ivermectin: an update.  Parasitol  Today, 1: 
    10-11.
    
    Chiou R, Stubbs RJ & Bayne WF (1987)  Detection of ivermectin in 
    human plasma and milk by high-performance liquid chromatography 
    with fluorescence detection.  J Chromatogr, 416(1): 196-202.
    
    Coulad JP, Laraviere M, Aziz MA, Gervais MC, Gaxotte P, Delud AM, 
    Cenac J (1984)  Ivermectin in onchocerciasis.  Lancet, 2: 526-
    527.
    
    Diallo S, Aziz MA, Nadir O, Badiane S, Bah IB, Gaye O (1987)  
    Dose ranging study of ivermectin in treatment of filariasis due 
    to wuchereria bancrofti (letter)  Lancet,  1: 1030.
    
    Edwards G, Dingsdale A, Helsby N et al. (1988)  The relative 
    stability of ivermectin after administration as capsule, table 
    and oral solution.  Eur J Clin Pharmacol, 35: 681-684.
    
    Hall AH, Spoerke DG, Bronstein AC, Kulig KW, Rumack BH (1985)  
    Human ivermectin exposure. J Emerg Med, 3(3): 217-220.
    
    Hayes WJ & Laws ER (Eds) (1991)  Handbook of pesticide 
    toxicology.  Volume 2.  Classes of pesticides.  Academic Press 
    Inc, San Diego, California, 1576 pp.
    
    Homeida MM, Bagi IS, Ghalib HW, Sheikh H, Ismail A, Yousif MM, 
    Suliman S, Ali HM, Bennet JL, William J (1988)  Prolongation of 
    prothrombin time with ivermectin.  Lancet, 1: 1346-1347.
    
    Iliff-Sizemore SA, Partlow MR, Kelley ST (1990)  Ivermectin 
    toxicology in a Rhesus Macaque.  Vet Hum Toxicol, 23(6): 530-532.

    
    MSD (Merck Sharp & Dohme) (1988)  Poison Control Monograph.  
    ivermectin.  Division of Merck & Co Ltd, West Point, Pennsylvania,
     18 pp.
    
    Reynolds JEF (Ed) (1993)  Martindale.  The extra pharmacopoeia.  
    29th Edition.  Pharmaceutical Press, London.
    
    Reynolds JEF (Ed) (1993)  Martindale.  The extra pharmacopoeia.  
    30th Edition.  Pharmaceutical Press, London.
    
    WHO (World Health Organization) (1990a)  Drug Information, Vol 
    4(2): 48-49.
    
    WHO (World Health Organization) (1990b)  Drug Information, Vol 
    4(49): 162-163.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    Authors: Wayne A. Temple and Nerida A. Smith
             National Toxicology Group
             University of Otago Medical School
             P.O. Box 913
             Dunedin
             New Zealand
    
             Tel:    64-3-4797244
             Fax:    64-3-4770509
    
    Date:    January 1992
    
    Peer review:    Newcastle, United Kingdom, February 1992
                    (Members of the Group: E. Wickstrom, J-C. Berger, 
                    R. Fernando, W. Temple)
    
    Review:  IPCS, May 1994



    See Also:
       Toxicological Abbreviations
       Ivermectin (WHO Food Additives Series 27)
       Ivermectin (WHO Food Additives Series 31)
       IVERMECTIN (JECFA Evaluation)